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{ "abstract": "BACKGROUND\nThe advent of well-tolerated and effective anti-retroviral drugs against human immunodeficiency virus-1 (HIV-1) infection has been a major step forward that has achieved long-term survival in recent years. The number of HIV-1 infected patients who experience difficulty in swallowing tablets is expected to increase as the HIV-infected population advances in age or develops comorbidities or treatment sequelae affecting the central nervous system.\n\n\nMETHODS\nHere, we describe two HIV-1-infected patients who experienced progressive dysphagia leading to inability to swallow the antiretroviral tablets included in the standard regimen. Both patients had a plasma viral load < 40 copies/mL while receiving anti-retroviral therapy with the recommended combination antiretroviral therapy (cART) regimen, but the dysphagia necessitated a switch. By switching to much smaller sized combined regimen of dolutegravir (DTG) plus rilpivirine (RPV) tablets, both of our patients were able to successfully continue treatment and maintain adherence without the need for crushing tablets or preparing an oral suspension. Additionally, switching from the recommended cART regimen to DTG plus RPV successfully maintained viral suppression. At the last available follow-up (12 months after switching to DTG/RPV), HIV-1 viral load remained below the lower limit of quantification.\n\n\nCONCLUSIONS\nAn alternative therapeutic option that takes tablet size into consideration could not only contribute to improved patient adherence, but also a reduced care burden for HIV-infected patients with dysphagia. Thus, switching to the \"small-tablet regimen\" of DTG plus RPV has the potential to improve the survival and well-being of patients with dysphagia.", "affiliations": "Department of Pharmacy, National Defense Medical College Hospital, 3-2, Namiki, Tokorozawa-shi, Saitama, 359-8513 Japan.;Department of Pharmacy, National Defense Medical College Hospital, 3-2, Namiki, Tokorozawa-shi, Saitama, 359-8513 Japan.;Division of Infectious Diseases and Pulmonary Medicine, Department of Internal Medicine, National Defense Medical College, 3-2, Namiki, Tokorozawa-shi, Saitama, 359-8513 Japan.;Division of Infectious Diseases and Pulmonary Medicine, Department of Internal Medicine, National Defense Medical College, 3-2, Namiki, Tokorozawa-shi, Saitama, 359-8513 Japan.;Division of Infectious Diseases and Pulmonary Medicine, Department of Internal Medicine, National Defense Medical College, 3-2, Namiki, Tokorozawa-shi, Saitama, 359-8513 Japan.;Division of Infectious Diseases and Pulmonary Medicine, Department of Internal Medicine, National Defense Medical College, 3-2, Namiki, Tokorozawa-shi, Saitama, 359-8513 Japan.;Division of Infectious Diseases and Pulmonary Medicine, Department of Internal Medicine, National Defense Medical College, 3-2, Namiki, Tokorozawa-shi, Saitama, 359-8513 Japan.;Department of Pharmacy, National Defense Medical College Hospital, 3-2, Namiki, Tokorozawa-shi, Saitama, 359-8513 Japan.;Division of Infectious Diseases and Pulmonary Medicine, Department of Internal Medicine, National Defense Medical College, 3-2, Namiki, Tokorozawa-shi, Saitama, 359-8513 Japan.", "authors": "Suzuki|Takefumi|T|;Hara|Nobuko|N|;Osa|Morichika|M|;Misawa|Kazuhisa|K|;Imai|Kazuo|K|;Fujikura|Yuji|Y|;Maeda|Takuya|T|0000-0003-0912-4643;Sonehara|Wataru|W|;Kawana|Akihiko|A|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1186/s40780-017-0093-8", "fulltext": "\n==== Front\nJ Pharm Health Care SciJ Pharm Health Care SciJournal of Pharmaceutical Health Care and Sciences2055-0294BioMed Central London 9310.1186/s40780-017-0093-8Case ReportEfficacy of switching to dolutegravir plus rilpivirine, the small-tablet regimen, in patients with dysphagia: two case reports Suzuki Takefumi 1Hara Nobuko 1Osa Morichika 2Misawa Kazuhisa 2Imai Kazuo 2Fujikura Yuji 2http://orcid.org/0000-0003-0912-4643Maeda Takuya +81-49-276-1109t_maeda@saitama-med.ac.jp 245Sonehara Wataru 13Kawana Akihiko 21 grid.416620.7Department of Pharmacy, National Defense Medical College Hospital, 3-2, Namiki, Tokorozawa-shi, Saitama, 359-8513 Japan 2 0000 0004 0374 0880grid.416614.0Division of Infectious Diseases and Pulmonary Medicine, Department of Internal Medicine, National Defense Medical College, 3-2, Namiki, Tokorozawa-shi, Saitama, 359-8513 Japan 3 Department of Pharmacy, Mishuku Hospital, 5-33-12, Kamimeguro, Meguro-ku, Tokyo, 153-0051 Japan 4 0000 0001 2216 2631grid.410802.fDepartment of Microbiology, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495 Japan 5 0000 0001 2216 2631grid.410802.fCenter for Clinical Infectious Diseases and Research, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495 Japan 19 9 2017 19 9 2017 2017 3 2331 5 2017 11 9 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nThe advent of well-tolerated and effective anti-retroviral drugs against human immunodeficiency virus-1 (HIV-1) infection has been a major step forward that has achieved long-term survival in recent years. The number of HIV-1 infected patients who experience difficulty in swallowing tablets is expected to increase as the HIV-infected population advances in age or develops comorbidities or treatment sequelae affecting the central nervous system.\n\nCase presentation\nHere, we describe two HIV-1-infected patients who experienced progressive dysphagia leading to inability to swallow the antiretroviral tablets included in the standard regimen. Both patients had a plasma viral load < 40 copies/mL while receiving anti-retroviral therapy with the recommended combination antiretroviral therapy (cART) regimen, but the dysphagia necessitated a switch. By switching to much smaller sized combined regimen of dolutegravir (DTG) plus rilpivirine (RPV) tablets, both of our patients were able to successfully continue treatment and maintain adherence without the need for crushing tablets or preparing an oral suspension. Additionally, switching from the recommended cART regimen to DTG plus RPV successfully maintained viral suppression. At the last available follow-up (12 months after switching to DTG/RPV), HIV-1 viral load remained below the lower limit of quantification.\n\nConclusions\nAn alternative therapeutic option that takes tablet size into consideration could not only contribute to improved patient adherence, but also a reduced care burden for HIV-infected patients with dysphagia. Thus, switching to the “small-tablet regimen” of DTG plus RPV has the potential to improve the survival and well-being of patients with dysphagia.\n\nKeywords\nDolutegravirRilpivirineDysphagiaNRTI-sparingissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nThe advent of well-tolerated and effective anti-retroviral drugs against human immunodeficiency virus-1 (HIV-1) infection has been a major step forward that has achieved long-term survival in recent years [1]. Moreover, the number of HIV-1 infected patients who experience difficulty in swallowing tablets is expected to increase as the HIV-infected population advances in age or develops comorbidities or treatment sequelae affecting the central nervous system [2]. With the long lifespan conferred by combination antiretroviral therapy (cART), the patient population affected by HIV-associated dementia (HAND) or Alzheimer’s disease is also growing. The standard regimens of cART consist of two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) plus a third drug, so it would be beneficial to reduce both the number of drugs and the tablet size for the medication to be easy to take and have good tolerability for all patients over the long term [1, 3].\n\nThe Food and Drug Administration (FDA) has previously suggested that patient adherence to medication regimens can be influenced by the size and shape of a tablet or capsule, and size specifically as the main reason for the difficulty in swallowing [4]. NRTI combination drugs (e.g., tenofovir/emtricitabine; TDF/FTC, abacavir/lamivudine; ABC/3Tc), including all recommended and alternative regimens in 2015, are >17 mm at their largest dimension and, despite being oval-shaped, can be difficult to swallow. Conversely, liquid formulations such as Kaletra® suspension are easier to administer, but caregivers would have the burden of refrigerating and measuring the liquids each day. Furthermore, Kaletra contains a high concentration of alcohol and therefore has the potential to lead to significant alcohol toxicity. Unfortunately, accepted and sufficiently safe liquid formulations are not yet licensed in Japan.\n\nDolutegravir (DTG) is a next-generation anti-retroviral drug, an integrase inhibitor with a long intracellular half-life that allows once daily dosing without the need for any boosting drugs [5, 6]. Its major metabolic pathway involves uridine diphosphate glucuronosyltransferase-1A1 with a minor metabolic component of cytochrome P450 isoforms, and therefore its interactions with co-medications are quite limited [7]. It is also noteworthy that its tablet size (9.1 mm), along with that of rilpivirine (RPV) which is the smallest tablet (6.4 mm) among non-NRTIs, is small enough for most patients to take orally. In recent years, several studies have focused on DTG monotherapy or DTG-based lightened regimens because of its powerful anti-viral effect, ease of medication, and excellent tolerability [8, 9]. Although the clinical effectiveness and safety of the combined regimen with DTG plus RPV is controversial and remains to be established, it has the potential to enable continued successful treatment and maintain adherence without the need for crushing or preparing an oral suspension when administering the drug to older patients or patients with dysphagia.\n\nWe describe here two cases of HIV-1-infected patients whose comorbidities involving the central nervous system (CNS) and/or aging led to difficulty swallowing the anti-retroviral tablets. Switching from the recommended cART regimen to a “small-tablet regimen” of DTG plus RPV, after patients consented to the unestablished regimen with the aim of treating their disease, successfully maintained viral suppression.\n\nCase presentation\nCase 1\nThe patient was a Japanese man with HIV-1 infection who also had multiple system atrophy (MSA), a progressive neurodegenerative disorder characterized by cerebellar ataxia, parkinsonism, and autonomic dysfunction. At age 59 years, he presented with complaints of decreased vision and myodesopsia in both eyes. The uveitis workup revealed positive serology for syphilis and HIV-1 with a CD4 cell count of 354 cells/μL and a HIV-1 viral load of 8.3 × 103 copies/mL. At age 61, he was diagnosed with left pulmonary adenocarcinoma of pathological stage pT3N0M0, pStage IIB and underwent left upper lobectomy and irradiation with 60 Gy (total dose). Prior to this surgery, anti-retroviral therapy was initiated with a cART regimen of raltegravir (RAL) plus TDF/FTC according to the national protocol. Although the HIV-1 viral load became undetectable during the first 12 months of therapy, he was switched to RAL plus ABC/3Tc at age 62 because he subsequently presented with reduced renal function as a side effect of the original therapy. Thereafter, he experienced asymptomatic orthostatic hypotension, slowed movement, progressive gait instability, and severe constipation. All these symptoms and signs persisted without cognitive changes, and co-treatment with levodopa/carbidopa and a dopamine agonist was started. At a medical evaluation at age 65 years in our hospital, brain magnetic resonance imaging (MRI) showed the “hot cross bun” sign in the pons, as well as cerebellar and brainstem atrophy [10]. Finally, MSA was diagnosed and taltirelin hydrate was added to his treatment. However, symptom progression continued, and additional progressive symptoms of dysphagia became apparent; therefore, oral tablets of levodopa/carbidopa, a dopamine agonist, and taltirelin hydrate had to be provided after crushing.\n\nAt age 66, he was switched to DTG/RPV dual therapy because the original anti-retroviral drug tablets were too large for him to take orally. At the last available follow-up (12 months after switching to DTG/RPV), HIV-1 viral load remained below the lower limit of quantification (< 40 copies/mL) and CD4 cell count was maintained at 474 cells/mL (Fig. 1). Although the dysphagia persisted and progressed, this change to a “small-tablet regimen” reduced the burden on his caregivers at home and enabled the patient to take the tablets on his own without needing to crush them for oral suspension.Fig. 1 Plasma viral load and CD4 cell count follow-up from 2008 to 2016 in Case 1. Arrow indicates the time of switching to DTG/RPV dual therapy. X + 0 indicates the time of first administration of anti-retroviral drugs. Abbreviations: TDF/FTC, tenofovir/emtricitabine; ABC/3Tc, abacavir/lamivudine; RPV, rilpivirine; DRV/r, darunavir/ritonavir; MVC, maraviroc; RAL, raltegravir; DTG, dolutegravir\n\n\n\n\nCase 2\nThe patient was a Japanese woman with HIV-1 infection and neurologic sequelae with progressive multifocal leukoencephalopathy (PML) showing fatal subacute demyelinating disease of the brain that occurs in immunosuppressed patients. At age 30 years, she presented to our hospital with complaints of progressive confusion, severe dyspnea, and asthenia. Blood testing showed a positive serology for HIV-1 with a CD4 cell count of 116 cells/μL and a HIV-1 viral load of 7.2 × 103 copies/mL. She underwent an extensive examination and based on clinical and brain MRI findings was finally diagnosed with pneumocystis pneumonia (PCP) complicated with possible PML. Despite attempts to optimize gas exchange and control infection with various antimicrobial agents, she required intubation and mechanical ventilation for a long duration. Anti-retroviral therapy was introduced via the feeding tubes primarily with crushed tablets of lopinavir/ritonavir (LPV/r) plus TDF/FTC. Consequently, HIV-1 viral load decreased and became consistently undetectable. She was also administered enteral nutrition via the same feeding tube. At age 32, she was switched to cART with EFV plus ABC/3Tc because she presented with pathological bone fractures and demineralization. Alongside intensive anti-retroviral treatment, simultaneous dysphagia and respiratory rehabilitation for more than 3 years led to progressive improvement of in her symptoms [11]. At age 36, she was successfully extubated without respiratory distress and was able to resume oral feeding. However, because the original anti-retroviral drug tablets were too large for her to take orally, she was switched to DTG/RPV dual therapy.\n\nAt the last available follow-up (12 months after switching to DTG/RPV), HIV-1 viral load remained below the lower limit of quantification (< 40 copies/mL) and CD4 cell count was maintained at 289 cells/mL (Fig. 2).Fig. 2 Plasma viral load and CD4 cell count follow-up from 2009 to 2016 in Case 2. Arrow indicates the time of switching to DTG/RPV dual therapy. X + 0 indicates the time of first administration of anti-retroviral drugs. Abbreviations: TDF/FTC, tenofovir/emtricitabine; ABC/3Tc, abacavir/lamivudine; RPV, rilpivirine; LPV/r, lopinavir/ritonavir; EFV, efavirenz; DTG, dolutegravir\n\n\n\n\nDiscussion\nThe CNS is a major site of disease in HIV-infected patients because it serves as a reservoir for the virus as well as a site for opportunistic infections [12]. Indeed, just short of 40% of HIV-infected patients will have some neuromuscular manifestations such as dysphagia. Moreover, due to the significantly reduced mortality of these patients, the impact of the aging combined with their neuromuscular issues accelerate their need for care [13]. Previously, anti-retroviral treatment itself led to side effects such as dysphagia and various gastric symptoms including nausea, vomiting, gastroesophageal reflux, and taste aversions. However, with drastic advances in cART, recent treatment strategies have led to fewer side effects, increased efficacy, and higher virologic response in clinical practice. Therefore, adherence to cART has become one of the major independent predictors of long-term treatment success in HIV patients.\n\nIn past studies, if the diameter of the tablet exceeded 8 mm, there was a high possibility that oral administration could become difficulty for adult patients. In addition, increasing tablet or capsule size is also believed to correlate with increasing difficulty with oropharyngeal transfer [14, 15]. Therefore, treatment constituting a combination of tablets, is suitable and therefore can be reasonably defined as a “small-tablet-regimen”. By switching to the much smaller tablets of the combined regimen of DTG (9.1 mm) plus RPV (6.4 mm) tablets once a day at home, both of our patients were able to continue successful treatment and maintain adherence without the need for crushing or preparing an oral suspension. Additionally, the burden on caregivers of maintaining the oral administration of the drugs was reduced compared with administering the medications via feeding tubes, and the efficacy of the drug and the stability of the preparation were also ensured [16]. Thus, switching to the “small-tablet regimen” of DTG plus RPV has the potential to improve the survival and well-being of patients with dysphagia.\n\nThe NRTI class (e.g., ABC, TDF) remains a key component of most antiretroviral regimens used in current HIV clinical practice. However, there are clinical situations in which eliminating NRTI exposure is desirable (e.g., in patients with a high risk of cardiovascular disease [17], positive HLA-B*5701 [18, 19], chronic kidney disease [20–22], or osteoporosis [23]). As noted in the 2016 guidelines from the US Department of Health and Human Services, two NRTI-sparing regimens—darunavir (DRV)/r plus RAL and LPV/r plus 3Tc—should be considered as alternative regimens when ABC or TDF cannot be used [3].\n\nNEAT001/ANRS143, a fully powered trial, demonstrated that DRV/r plus RAL as first-line anti-retroviral therapy was non-inferior to the standard treatment and thus presented a therapeutic option for patients with baseline CD4 cell counts > 200/μL [24]. A small single-arm study of DRV/r plus RAL, however, showed high rates of virologic failure in patients with baseline viral load > 100,000 copies/mL [25]. In the GARDEL study, the LPV/r plus 3Tc regimen was better tolerated than the LPV/r plus 2-NRTI regimen, although LPV/r is not considered a viable alternative because of its metabolic complications and pill burden [26]. Together, these data suggest that NRTI-sparing regimens have weaker efficacy than the recommended regimens. On the other hand, it has been reported that the NRTI-sparing regimen was efficacious and safe as a replacement regimen especially in patients showing long-lasting virologic suppression. A particularly attractive option currently under study is the long-acting combination of an integrase inhibitor plus a non-NRTI, the most metabolism-friendly antiretroviral drug class, for the maintenance of viral suppression [27]. The SWORD-1 and SWORD-2 sponsor-initiative clinical trials are currently ongoing to assess the antiviral activity and safety of DTG plus RPV and a current antiretroviral therapy for 48 weeks in patients with suppressed viral load [28].\n\nWith the rapid increase in the number of elderly HIV-infected patients worldwide, comorbidities associated with aging, such as dysphagia, are expected to become significant factors affecting treatment outcomes and patient quality of life. An alternative therapeutic option that takes tablet size into consideration could not only contribute to improved patient adherence, but also a reduced care burden for HIV-infected patients with dysphagia. Further studies are needed to confirm the long-term efficacy and safety of the DTG plus RPV regimen in HIV-infected patients with suppressed viral load.\n\nConclusions\nDTG + RPV dual therapy is effective in patients with difficulty swallowing, can be considered as alternative regimens for the maintenance of viral suppression.\n\nAbbreviations\ncARTCombination antiretroviral therapy\n\nDTGDolutegravir\n\nNRTINucleoside reverse transcriptase inhibitors\n\nPIProtease inhibitors\n\nRPVRilpivirine\n\nAcknowledgements\nNot applicable.\n\nFunding\nThe authors received no financial support for the research, authorship, and/or publication of this article.\n\nAvailability of data and materials\nData used in this case report will not be shared due to the risk of identifying an individual, although most patient’s data are presented in the main paper.\n\nAuthors’ contributions\nTS and TM wrote the manuscript. NH, MO, KM, KI, YF, WS, and AK helped to draft the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThis study was approved by the National Defense Medical College Research Ethics Committee (reference 2270). Written informed consent was obtained from the patients for this case report.\n\nConsent for publication\nA copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interest.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Günthard HF Aberg JA Eron JJ Hoy JF Telenti A Benson CA Antiretroviral treatment of adult HIV infection: 2014 recommendations of the international antiviral society-USA panel JAMA 2014 312 410 415 10.1001/jama.2014.8722 25038359 \n2. 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ClinicalTrials.gov, Regimen Switch to Dolutegravir + Rilpivirine From Current Antiretroviral Regimen in Human Immunodeficiency Virus Type 1 Infected and Virologically Suppressed Adults. Identifier: NCT02429791/NCT02422797 (accessed 21 Apr 2016).\n\n", "fulltext_license": "CC BY", "issn_linking": "2055-0294", "issue": "3()", "journal": "Journal of pharmaceutical health care and sciences", "keywords": "Dolutegravir; Dysphagia; NRTI-sparing; Rilpivirine", "medline_ta": "J Pharm Health Care Sci", "mesh_terms": null, "nlm_unique_id": "101672177", "other_id": null, "pages": "23", "pmc": null, "pmid": "28944075", "pubdate": "2017", "publication_types": "D002363:Case Reports", "references": "25698454;26712907;18444831;18171292;22568508;26201299;25259702;21857490;21716073;18808976;23824675;25845765;27021341;18382171;22730929;21716077;18256392;6816343;25440019;25038359;12511743;19696652;3950057;25103176;24783988", "title": "Efficacy of switching to dolutegravir plus rilpivirine, the small-tablet regimen, in patients with dysphagia: two case reports.", "title_normalized": "efficacy of switching to dolutegravir plus rilpivirine the small tablet regimen in patients with dysphagia two case reports" }

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Efficacy of switching to dolutegravir plus rilpivirine, the small-tablet regimen, in patients with dysphagia: Two case reports. 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EFFICACY OF SWITCHING TO DOLUTEGRAVIR PLUS RILPIVIRINE, THE SMALL-TABLET REGIMEN, IN PATIENTS WITH DYSPHAGIA: TWO CASE REPORTS.. 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{ "abstract": "More active high-dose chemotherapy (HDC) regimens are needed for refractory lymphomas. The authors previously combined infusional gemcitabine with busulfan and melphalan (Gem/Bu/Mel) pursuing DNA damage repair inhibition. Subsequently, they combined Gem/Bu/Mel with vorinostat, which facilitates chemotherapy access to DNA. The resulting regimen was safe and synergistic. However, vorinostat induced DNA methyltransferase up-regulation, which could be preclinically abrogated by azacitidine, increasing tumor-cell kill. Those observations led to a clinical combination of azacitidine with vorinostat/Gem/Bu/Mel.\n\n\n\nPatients ages 12 to 65 years with refractory or poor-risk relapsed lymphomas were eligible. They received intravenous azacitidine on days -11 through -3 at doses from 15 to 35 mg/m(2) daily (dose levels 1-3), followed by oral vorinostat (1000 mg once daily on days -11 through -3), gemcitabine (2775 mg/m(2) over 4.5 × 2), busulfan (at an area under the receiver operating characteristic curve of 4000 daily × 4), and melphalan (60 mg/m(2) × 2). Patients who had tumors that were positive for CD20 (cluster of differentiation 20; B-lymphocyte antigen) received rituximab on day -9.\n\n\n\nIn total, 60 patients were enrolled, including 26 with diffuse large B-cell lymphoma (DLBCL) (10 double hit/double expressors), 21 with Hodgkin lymphoma, 8 with T-cell lymphoma, and 5 with other B-cell lymphomas. The median patient age was 41 years (range, 16-65 years), patients had received a median of 3 prior lines of chemotherapy (range, 2-7 lines of chemotherapy); and 32% of tumors were positive on positron emission tomography studies at the time of HDC. Two patients died from treatment complications (respiratory syncytial virus pneumonia and sepsis, respectively). The maximum tolerated dose of azacitidine was encountered at dose level 1 (15 mg/m(2) daily). The toxicity profile (mainly mucositis and dermatitis) was manageable and was identical to that of vorinostat/Gem/Bu/Mel. Neutrophils and platelets engrafted promptly. At a median follow-up of 15 months (range, 8-27 months), the event-free and overall survival rates were 65% and 77%, respectively, among patients with DLBCL; 76% and 95%, respectively, among patients with Hodgkin lymphoma; and 88% for both among patients with T-cell lymphoma.\n\n\n\nDouble epigenetic modulation of Gem/Bu/Mel with azacitidine/vorinostat is feasible and highly active in patients with refractory/poor-risk relapsed lymphomas, warranting further evaluation. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2680-2688. © 2016 American Cancer Society.", "affiliations": "Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.", "authors": "Nieto|Yago|Y|;Valdez|Benigno C|BC|;Thall|Peter F|PF|;Jones|Roy B|RB|;Wei|Wei|W|;Myers|Alan|A|;Hosing|Chitra|C|;Ahmed|Sairah|S|;Popat|Uday|U|;Shpall|Elizabeth J|EJ|;Qazilbash|Muzaffar|M|;Gulbis|Alison|A|;Anderlini|Paolo|P|;Shah|Nina|N|;Bashir|Qaiser|Q|;Alousi|Amin|A|;Oki|Yasuhiro|Y|;Fanale|Michelle|M|;Dabaja|Bouthaina|B|;Pinnix|Chelsea|C|;Champlin|Richard|R|;Andersson|Borje S|BS|", "chemical_list": "D006877:Hydroxamic Acids; D003841:Deoxycytidine; D000077337:Vorinostat; C056507:gemcitabine; D002066:Busulfan; D001374:Azacitidine; D008558:Melphalan", "country": "United States", "delete": false, "doi": "10.1002/cncr.30100", "fulltext": null, "fulltext_license": null, "issn_linking": "0008-543X", "issue": "122(17)", "journal": "Cancer", "keywords": "autologous stem-cell transplantation; azacitidine; high-dose chemotherapy; lymphoma; phase 1 trial; vorinostat", "medline_ta": "Cancer", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001374:Azacitidine; D002066:Busulfan; D002648:Child; D003841:Deoxycytidine; D019008:Drug Resistance, Neoplasm; D044127:Epigenesis, Genetic; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006877:Hydroxamic Acids; D008223:Lymphoma; D008297:Male; D008558:Melphalan; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D011379:Prognosis; D015996:Survival Rate; D000077337:Vorinostat; D055815:Young Adult", "nlm_unique_id": "0374236", "other_id": null, "pages": "2680-8", "pmc": null, "pmid": "27203405", "pubdate": "2016-09-01", "publication_types": "D016428:Journal Article", "references": "14504078;20660832;9808548;19289617;17242396;25113753;8096958;22432519;7477169;22643322;20173786;20674757;9779700;19230772;18940674;22687754;26071868;19944463;23128322;11821446;1740680;12086759;16955068;23300745;21772049;11208832;12488306;5910392;26743341;2350571;20551943;11313668;15073038;15737986", "title": "Double epigenetic modulation of high-dose chemotherapy with azacitidine and vorinostat for patients with refractory or poor-risk relapsed lymphoma.", "title_normalized": "double epigenetic modulation of high dose chemotherapy with azacitidine and vorinostat for patients with refractory or poor risk relapsed lymphoma" }

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DOUBLE EPIGENETIC MODULATION OF HIGH-DOSE CHEMOTHERAPY WITH AZACITIDINE AND VORINOSTAT FOR PATIENTS WITH REFRACTORY OR POOR-RISK RELAPSED LYMPHOMA. 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"reaction": [ { "reactionmeddrapt": "Transaminases increased", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash erythematous", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood bilirubin increased", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Clostridium difficile colitis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dermatitis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nephropathy toxic", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Febrile neutropenia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mucosal inflammation", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonitis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia cytomegaloviral", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Escherichia bacteraemia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "YAGO N. DOUBLE EPIGENETIC MODULATION OF HIGH-DOSE CHEMOTHERAPY WITH AZACITIDINE AND VORINOSTAT FOR PATIENTS WITH REFRACTORY OR POOR-RISK RELAPSED LYMPHOMA.. 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null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GLUTAMINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pneumonia respiratory syncytial viral", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "NIETO Y, VALDEZ BC, THALL PF, JONES RB, WEI W, MYERS A ET AL. DOUBLE EPIGENETIC MODULATION OF HIGH?DOSE CHEMOTHERAPY WITH AZACITIDINE AND VORINOSTAT FOR PATIENTS WITH REFRACTORY OR POOR?RISK RELAPSED LYMPHOMA. CANCER. 2016;122(17):2680-8", "literaturereference_normalized": "double epigenetic modulation of high dose chemotherapy with azacitidine and vorinostat for patients with refractory or poor risk relapsed lymphoma", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170217", "receivedate": "20170217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13246703, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170428" } ]

{ "abstract": "BACKGROUND\nThe occurrence of chemotherapy-related adverse cutaneous reactions in the setting of capillary leak syndrome (CLS) is quite rare. Our objective was to identify the type of skin reactions associated with CLS.\n\n\nMETHODS\nLeukemia or hematopoietic stem cell transplant patients between January 2010 and December 2017 were identified, and medical records were reviewed for a dermatology consultation occurring concomitantly with CLS.\n\n\nRESULTS\nFive patients were identified, two with a diagnosis of toxic erythema of chemotherapy (TEC) and three others with a skin diagnosis of toxic epidermal necrolysis (TEN). Pathology of all patients was available for clinical-pathologic confirmation.\n\n\nCONCLUSIONS\nAlthough TEC is generally self-limited, both TEC and TEN can present with severe adverse skin manifestations during CLS secondary to toxicity from chemotherapy.", "affiliations": "Sandwell and West Birmingham Hospital Trusts, Birmingham, UK.;Mayo Clinic Medical Scientist Training Program, Mayo Clinic Alix School of Medicine and Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN, USA.;Icahn School of Medicine at Mount Sinai West, New York, NY, USA.;Department of Dermatology, Mayo Clinic, Rochester, MN, USA.;Department of Dermatology, Mayo Clinic, Rochester, MN, USA.;Department of Hematology and Oncology, Mayo Clinic, Rochester, MN, USA.;Department of Dermatology, Mayo Clinic, Rochester, MN, USA.", "authors": "Hunjan|Manrup K|MK|;Nowsheen|Somaira|S|;Ramos-Rodriguez|Alvaro J|AJ|;Bridges|Alina G|AG|;Lehman|Julia S|JS|;Hashmi|Shahrukh K|SK|;El-Azhary|Rokea A|RA|", "chemical_list": "D003561:Cytarabine; D000077866:Clofarabine", "country": "England", "delete": false, "doi": "10.1111/ijd.14392", "fulltext": null, "fulltext_license": null, "issn_linking": "0011-9059", "issue": "58(7)", "journal": "International journal of dermatology", "keywords": null, "medline_ta": "Int J Dermatol", "mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D019559:Capillary Leak Syndrome; D000077866:Clofarabine; D003561:Cytarabine; D004890:Erythema; D005260:Female; D006801:Humans; D007938:Leukemia; D008297:Male; D008875:Middle Aged; D012867:Skin; D013262:Stevens-Johnson Syndrome", "nlm_unique_id": "0243704", "other_id": null, "pages": "856-860", "pmc": null, "pmid": "30847892", "pubdate": "2019-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Chemotherapy-induced skin toxicity and capillary leak syndrome.", "title_normalized": "chemotherapy induced skin toxicity and capillary leak syndrome" }

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CHEMOTHERAPY-INDUCED SKIN TOXICITY AND CAPILLARY LEAK SYNDROME. INT-J-DERMATOL 2019?58(7):856-860.", "literaturereference_normalized": "chemotherapy induced skin toxicity and capillary leak syndrome", "qualification": "1", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190711", "receivedate": "20190711", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16560097, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20191004" }, { "companynumb": "US-TEVA-2019-US-1073599", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "078610", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MELPHALAN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "206018", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "70", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "69", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxic erythema of chemotherapy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Circulatory collapse", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Capillary leak syndrome", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HUNJAN MK, NOWSHEEN S, RAMOS-RODRIGUEZ AJ, BRIDGES AG, LEHMAN JS, HASHMI SK, ET AL. CHEMOTHERAPY-INDUCED SKIN TOXICITY AND CAPILLARY LEAK SYNDROME. INT-J-DERMATOL 2019?58(7):856-860.", "literaturereference_normalized": "chemotherapy induced skin toxicity and capillary leak syndrome", "qualification": "1", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190711", "receivedate": "20190711", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16560442, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20191004" }, { "companynumb": "US-TEVA-2019-US-1073595", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "016793", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3000 MG/M2 DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3000", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "81099", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSE: 3.5 G/M 2/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": "29", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Fungaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Toxic epidermal necrolysis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Circulatory collapse", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Capillary leak syndrome", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "HUNJAN MK, NOWSHEEN S, RAMOS-RODRIGUEZ AJ, BRIDGES AG, LEHMAN JS, HASHMI SK, ET AL. CHEMOTHERAPY-INDUCED SKIN TOXICITY AND CAPILLARY LEAK SYNDROME. INT-J-DERMATOL 2019?58(7):856-860.", "literaturereference_normalized": "chemotherapy induced skin toxicity and capillary leak syndrome", "qualification": "1", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190711", "receivedate": "20190711", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16560402, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20191004" }, { "companynumb": "US-TEVA-2019-US-1073597", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOFARABINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG/M2 DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOFARABINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "016793", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MG/M2 DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxic erythema of chemotherapy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Capillary leak syndrome", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Circulatory collapse", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Cardio-respiratory arrest", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "HUNJAN MK, NOWSHEEN S, RAMOS-RODRIGUEZ AJ, BRIDGES AG, LEHMAN JS, HASHMI SK, ET AL. CHEMOTHERAPY-INDUCED SKIN TOXICITY AND CAPILLARY LEAK SYNDROME. INT-J-DERMATOL 2019?58(7):856-860.", "literaturereference_normalized": "chemotherapy induced skin toxicity and capillary leak syndrome", "qualification": "1", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190711", "receivedate": "20190711", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16560105, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20191004" } ]

{ "abstract": "BACKGROUND\nNon-tuberculous mycobacteria (NTM) are ubiquitous, being found in water, soil, and animals. Al-though more than 170 species have been identified, the majority of human NTM diseases are caused by fewer than 20 species. Reported mycobacteria osteomyelitis cases are fewer than 200 worldwide, with patient age ranging from 6 - 88 years. Many underlying conditions, including immunocompromised patients, wounds, and physical exercise, are associated with the disease. When treating this infection, the first step to consider is an early diagnosis in the course of illness to prevent significant bone destruction and loss of function. To treat mycobacteria osteomyelitis, prolonged antibiotic administration, often in conjunction with surgical intervention, is typically required.\n\n\nRESULTS\nA case of non-tuberculous mycobacteria infection leading to calcaneal osteomyelitis after ankle local injection therapy is diagnosed with magnetic resonance imaging (MRI), bacteria culture, and is further confirmed by the Next Generation Sequencing of the nucleotides. The patient recovered gradually after more than 8 months of treatment.\n\n\nCONCLUSIONS\nDiagnosis of non-tuberculous mycobacteria infection could be challenging especially with osteomyelitis. Early diagnosis is critical to prevent prolonged treatment and adverse effects, as well as destruction of the bone and resulting dysfunction.", "affiliations": null, "authors": "Liang|Xiaoying|X|;Nong|Shaoyun|S|;Zhou|Lixin|L|;Hochwald|Steven|S|;Huang|Huayi|H|", "chemical_list": "D000900:Anti-Bacterial Agents", "country": "Germany", "delete": false, "doi": "10.7754/Clin.Lab.2020.201143", "fulltext": null, "fulltext_license": null, "issn_linking": "1433-6510", "issue": "67(7)", "journal": "Clinical laboratory", "keywords": null, "medline_ta": "Clin Lab", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000842:Ankle; D000900:Anti-Bacterial Agents; D002648:Child; D003955:Diagnostic Tests, Routine; D006801:Humans; D008875:Middle Aged; D009170:Nontuberculous Mycobacteria; D010019:Osteomyelitis; D055815:Young Adult", "nlm_unique_id": "9705611", "other_id": null, "pages": null, "pmc": null, "pmid": "34258968", "pubdate": "2021-07-01", "publication_types": "D002363:Case Reports", "references": null, "title": "Non-Tuberculous Mycobacteria Caused Calcaneal Osteomyelitis after Ankle Local Injection Therapy.", "title_normalized": "non tuberculous mycobacteria caused calcaneal osteomyelitis after ankle local injection therapy" }

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"Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Mycobacterial infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETHAMBUTOL HYDROCHLORIDE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "078939", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", 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"Drug ineffective for unapproved indication", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Liang X, Nong S, Zhou L, Hochwald S, Huang H. Non-tuberculous mycobacteria caused calcaneal osteomyelitis after ankle local injection therapy. Clinical Laboratory. 2021;67(7):1737-1740", "literaturereference_normalized": "non tuberculous mycobacteria caused calcaneal osteomyelitis after ankle local injection therapy", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20211228", "receivedate": "20211228", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20235404, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220303" } ]

{ "abstract": "Venous thromboembolism following elective knee arthroscopy remains relatively rare. NuvaRing (Merck & Co), an intravaginal contraceptive device, has received attention recently due to reports detailing unexpected catastrophic pulmonary embolism and further suggesting an increased risk of venous and arterial thrombotic events in women who use it. A healthy, 30-year-old woman with a NuvaRing contraceptive device presented to the sports medicine clinic with knee pain, swelling, and mechanical symptoms. She was diagnosed with a lateral meniscus tear via magnetic resonance imaging and subsequently underwent a routine partial lateral meniscectomy. Her postoperative course was complicated by a rare deep venous thrombosis requiring anticoagulation therapy. This case highlights the risk of NuvaRing contraception and raises awareness within the orthopedic community regarding its use among patients undergoing arthroscopic outpatient surgery. [Orthopedics. 2021;44(5):e687-e690.].", "affiliations": null, "authors": "Parisien|Robert L|RL|;Henkelman|Erik S|ES|;McCartney|Ronald E|RE|;Nicoletta|Robert|R|", "chemical_list": "D000925:Anticoagulants", "country": "United States", "delete": false, "doi": "10.3928/01477447-20210818-02", "fulltext": null, "fulltext_license": null, "issn_linking": "0147-7447", "issue": "44(5)", "journal": "Orthopedics", "keywords": null, "medline_ta": "Orthopedics", "mesh_terms": "D000328:Adult; D000925:Anticoagulants; D001182:Arthroscopy; D003273:Contraceptive Devices; D005260:Female; D006801:Humans; D007719:Knee Joint; D054556:Venous Thromboembolism", "nlm_unique_id": "7806107", "other_id": null, "pages": "e687-e690", "pmc": null, "pmid": "34590952", "pubdate": "2021", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Venous Thromboembolism Requiring Anticoagulation Following Knee Arthroscopy in a Young Woman With an Intravaginal Contraceptive Device.", "title_normalized": "venous thromboembolism requiring anticoagulation following knee arthroscopy in a young woman with an intravaginal contraceptive device" }

[ { "companynumb": "US-ORGANON-O2110USA002235", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ETHINYL ESTRADIOL\\ETONOGESTREL" }, "drugadditional": "1", "drugadministrationroute": "067", "drugauthorizationnumb": "21187", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "VAGINAL RING", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Contraception", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NUVARING" } ], "patientagegroup": null, "patientonsetage": "30", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Deep vein thrombosis postoperative", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Parisien RL, Henkelman ES, Mccartney RE, Nicoletta R.. Venous Thromboembolism Requiring Anticoagulation Following Knee Arthroscopy in a Young Woman With an Intravaginal Contraceptive Device. Orthopedics. 2021;44(5):687-90", "literaturereference_normalized": "venous thromboembolism requiring anticoagulation following knee arthroscopy in a young woman with an intravaginal contraceptive device", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211027", "receivedate": "20211027", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20004543, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" } ]

{ "abstract": "It is widely recognized that the risk of secondary neoplasms increases as childhood cancer survivors progress through adulthood. These are mainly hematological malignancies, and recurrent chromosome translocations are commonly detected in such cases. On the other hand, while secondary epithelial malignancies have sometimes been reported, chromosome translocations in these epithelial malignancies have not. A 33-year-old man who had been diagnosed with acute lymphoblastic leukemia and treated with chemotherapy almost 20 years earlier was diagnosed with lung adenocarcinoma. After chromosomal rearrangement of echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene was detected in this adenocarcinoma, he responded to treatment with crizotinib. It was therefore concluded that this echinoderm microtubule-associated protein-like 4 gene-anaplastic lymphoma kinase gene-positive lung adenocarcinoma was a secondary epithelial malignancy.", "affiliations": "Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki yi-nakamu@umin.ac.jp.;Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki.;Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki.;Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki.;Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki.;Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki.;Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki.;Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki.;Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.;Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki.", "authors": "Nakamura|Yoichi|Y|;Taniguchi|Hirokazu|H|;Mizoguchi|Kosuke|K|;Ikeda|Takaya|T|;Motoshima|Kohei|K|;Yamaguchi|Hiroyuki|H|;Nagashima|Seiji|S|;Nakatomi|Katsumi|K|;Soda|Manabu|M|;Mano|Hiroyuki|H|;Kohno|Shigeru|S|", "chemical_list": "D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C522504:EML4-ALK fusion protein, human; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib", "country": "England", "delete": false, "doi": "10.1093/jjco/hyu028", "fulltext": null, "fulltext_license": null, "issn_linking": "0368-2811", "issue": "44(6)", "journal": "Japanese journal of clinical oncology", "keywords": "EML4–ALK; cancer survivor; secondary lung adenocarcinoma", "medline_ta": "Jpn J Clin Oncol", "mesh_terms": "D000230:Adenocarcinoma; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000077547:Crizotinib; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D058990:Molecular Targeted Therapy; D016609:Neoplasms, Second Primary; D015514:Oncogene Proteins, Fusion; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D017741:Survivors; D016896:Treatment Outcome", "nlm_unique_id": "0313225", "other_id": null, "pages": "593-6", "pmc": null, "pmid": "24688086", "pubdate": "2014-06", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Secondary EML4-ALK-positive lung adenocarcinoma in a patient previously treated for acute lymphoblastic leukemia in childhood: a case report.", "title_normalized": "secondary eml4 alk positive lung adenocarcinoma in a patient previously treated for acute lymphoblastic leukemia in childhood a case report" }

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null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUNASE" } ], "patientagegroup": null, "patientonsetage": "33", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "17.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Lung adenocarcinoma", "reactionmeddraversionpt": "17.1", "reactionoutcome": "5" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201001" } }, "primarysource": { "literaturereference": "YOICHI NAKAMURA ET AL.. SECONDARY EML4-ALK-POSITIVE LUNG ADENOCARCINOMA IN A PATIENT PREVIOUSLY TREATED FOR ACUTE LYMPHOBLASTIC LEUKEMIA IN CHILDHOOD: A CASE REPORT. 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CYCLES WITH CARBOPLATIN AND PACLITAXEL", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG NEOPLASM MALIGNANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BEVACIZUMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GIMERACIL\\OTERACIL\\TEGAFUR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG NEOPLASM MALIGNANT", "drugintervaldosagedefinition": 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"drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CRIZOTINIB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "YOICHI NAKAMURA, HIROKAZU TANIGUCHI, KOSUKE MIZOGUCHI, TAKAYA IKEDA, KOHEI MOTOSHIMA.. SECONDARY EML4-ALK-POSITIVE LUNG ADENOCARCINOMA IN A PATIENT PREVIOUSLY TREATED FOR ACUTE LYMPHOBLASTIC LEUKEMIA IN CHILDHOOD:A CASE REPORT. JAPANESE JOURNAL OF CLINICAL ONCOLOGY. 2014;44:593-596", "literaturereference_normalized": "secondary eml4 alk positive lung adenocarcinoma in a patient previously treated for acute lymphoblastic leukemia in childhood a case report", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20150302", "receivedate": "20150302", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10877486, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" }, { "companynumb": "JP-BAXTER-2014BAX039897", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MERCAPTOPURINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, 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"drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "L-ASPARAGINASE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" } ], "patientagegroup": null, "patientonsetage": "33", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "17.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Lung adenocarcinoma", "reactionmeddraversionpt": "17.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "NAKAMURA Y, TANIGUCHI H, MIZOGUCHI K, IKEDA T, MOTOSHIMA K, YAMAGUCHI H, NAGASHIMA S, NAKATOMI K, SODA M, MANO H, KOHNO S. SECONDARY EML4-ALK-POSITIVE LUNG ADENOCARCINOMA IN A PATIENT PREVIOUSLY TREATED FOR ACUTE LYMPHOBLASTIC LEUKEMIA IN CHILDHOOD: A CASE REPORT. JAPANESE JOURNAL OF CLINICAL ONCOLOGY. 2014 JAN 01;44(6):593-596.", "literaturereference_normalized": "secondary eml4 alk positive lung adenocarcinoma in a patient previously treated for acute lymphoblastic leukemia in childhood a case report", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20140731", "receivedate": "20140717", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10311955, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150326" } ]

{ "abstract": "Even in 2021, coronavirus disease 2019 (COVID-19) remains a major global health concern, especially in developing countries. The burden of this disease, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which affects not only primary respiratory but also other organ systems, keeps rising as the pandemic continues. Primary health care centers are the first line where COVID-19 patients are managed and should be able to manage the vast majority of them successfully. In this paper, we present a case series and concept of beneficial management of even deteriorating and severe patients treated entirely in our primary health center. The management is based on well-timed and rational dexamethasone use, as well as on various other pharmacological and nonpharmacological treatments and interventions, and is supported by provided statistical data. According to the presented experience and positive outcomes achieved, it seems that even deteriorating and severe COVID-19 patients can be treated successfully to some extent or even completely in primary care settings. This kind of approach could be particularly beneficial in conditions of overload of higher-level health care institutions.", "affiliations": "Grude Health Center, Grude, Bosnia and Herzegovina.;Institute for Public Health of West Herzegovina County, Grude, Bosnia and Herzegovina.;Grude Health Center, Grude, Bosnia and Herzegovina.;Grude Health Center, Grude, Bosnia and Herzegovina.;Grude Health Center, Grude, Bosnia and Herzegovina.;Grude Health Center, Grude, Bosnia and Herzegovina.;Department of Dermatology and Venerology, University Clinical Hospital Mostar, Mostar, Bosnia and Herzegovina.;Department of Dermatology and Venerology, University Clinical Hospital Mostar, Mostar, Bosnia and Herzegovina.", "authors": "Vukoja|Damir|D|;Jurić|Andrea|A|;Erkapić|Zdravka|Z|;Pejić|Tomislav|T|;Zovko|Željko|Ž|;Juričić|Josipa|J|;Pejić|Jelena|J|;Ćorluka|Matea|M|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.3389/fphar.2021.684537", "fulltext": "\n==== Front\nFront Pharmacol\nFront Pharmacol\nFront. Pharmacol.\nFrontiers in Pharmacology\n1663-9812\nFrontiers Media S.A.\n\n684537\n10.3389/fphar.2021.684537\nPharmacology\nCase Report\nBeneficial Treatment Outcomes of Severe COVID-19 Patients Treated Entirely in Primary Care Settings With Dexamethasone Including Regimen—Case Series Report\nVukoja et al.\nCOVID-19 Beneficial Treatment Outcomes\nVukoja Damir 1 *\n\nJurić Andrea 2\nErkapić Zdravka 1\nPejić Tomislav 1 3\nZovko Željko 1 4\n\nJuričić Josipa 1\nPejić Jelena 5\nĆorluka Matea 5\n1 Grude Health Center, Grude, Bosnia and Herzegovina\n2 Institute for Public Health of West Herzegovina County, Grude, Bosnia and Herzegovina\n3 Ministry of Health, Labor and Social Welfare of West Herzegovina County, Grude, Bosnia and Herzegovina\n4 Department of Emergency Medicine, University Clinical Hospital Mostar, Mostar, Bosnia and Herzegovina\n5 Department of Dermatology and Venerology, University Clinical Hospital Mostar, Mostar, Bosnia and Herzegovina\nEdited by:Pei-Hui Wang, Shandong University, China\n\nReviewed by:Ravi Misra, University of Rochester, United States\n\nAntonio Molino, University of Naples Federico II, Italy\n\nXiaofeng Huang, Cornell University, United States\n\nXiaohua Duan, Cornell University, United States\n\nXuming Tang, Cornell University, United States\n\nJing Chen, The University of Hong Kong, China\n\n*Correspondence: Damir Vukoja, damirvukoja5@gmail.com\nThis article was submitted to Respiratory Pharmacology, a section of the journal Frontiers in Pharmacology\n\n12 8 2021\n2021\n12 8 2021\n12 68453723 3 2021\n12 7 2021\nCopyright © 2021 Vukoja, Jurić, Erkapić, Pejić, Zovko, Juričić, Pejić and Ćorluka.\n2021\nVukoja, Jurić, Erkapić, Pejić, Zovko, Juričić, Pejić and Ćorluka\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nEven in 2021, coronavirus disease 2019 (COVID-19) remains a major global health concern, especially in developing countries. The burden of this disease, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which affects not only primary respiratory but also other organ systems, keeps rising as the pandemic continues. Primary health care centers are the first line where COVID-19 patients are managed and should be able to manage the vast majority of them successfully. In this paper, we present a case series and concept of beneficial management of even deteriorating and severe patients treated entirely in our primary health center. The management is based on well-timed and rational dexamethasone use, as well as on various other pharmacological and nonpharmacological treatments and interventions, and is supported by provided statistical data. According to the presented experience and positive outcomes achieved, it seems that even deteriorating and severe COVID-19 patients can be treated successfully to some extent or even completely in primary care settings. This kind of approach could be particularly beneficial in conditions of overload of higher-level health care institutions.\n\nCOVID-19\ncoronavirus\nSARS-CoV-2\ndexamethasone\ncorticosteroids\nprimary health care\ntreatment\n==== Body\nIntroduction\n\nWith the end of the year 2020 (as of December 31), more than 81 million cases of coronavirus disease 2019 (COVID-19) were confirmed worldwide with a death toll reaching almost 1.8 million and a global case fatality rate (CFR) of around 2.2% (World Health Organization, 2020b). In a little over a year since it first appeared, this disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged as the leading global threat of the moment by affecting almost every country and changing everyday life routine. Health system overload, economic decline, and an increase in the rate and severity of mental illness are just a few indicators of the burden of this pandemic (Dubey et al., 2020; Goulabchand et al., 2020; London et al., 2020; Yelin et al., 2020; Yusuf and Tisler, 2020).\n\nAccording to emerging literature, the clinical presentation of COVID-19 can range from asymptomatic infection to mild respiratory illness, all up to more severe conditions affecting one or more organ systems requiring hospitalization and even intensive care unit admission. However, a major concern and treatment challenge correspond to often extensive viral pneumonia and severe respiratory illness accompanied with it. Regardless, there are some disparities in relevant literature in terms of criteria for classifying the illness as “severe.” Namely, while the US National Institutes of Health (NIH) considers COVID-19 patients with a saturation of oxygen (SpO2) ≤93% along/or with the fulfillment of other criteria like dyspnea or respiratory frequency ≥30 breaths/min as “severe,” the WHO’s living guideline sets the limit of saturation at <90% to classify patient as severe. But, current data agree that most patients are asymptomatic or have mild disease, with a tendency of older adults, men, obese, and patients with other comorbidities to be more susceptible to severe illness (World Health Organization, 2020a; Cuschieri and Grech, 2020; Patil et al., 2020; Wiersinga et al., 2020; Dehingia and Raj, 2021; National Institutes of Health (NIH), 2021).\n\nDespite many treatment options with proven or promising benefits that appeared so far (including antivirals, corticosteroids, other anti-inflammatory agents, immunomodulatory agents, antibodies, and others) and available living treatment guidelines, the therapeutic management of patients with COVID-19 still remains the area of uncertainty (World Health Organization, 2020b; Sahebnasagh et al., 2020; Wiersinga et al., 2020; Asselah et al., 2021; National Institutes of Health (NIH), 2021). It is a fact that mortality related to COVID-19 drops as time passes, but it is still unclear how much of that reduction can be attributed to better managing of these patients (Fan et al., 2020; Preskorn, 2020). And yet, the mortality rates are still high considering the prevalence of the disease and the overall number of deaths as a consequence (Ghayda et al., 2020; Sorci et al., 2020). Considering all the above mentioned, it can be said that treating and managing these patients still poses a challenge to health professionals, especially in low to middle resource countries/regions (Sorci et al., 2020).\n\nIndeed, the country’s income status usually impacts to a significant extent the national health care system quality, especially in these modern times more than ever. This means that the start positions and possibilities to respond and adjust to new conditions such as this pandemic vary among different countries. In the case of COVID-19, this also implies the concern with disparities in vaccine availability among countries and regions to a point where it becomes the question of ethics and human rights (Beyrer, 2021; Lambert, 2021). Accordingly, as Bosnia and Herzegovina belongs to middle-income countries and is among the weakest European economies, it is clear that its health care system found itself in an unenviable position during the COVID-19 outbreak. This is especially true considering the postwar consequences that may still be taking their toll in the present to a significant point (Sabes-Figuera et al., 2012). Therefore, heads of institutions of all three levels of health care had to put a lot of knowledge and effort into adjusting the health care system’s functioning in the best possible way given the low resources at their disposal. And, most importantly, these conditions forced not just corresponding executives but also “first line” physicians to improvise in many ways (Turner et al., 2019; Chowdhury et al., 2020; Kovacevic et al., 2021).\n\nAs a result, despite all the efforts and resourcefulness, by the end of the year 2020, there were 110,985 confirmed cases of COVID-19 in Bosnia and Herzegovina with a CFR of almost 3.7%, respectively (World Health Organization, 2020b). Based on these data, Bosnia and Herzegovina counts among the European countries with the highest mortality rates due to COVID-19 (University of Oxford, 2020). Nevertheless, there were, and still are, significant differences in CFR values among different administrative units within the country (Institute for Public Health of Federation of Bosnia and Herzegovina, 2020). Divergency in mortality rates seen among different areas in the country may be attributed to many factors such as demographic, economic, political, etc. However, this phenomenon probably depends largely on diverse local/regional health care system organization and approach of primary and higher health care institutions to its patients, as well as to different therapeutic approaches and management toward these patients by medical professionals. For instance, the municipality of Grude as part of West Herzegovina County stands out among others with a very low CFR of <1% despite the high prevalence of the disease (Institute for Public Health of Federation of Bosnia and Herzegovina, 2020). Hence, as conscientious medical professionals from the Health Center Grude (which is the primary health care institution in charge of Grude municipality patients), we were obliged to share our experience, work scheme, therapeutic approach, and management of COVID-19 patients, which seem to be overall beneficial.\n\nCases\n\nAmong many other cases of successful management of severe COVID-19 patients at this primary health institution, the most suggestive and representative ones were selected and presented in the following. The patient was considered as severe if the criteria by NIH definition were met (National Institutes of Health (NIH), 2021). Similar to those here presented, the other severe and some “almost severe” patients were managed in like manner too by following and applying current and updated treatment guidelines as much as possible (World Health Organization, 2020a; The National Institute for Health and Care Excellence (NICE), XX; Chow et al., 2020; Gautret et al., 2020; Wiersinga et al., 2020; Bottari et al., 2021; Gyselinck et al., 2021; National Institutes of Health (NIH), 2021), while respecting an individualized approach.\n\nCase 1\n\nA 57-year-old male patient, nonsmoker for more than 10 years, with comorbidities of bronchial asthma and Parkinson’s disease, presented to a general practitioner two days after the onset of symptoms. The patient was subfebrile up to the presentation, had a dry cough, and denied any other symptoms, either new or worsened health difficulties. In the epidemiological anamnesis, there was no information of significant importance. Physical examination revealed hypokinesia and graceful body composition by inspection. Lung auscultation showed slightly decreased breathing sounds, especially in the lower fields. Blood oxygen saturation (SpO2) was at 98%. Basic blood laboratory analysis and chest radiograph were performed (Figure 1A), none of which showed significant pathology (except for a slight increase in granulocytes regarding lab work). The patient was advised to take symptomatic measures and was referred for a PCR test for SARS-CoV-2 the next day. The test result was positive; the diagnosis of COVID-19 was made. Having in mind the patient’s comorbidities as well as age, sex, lung auscultation finding, and other factors, treatment with azithromycin 500 mg once daily and aspirin 400 mg daily divided into two doses was initiated. An over-the-counter (OTC) supplement containing beta-glucan, vitamins, minerals, enzymes, peptides, and amino acids formulated to boost immunity and recovery was recommended. At the control appointment two days later (the sixth day from the start of the disease), there were no significant changes in symptoms or body temperature rises, the SpO2 was at 97%, but a control X-ray image of the chest was done to screen for viral pneumonia. Bilateral pneumonia of lower lung fields was described by a radiologist (Figure 1B). At follow-up encounter two days later (the eighth day of the disease), the patient is still subfebrile but with body temperature values lower than earlier and is still coughing but mostly when changes milieus with different air conditions (cold/warm and vice versa). By inspection, mild dyspnea is noticed and SpO2 is at 95%. At this point, parenteral therapy with dexamethasone 8 mg and crystalloid solutions 250–500 ml daily (mostly Ringer’s and saline solution) was started and received at adequate spaces for such patients at the health center. The aspirin dose was reduced to 100 mg daily. The next day, the lab follow-up was done and it showed mildly elevated c-reactive peptide (CRP) levels at 15.7 (mg/L), while liver, renal, and cardiac parameters were regular. Since it was the last day of taking azithromycin, moxifloxacin 400 mg daily was prescribed for the following period alongside probiotic containing yeast Saccharomyces boulardii. On the 12th day from the onset of symptoms, the patient was still dyspnoic, SpO2 was at 92%, his appearance had worsened, and his family member reported that he looks weaker. Control chest radiogram showed progressive dynamic of bilateral pneumonia and discrete pleural effusion in the projection of the left lateral phrenicocostal sinus (Figure 1C), while CRP value was reduced to 6.5. Hospital treatment was suggested, but the patient and his family preferred to continue the treatment at the health center under the supervision of the same doctor. Thus, the same treatment was continued but with dose deescalation of dexamethasone to 6 mg daily for following days, and administration of supplemental oxygen was started (up to 5 L/min via nasal cannula for about 90 mins a day). In the following days, the saturation slowly started to rise up; the patient was less dyspnoic and was feeling stronger. At follow-up encounter with the doctor three days later (15th day of the disease), the SpO2 rises up to 95%, there is no longer noticeable dyspnea, the cough was reduced, and the patient was afebrile for a couple of past days. Control lab work was without significant deviations (except the elevated total leukocyte count, which was attributed to dexamethasone use). It was suggested to continue taking moxifloxacin and dexamethasone 4 mg orally for the next four days as well as probiotics, earlier mentioned supplements, and aspirin. 20 mg pantoprazole was added to therapy, while parenteral administration of fluids as well as oxygen therapy was discontinued. At the final control appointment three days later (18th day from the onset of symptoms), the patient was feeling well; control lab work showed CRP value reduction to 0.8, while other blood parameters were normal as well, except mildly increased ALT and still elevated leukocyte count. Further, a control chest X-ray showed mild regressive dynamic of infiltrative inflammatory changes of lung parenchyma (Figure 1D). The patient was advised to continue taking probiotics, pantoprazole, and aspirin for two more weeks and was recommended to visit a pulmonologist and internist in about one month with a control chest radiograph and blood lab analysis. Approximately a month and a half later, the patient appeared at an appointment at specialists, and the control chest X-ray image was described as a normal finding by a radiologist, meaning that no scaring changes in terms of postinflammatory fibrosis were observed (Figure 1E).\n\nFIGURE 1 Series of chest X-ray images of COVID-19 patient from case 1. The images are chronologically* arranged in a–z order (the letter mark is indicated in the lower right corner of each image)§. *The dates of records are visible in the top right corner of each image. §Identifiable patient’s data are covered.\n\nCase 2\n\nA 50-year-old female patient with an extensive medical history presented to the physician’s office for being febrile up to 39°C for more than 10 days. She is a nonsmoker and her current medical problems include hypertension, hypothyroidism as a consequence of autoimmune thyroiditis, and irritable bowel syndrome, for all of which she is taking medications (bisoprolol 2,5 mg, levothyroxine 50 mg, and mebeverine 300 mg XR daily). Looking into her medical history reveals a couple of episodes of sideropenic anemia due to dysmenorrhea in recent years, gout arthropathy, an episode of pericarditis four years ago, and an episode of transient ischemic attack (TIA) 11 years ago; the patient also had a tonsillectomy in her youth due to frequent strep throat episodes and cholecystectomy approximately 10 years ago. Besides, the patient is obese and has chronic lower back issues. At the presentation, she admitted that she has been taking azithromycin 500 mg daily in the past three days “on her own.” In the physical examination, a lower blood pressure of 90/60 (mm/Hg) was detected; lung auscultation showed slightly muffled breathing sounds diffusely and small crackles in the projection of lower lung fields, while saturation (SpO2) was at 89–90%. Despite these decreased saturation values, the patient was not dyspnoic, and she had not had noticeable respiratory difficulties. Basic laboratory blood analysis and chest X-ray processing were done. Remarkably elevated CRP value (90.4 mg/L) and granulocytosis were detected as significant among other biochemical and blood count parameters. Equally important, an X-ray image of the chest was described as “extensive infiltrative changes of the lung parenchyma bilaterally” by a radiologist (Figure 2A). Based on these findings, it was suspected that the patient is having COVID-19. Taking into account all the above-mentioned parameters, the patient was considered to be at high risk of developing a severe form of the disease. Since she first presented to the doctor at an advanced stage, hospitalization was strongly suggested after a detailed explanation of her health condition and prognosis. Nevertheless, the patient and her family member refused hospitalization, so the treatment was started in the primary health care institution (i.e., local health center). The treatment began with parenteral fluids (crystalloids) and dexamethasone in doses of 8 mg once daily alongside oxygen therapy in the duration of a minimum of 1 h a day. It was suggested to continue azithromycin 500 mg for two more days and to add moxifloxacin 400 mg, as well as aspirin 400 mg daily, per os. Also, it was recommended to take the supplement mentioned in Case 1 and probiotic containing yeast Saccharomyces boulardii. The following day, patient had a control appointment, and a PCR test for COVID-19 was done. The patient was not reporting the deterioration of her health condition and denied difficulties with breathing. However, the blood oxygen saturation (SpO2) measured with a pulse oximeter was not higher than 81% despite various measurements. Although the hospitalization was strongly advised, the patient refused once again. So, the same treatment was continued for the next days; the patient continued oral therapy and came twice a day for the oxygen therapy and parenteral administration of fluids while being supervised by her doctor. In the meanwhile, the test result for novel coronavirus came positive, so the diagnosis of COVID-19 was made. During the following days, the patient was stable by saturation and general condition. At the control appointment with the doctor three days later (the 15th day from the onset of symptoms and the fifth day of the parenteral treatment initiation), the patient felt better and was afebrile for the past four days, while the SpO2 was up to 95%. Control lab work was done and it showed the CRP reduction to 6.4 (mg/L), while the platelets were mildly elevated (as well as leukocyte and granulocyte count, but it was attributed to dexamethasone action). It was suggested to continue with the same per os therapy, while the parenteral and oxygen therapy were discontinued. Dexamethasone was prescribed in the form of tablets with dose deescalation to 6 mg daily, alongside 20 mg of pantoprazole. At the follow-up appointment three days later (the 18th day from the disease onset and the eighth day of initiation of dexamethasone), the patient was feeling well and “practically healthy,” the saturation was at 96%, and she was referred to control chest X-ray imaging. The image showed “almost complete regression of the infiltrative changes along with suspected fibrose changes here and there in the lung parenchyma,” described by the words of the radiologist (this image was lost due to technical malfunction and thus not shown here). The same treatment was continued but with a lower dose of dexamethasone (4 mg) for three more days and deescalation of aspirin to 100 mg daily, which was recommended for three more weeks. It was recommended to seek pulmonologist and internist control in a month to month and a half. Later on, as part of the specialist’s examination, new control chest X-ray imaging was performed and it was described as a “normal finding” by the radiologist, meaning that no previously described fibrose changes were now visible (Figure 2B).\n\nFIGURE 2 Series of chest X-ray images of COVID-19 patient from case 2. The images are chronologically* arranged in a–z order (the letter mark is indicated in the lower right corner of each image)§. *The dates of records are visible in the top right corner of each image. §Identifiable patient’s data are covered.\n\nCase 3\n\nA 68-year-old male patient, nonsmoker and overweight, presented to the physicians’ office for being subfebrile and having dry cough for the past four days. His medical records show a previous history of myocardial infarction and ongoing hypertension, for which he has been taking carvedilol 12.5 mg, lisinopril/hydrochlorothiazide 10/12.5 mg, aspirin 100 mg, and atorvastatin 20 mg once daily perorally for more than nine years. Patient anamnesis regarding his current condition did not reveal much additional significant data; he did not have any other developed symptoms, and his epidemiological anamnesis was nonsignificant. The physical examination revealed slightly decreased breathing sounds in the projection of lower lung fields bilaterally, while the SpO2 was 96%. There were no other significant findings, so the basic lab work and chest X-ray were ordered. The laboratory analysis did not show any remarkably disturbed parameter, while the chest radiograph revealed a mildly more pronounced interstitial pattern basally and toward the periphery of lower lung fields (Figure 3A). For the radiologist, this finding was most suggestive for incipient atypical pneumonia. At this point, the COVID-19 was suspected and the patient was referred for PCR testing, which later came out as positive. The treatment with azithromycin 500 mg, some herbal cough relief tablets, and an immune supplement (containing beta-glucans, vitamin D, vitamin C, and group B vitamins, as well as elements such as zinc, selenium, copper, and manganese) was initiated. An additional recommendation was to increase the daily dose of aspirin to 300 mg for a couple of following days. Two days later, on the seventh day from the onset of symptoms, the patient reported that he feels weaker and gets tired easily, his taste sense changed, and he lost appetite. At the presentation the following day (the eighth day from the onset of the disease), the SpO2 was notably decreased to 91–2%, and (by inspection) the patient did look weaker indeed and would even get tired while speaking. So, the control lab work and an X-ray chest imaging were done. The chest radiograph showed progressive dynamic of inflammatory changes (Figure 3B), while the blood count revealed slightly reduced total leucocytes and platelets and mildly elevated granulocytes. Among biochemical parameters, CRP was surprisingly low (5.7 mg/L), while transaminases and urea were mildly elevated. Other liver, renal, and cardiac markers were within physiological limits. Parenteral intravenous solutions were given (750 ml in total) as well as dexamethasone 8 mg and pantoprazole 20 mg through the same route. This resulted in increased SpO2 at the end of the therapy (up to 94%), and the patient was feeling better as well. Moxifloxacin 400 mg once daily was added to peroral therapy. The next day (day nine), the patient again looked weak, a little unstable on his feet, and was pale; discrete dyspnea was noticed and SpO2 was 91%. Same parenteral therapy was given and oxygen therapy was initiated (1.5 L/min through the nasal cannula for an hour and a half). Due to chronic heart disease, an internist was consulted and trimetazidine 35 mg MR twice daily was added to therapy (off-label) to support the heart function in the conditions of lower blood oxygen levels and inflammation. On day 10, the patient had similar appearance, the SpO2 was 90%, and dyspnea was more noticeable. The hospitalization was proposed, but the patient was not motivated at the moment. So, the treatment was continued with 500 ml of parenteral intravenous fluids, as well as 6 mg of dexamethasone, 20 mg of pantoprazole, and oxygen therapy (2 L/min). On day 11, the patient is afebrile for two days, the cough is only present when changing rooms with different air temperature or humidity, but the physical appearance is worse in terms of exhausting look and noticeable depressed mood. Hospitalization was now strongly suggested, but the patient refuses it. The same treatment was continued with the rise in oxygen flow to 3 L/min. Anxiolytic drug alprazolam 0.5 mg XR once daily was added to therapy and the importance of breathing exercises was explained to the patient. For the next two days (12th and 13th days), the patient’s condition was still poor with an even lower SpO2 value (88–89%), but the same treatment scheme was continued with raised oxygen flow up to 5 L/min. On the 14th day from the disease’s onset, the patient’s overall appearance and condition were a little better, and the SpO2 started to rise to 90–1%. Crepitations were discovered in lower lung fields by auscultation and noticeably shortened inspiration as well. Therefore, administration of intravenous fluids was reduced, and at the end of it, furosemide 20 mg was given via intramuscular route. Accordingly, oxygen flow was reduced to 3 L/min as well. Control lab work was done, and it did not reveal any new change of importance. On day 15, the SpO2 was 92%, the patient was feeling even better, but he was still with a reduced ability to tolerate everyday activities such as walking upstairs. Control chest imaging was performed and it showed initial regressive dynamic of inflammatory changes (Figure 3C). Since the patient’s condition improved, it was suggested to discontinue alprazolam and to reduce aspirin’s dose back to 100 mg. At the control appointment the next (16th) day, the SpO2 was 93%, so it was the last day of the same parenteral and oxygen therapy as the day earlier. Dexamethasone was continued perorally 4 mg daily for the next four days, as well as pantoprazole 20 mg. The patient continued to practice breathing exercises, and his ability to tolerate the exertion improved continuously with every new day. Interestingly, according to the PCR retest performed on the 18th day from the onset of the symptoms, the patient was still positive for SARS-CoV-2, which confirms that this patient’s viral load was probably very high. Approximately a week later, the SpO2 value was 95–6% and he was feeling almost completely recovered. It was recommended to him to seek an internist and pulmonologist control checkup in a month to month and a half. In that period, the patient was experiencing some “post-COVID syndrome” symptoms, but they were tolerable and easily manageable. Prior to specialist controls, the new chest radiograph was performed and it was described as “almost complete regression of the inflammatory changes of the lung parenchyma” by the radiologist (Figure 3D).\n\nFIGURE 3 Series of chest X-ray images of COVID-19 patient from case 3. The images are chronologically* arranged in a–z order (the letter mark is indicated in the lower right corner of each image)§. *The dates of records are visible in the top right corner of each image. §Identifiable patient’s data are covered.\n\nCases Commentary\n\nDue to the word count limitation of the article and in order not to lose its flow and purpose, the cases’ presentation was brought down to these three, although there were many more worth presenting. Therefore, the bottom line and common characteristics for them all should be stated. In brief, there is a consensual collective approach to patients suspected or confirmed for SARS-CoV-2 infection in this primary health care institution. According to it, the initial approach should be to individually and orientationally access the most likely course and prognosis of disease severity for every single patient at the very start. In order to obtain a proper assessment, every patient is first looked through a prism of main characteristics that are known as important COVID-19 prognosis factors such as age, sex, comorbidities, and BMI. Additionally, findings collected by anamnesis, physical examination (lung auscultation including), and diagnostic tests such as laboratory analysis and X-ray imaging are summed up to get the full picture and final assessment of every patient. Based on the assessment, the patients are roughly divided into low, intermediate, and high-risk groups, which then determine further therapeutic management. In particular, patients considered as with low risk of developing a serious disease (which are usually young, healthy people, and especially female) usually receive just symptomatic therapy and are advised to inform the doctor if their condition is progressively worse, if they experience “jump” rise in body temperature, any breathing difficulties, or unusual symptoms, or if the symptoms last for more than 5–7 days. From our experience, patients assessed as low risk usually do not need follow-up encounters except if they notice something unusual in their general condition. The next group comprises patients accessed as intermediate risk, most often middle-aged men with or without comorbidities. They usually receive just symptomatic and supportive therapy but are strongly advised to have a control encounter in a couple of days to check up and adjust the therapy if needed. In many cases, they do develop pneumonia which is usually not that extensive and is pretty much well controlled with azithromycin. If pneumonia developed, they are urged to have another control appointment(s) and usually additionally receive aspirin (firstly in higher doses and then prophylactic antiaggregating dose for a month). Many of them are prescribed with additional n-acetylcysteine 600 mg daily as long as pneumonia lasts. Some need an additional antibiotic if later signs of bacterial superinfection are noticed. Finally, the most “demanding” are high-risk patients, which usually are mature adulthood men and especially age group between roughly 55–75 years with or without comorbidities, as well as obese patients of practically any age. Once accessed as “high risk,” they usually receive azithromycin 500 mg daily for 5 days, n-acetylcysteine 600 mg daily, and aspirin (usually in higher doses in the first few days, except if they already have an anticoagulant in their therapy), alongside symptomatic and supportive therapy. These patients require almost everyday control check-ups, especially in the disease’s phase when they start to deteriorate, which is usually due to extensive bilateral pneumonia progression. At this point, the parenteral therapy is started with intravenous fluids and dexamethasone (along with gastroprotective therapy) if the earlier criteria for its administration are met. If there are signs of significant bacterial coinfection, intravenous antibiotics are also received. Indeed, as suggested by the relevant literature, it is common that patients who have antibiotics in their therapy are prescribed additional probiotics due to their supposed favorable properties (Bottari et al., 2021).\n\nPatients who meet the WHO (not the NIH) criteria of severe COVID-19 (World Health Organization, 2020a) are suggested for hospitalization. However, very often patients refuse hospitalization despite the serious deterioration of their health. In these cases, the doctor is obliged to manage the patient as if he is a clinician. This usually requires supplemental oxygen for a patient at least for a few hours daily, and even other additional measures such as low-molecular-weight heparin administration where indicated. These patients are encouraged to do breathing exercises daily and are advised to spend as much of their time in sitting and standing positions so the lungs can ventilate properly. For them, special rooms are arranged as part of the health center in a form of a “daily hospital” where they can stay for an hour to two receiving their therapy. It is crucial that the same doctor follows, monitors, and treats the patient throughout the entire disease process. Of course, the doctor is always consulting his colleagues regarding patient condition if needed. From our experience, almost all of these patients treated exclusively in our primary health center had beneficial outcomes, speaking of their overall wellbeing, taking into count expectations of general condition and health status after overcoming COVID-19. These aspects will be further discussed.\n\nDiscussion\n\nDespite the fact that more than a year has passed since the COVID-19 is present in our worldwide society, and although vaccination against its causative agent already started in many countries, we witness that this disease still represents a major global concern even in the first part of 2021. By looking into daily reports of newly confirmed cases and deaths, as well as trends with vaccination, the chances are it will continue to stay so for a while longer. This is especially true for developing countries where the pandemic’s toll is even higher, which is also seen here in Bosnia and Herzegovina and is mostly due to poor economic status (meaning weaker health system as well) and less accessible vaccines. Another key factor that must not be overlooked is the continuous emergence of mutant strains of SARS-CoV-2, which threatens the efficacy of the developed vaccines. Additionally, having in mind the high prevalence of the disease and also relatively high mortality associated with it, despite the advances in its treatment and management, it is still reasonable and even crucial to discuss the ways of improving outcomes of the patients suffering from it (World Health Organization, 2020a; Chowdhury et al., 2020; Gautret et al., 2020; Sorci et al., 2020; Beyrer, 2021; Kovacevic et al., 2021; Lambert, 2021).\n\nSpeaking of outcomes of patients treated from COVID-19, there is a strong need that all the data, experiences, and findings of medical professionals in charge of these patients are shared with the worldwide healthcare community in order to improve the management and consequently the outcomes of these patients. Hence, the results achieved here at Grude Health Center, with the CFR below 1% for the Grude municipality comparing to the county’s CFR of nearly 2% and the one on a country’s level of around 3.7% (all as of December 31, 2020), definitely should be shown and discussed. To mention, the municipality of Grude belongs to West Herzegovina County where there are in total four primary health care centers (one on each municipality), without any other higher-level health institution. Thus, all patients requiring hospital admission are sent to the neighboring county’s university clinical hospital. Anyway, regarding local COVID-19 statistical data, the county’s official data (also as of December 31, 2020) were kindly provided by the Institute for Public Health of West Herzegovina County (shown in Supplementary Table 1). As clearly seen from Supplementary Table 1 and belonging graphical representation (Figure 4), the municipality of Grude has the far lowest rate of hospitalizations as well as mortality rates (CFR) from COVID-19, despite having the highest rate of confirmed cases per capita. To illustrate, there was only one out of every 21 COVID-19 patients hospitalized from Grude compared to 1/16 from Široki Brijeg, 1/13 from Ljubuški, and 1/10 from Posušje. Further, when comparing COVID-19 mortality rates among the municipalities, the CFR is almost half the rate for Grude than for Široki Brijeg and even more than two and a half times lower compared to Ljubuški and Posušje. Another meaningful comparison may be drawn toward neighboring counties (Herzegovina-Neretva County and Canton 10) since all patients from these three counties gravitate toward the same tertiary health care facility. Thus, again by the end of 2020 (as of December 31st), the CFR in the Herzegovina-Neretva County was around 1.2%, while it was around 2% in the Canton 10, which is still noticeably higher than that in the municipality of Grude (Institute for Public Health of Federation of Bosnia and Herzegovina, 2020).\n\nFIGURE 4 Graphical representation of data showed in Supplementary Table 1. Accordingly, the municipality of Grude has the far lowest rate of hospitalizations (4.67%) as well as mortality rates (CFR) from COVID-19 (0, 99%), despite having the highest rate of confirmed cases per capita (∼6.4%).\n\nConsidering all presented data and earlier described general approach to COVID-19 patients as well as particular in detail real cases examples, it could easily be assumed that the management of these patients, which is practiced at Grude Health Center, may be beneficial and may result in better outcomes. Briefly, this management implies watchful care of those COVID-19 patients who may deteriorate or are deteriorating, in the form of adequate peroral therapy, regular check-ups, and case-to-case customized medical interventions of a single physician for each patient. The physician consults if needed other colleges during the process of managing each patient. Medical interventions performed during the treatment process are expanded, if needed, from the ones on a primary health care level to those on a secondary health care level in the form of “daily hospital.” The emphasis here is on well-timed parenteral dexamethasone or other approved corticosteroid treatment initiations, intravenous fluids, oxygen therapy, and parenteral antibiotics (if needed on a case-to-case basis). These interventions are performed at the same primary health care institution and under the same physician’s supervision. In order to achieve all of this, particular work and spatial organization are required. This means that there should be specially allocated and equipped spaces for the care of these patients only, preferably with entrance to these spaces directly from outside (while bypassing the institution's shared interior spaces) or using dislocated spaces for this purpose only. In the end, each patient is managed in the primary health care institution until his supervising doctor, based on clinical judgment, decides that the patient met the criteria for hospitalization. This is usually if the patient first presented with advanced disease or is deteriorating rapidly (usually in a matter of days), or there are signs of serious complications such as pulmonary thromboembolism. Of course, an individualized and rational approach is respected in the case of every patient.\n\nBased on the achieved results, the authors of this study believe that COVID-19 patients may benefit more from a “home stay-daily hospital” combined approach than from an early hospitalization. The authors also believe that each day more spent surrounded by family with the ability to move around home freely and to take some fresh air and sun and each day less in the “COVID hospital” can bring overall better outcomes for these patients. In other words, the more days the severe COVID-19 patient spends under the primary health care system supervision in the manner described here, avoiding the “COVID hospital” if possible or at least by postponing hospitalization, the better the outcomes of the treatment process could be achieved. So, the idea is that the hospitalization threshold should not be as high and that even severe COVID-19 patients should be given a chance to continue treatment in the primary care settings for as long as possible (Levine et al., 2020). These thoughts should be especially considered if the adverse effects of patient isolation, which is often practiced and seen in “COVID departments,” are taken into count (Abad et al., 2010). More recently, even the idea of “Virtual Hospital” shows up as a positive model in managing the COVID-19 patients, thus supporting our reflections as well (Sitammagari et al., 2021). Another point is that these patients are probably “overtreated” in many cases, especially in terms of antibiotics use, which requires critical considerations regarding possible harms of “overtreatment” and definitely should be further investigated. Unfortunately, there are not many studies regarding this issue, and to our best knowledge, no other studies discussed the benefits of a similar concept of therapeutic management of severe COVID-19 patients in primary care settings. Therefore, the additional rationale behind this concept as well as convenient and larger studies should be conducted in order to further determine its benefits.\n\nAdditional thinking is provided as follows. Since the treatment and management of these patients depend heavily on the severity of the illness, the authors of this study put to the table the idea of adding the term “subsevere” to the current WHO classification of disease severity on nonsevere, severe and critical (World Health Organization, 2020a). It would include those patients whose health condition started to deteriorate but have not met the criteria of “severe” illness yet. In that way, this simple modification could improve the approach to the treatment of these patients and consequently the outcomes as well.\n\nTo this end, even though this study provides solid evidence in favor of a more comprehensive approach and therapeutic management of severe COVID-19 patients in primary health care centers, especially in developing countries, it still may have some limitations. Namely, possible sociodemographic differences among compared territories as well as differences in testing protocols among medical centers of each compared territory may affect the CFR values. However, it can generally be considered that these factors are pretty much similar for compared territories and thus likely not affecting the CFR values to a significant extent. Another possible disadvantage of the study is that it does not provide information on the patient’s long-term outcomes, which could provide additional evidence of the suggested concept. Anyway, since this could be a whole paper for itself, the authors of this study plan to do so in the near future, leaving, for now, these positive results and experiences as preliminary evidence.\n\nConclusion\n\nTo conclude, mild cases of COVID-19 are not the only ones that could (and should) be treated in primary health care settings, deteriorating and severe COVID-19 patients as well can be treated and managed successfully, as seen. It seems that the commitment, resourcefulness, courage, and professionalism of primary health care physicians are required to achieve beneficial outcomes for these patients. Well-timed and prompt pharmacological and other treatment options’ initiation and administration by the same physician throughout (and after) the disease’s course may “spare” deteriorating and even severe COVID-19 patient from the hospitalization and thus bring better overall outcomes. Our experiences and results suggest that these patients usually can be managed well in the primary health care all up until rapid (in a matter of days) or acute (in a form of a complication) deterioration of health condition occurs, or the patient first presents to a physician in an advanced phase of a severe disease, where the hospitalization is strongly recommended. The concept presented here could be applied especially for lower to middle resources countries where the health care system’s capacities are limited, requiring constant improvisations and adjustments to current conditions.\n\nThe authors acknowledge the invested efforts and work discipline of all Grude Health Center personnel during the COVID-19 pandemic. Special thanks are addressed to fellow physicians and colleagues Katarina Zovko, Vlado Šimunović, Vinka Đevenica, Gabrijela Majić, Antonela Leventić, Ivo Ostojić, Branka Galić, Marija Prlić, Mario Bunoza, and Marina Bogut for their substantial contribution to achieved results. The authors also thank the institutions that aided and supported the study’s publishing: Ministry of Health, Labor and Social Welfare of West Herzegovina County, Health Insurance Institute of West Herzegovina County, and Institute for Public Health of West Herzegovina County.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/Supplementary Material; further inquiries can be directed to the corresponding author.\n\nEthics Statement\n\nWritten informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nDV initiated the study and contributed the most to its completion. AJ provided and processed the data collected from the county’s Institute for Public Health. ZE and TP provided conceptual and technical solutions to changing conditions during the pandemic, thereby enabling and supporting quality work of health professionals, but also made major suggestions to the final manuscript. ŽZ and JJ made written contributions to the final manuscript. JP and MĆ assisted with reference finding and contributed intellectually to study finalization. All authors approved the final version of the manuscript.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nPublisher’s Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2021.684537/full#supplementary-material\n\nClick here for additional data file.\n\nAbbreviations\n\nAL, alanine transaminase; BMI, body mass index; MR, modified release; PCR, polymerase chain reaction; WHO, World Health Organization; XR, extended release; US, United States.\n==== Refs\nReferences\n\nAbad C. Fearday A. Safdar N. (2010). Adverse Effects of Isolation in Hospitalised Patients: a Systematic Review. J. Hosp. Infect. 76 (2 ), 97–102. 10.1016/j.jhin.2010.04.027 20619929\nAsselah T. Durantel D. Pasmant E. Lau G. Schinazi R. F. (2021). COVID-19: Discovery, Diagnostics and Drug Development. J. Hepatol. 74 (1 ), 168–184. 10.1016/j.jhep.2020.09.031 33038433\nBeyrer C. (2021). 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Hypotheses. 143 , 110069. 10.1016/j.mehy.2020.110069 32688184\n\n", "fulltext_license": "CC BY", "issn_linking": "1663-9812", "issue": "12()", "journal": "Frontiers in pharmacology", "keywords": "COVID-19; SARS-CoV-2; coronavirus; corticosteroids; dexamethasone; primary health care; treatment", "medline_ta": "Front Pharmacol", "mesh_terms": null, "nlm_unique_id": "101548923", "other_id": null, "pages": "684537", "pmc": null, "pmid": "34456719", "pubdate": "2021", "publication_types": "D002363:Case Reports", "references": "32648899;33160453;33144595;33175567;22238627;33773117;32882434;32865940;32656618;32945643;20619929;32688184;33282327;32576501;31297248;33491107;32716647;32892500;32787470;32888409;33038433;32526627;33093359;31842232;32816200;33441373;33356661", "title": "Beneficial Treatment Outcomes of Severe COVID-19 Patients Treated Entirely in Primary Care Settings With Dexamethasone Including Regimen-Case Series Report.", "title_normalized": "beneficial treatment outcomes of severe covid 19 patients treated entirely in primary care settings with dexamethasone including regimen case series report" }

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Beneficial treatment outcomes of severe COVID-19 patients treated entirely in primary care settings with Dexamethasone including regimen-Case series report. 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null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MILLIGRAM, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FUROSEMIDE" } ], "patientagegroup": null, "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Vukoja D, Juric A, Erkapic Z, Pejic T, Zovko Z, Juricic J, et al. Beneficial treatment outcomes of severe COVID-19 patients treated entirely in primary care settings with Dexamethasone including regimen-Case series report. Frontiers in Pharmacology. 2021;12(684537):1-11", "literaturereference_normalized": "beneficial treatment outcomes of severe covid 19 patients treated entirely in primary care settings with dexamethasone including regimen case series report", "qualification": "3", "reportercountry": "BA" }, "primarysourcecountry": "BA", "receiptdate": "20211011", "receivedate": "20211011", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19938190, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220303" } ]

{ "abstract": "Rothia spp. are increasingly being recognized as emerging opportunistic pathogens associated with serious infections in immune-compromised hosts. Risk factors include neutropenia, hematologic malignancies, prosthetic devices, and intravascular catheters. We describe 29 patients at our institute from 2006 to 2014 with positive blood cultures for Rothia spp. Neutropenia was observed in 21/29 (72%) patients at the time of bacteremia, and 16/29 (61%) had leukemia. Neutropenic patients were less likely than nonneutropenic patients to have polymicrobial infection (24% versus 63%; P= 0.083) and were also more likely to have multiple positive blood cultures (76% versus 0%; P= 0.0003), indicating true infection. Sources of bacteremia included intravascular catheters, mucositis, and presumed gut translocation. A significant association was seen with steroid use (81% versus 13%; P= 0.0014) and fluoroquinolone use (86% versus 13%; P≤ 0.0001) preceding bacteremia in neutropenic patients. There was no difference between the 2 groups for admission to intensive care unit or mortality. One death was reported possibly due to Rothia infection.", "affiliations": "Division of Infectious Disease, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA. Electronic address: mabidi@outlook.com.;Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, USA.;Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI, USA.;Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.", "authors": "Abidi|M Z|MZ|;Ledeboer|N|N|;Banerjee|A|A|;Hari|P|P|", "chemical_list": "D000900:Anti-Bacterial Agents", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0732-8893", "issue": "85(1)", "journal": "Diagnostic microbiology and infectious disease", "keywords": "Bacteremia; Neutropenia; Rothia mucilaginosa", "medline_ta": "Diagn Microbiol Infect Dis", "mesh_terms": "D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D015897:Comorbidity; D005260:Female; D016908:Gram-Positive Bacterial Infections; D019337:Hematologic Neoplasms; D006801:Humans; D015994:Incidence; D008297:Male; D008835:Micrococcaceae; D008875:Middle Aged; D009017:Morbidity; D009026:Mortality; D009503:Neutropenia; D012189:Retrospective Studies; D033581:Stem Cell Transplantation", "nlm_unique_id": "8305899", "other_id": null, "pages": "116-20", "pmc": null, "pmid": "26906191", "pubdate": "2016-05", "publication_types": "D016428:Journal Article", "references": null, "title": "Morbidity and mortality attributable to Rothia bacteremia in neutropenic and nonneutropenic patients.", "title_normalized": "morbidity and mortality attributable to rothia bacteremia in neutropenic and nonneutropenic patients" }

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MORBIDITY AND MORTALITY ATTRIBUTABLE TO ROTHIA BACTEREMIA IN NEUTROPENIC AND NONNEUTROPENIC PATIENTS.. DIAGN-MICROBIOL-INFECT-DIS 2016;85(1):116-120.", "literaturereference_normalized": "morbidity and mortality attributable to rothia bacteremia in neutropenic and nonneutropenic patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170301", "receivedate": "20170301", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13284604, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "US-APOTEX-2017AP007449", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MEROPENEM" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MEROPENEM." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CIPROFLOXACIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "076896", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Bacteraemia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Stomatococcal infection", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Multiple organ dysfunction syndrome", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ABIDI MZ, LEDEBOER N, BANERJEE A, HARI P. MORBIDITY AND MORTALITY ATTRIBUTABLE TO ROTHIA BACTEREMIA IN NEUTROPENIC AND NONNEUTROPENIC PATIENTS. DIAGNOSTIC MICROBIOLOGY AND INFECTIOUS DISEASE. 2016;85(1):116-120", "literaturereference_normalized": "morbidity and mortality attributable to rothia bacteremia in neutropenic and nonneutropenic patients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170301", "receivedate": "20170301", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13281554, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "US-TARO PHARMACEUTICALS USA.,INC-2017SUN00058", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": "76912", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." } ], "patientagegroup": null, "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Streptococcus test positive", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Multiple organ dysfunction syndrome", "reactionmeddraversionpt": "19.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "19.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Bacteraemia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Stomatococcal infection", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ABIDI MZ, LEDEBOER N, BANERJEE A, HARI P. MORBIDITY AND MORTALITY ATTRIBUTABLE TO ROTHIA BACTEREMIA IN NEUTROPENIC AND NONNEUTROPENIC PATIENTS. DIAGN MICROBIOL INFECT DIS. 2016;85(1):116-120", "literaturereference_normalized": "morbidity and mortality attributable to rothia bacteremia in neutropenic and nonneutropenic patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170310", "receivedate": "20170310", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13317607, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "US-MYLANLABS-2017M1011250", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FILGRASTIM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FILGRASTIM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLADRIBINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLADRIBINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MITOXANTRONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MITOXANTRONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "075817", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Endocarditis bacterial", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ABIDI MZ, LEDEBOER N, BANERJEE A, HARI P. MORBIDITY AND MORTALITY ATTRIBUTABLE TO ROTHIA BACTEREMIA IN NEUTROPENIC AND NONNEUTROPENIC PATIENTS. DIAGN-MICROBIOL-INFECT-DIS 2016;85(1):116-120.", "literaturereference_normalized": "morbidity and mortality attributable to rothia bacteremia in neutropenic and nonneutropenic patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170228", "receivedate": "20170228", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13278528, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "US-TEVA-745396USA", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLADRIBINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLADRIBINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "77782", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MITOXANTRONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "77356", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MITOXANTRONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FILGRASTIM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FILGRASTIM" } ], "patientagegroup": null, "patientonsetage": "66", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Endocarditis bacterial", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ABIDI MZ, LEDEBOER N, BANERJEE A, HARI P. MORBIDITY AND MORTALITY ATTRIBUTABLE TO ROTHIA BACTEREMIA IN NEUTROPENIC AND NONNEUTROPENIC PATIENTS. DIAGN-MICROBIOL-INFECT-DIS 2016;85(1):116-120.", "literaturereference_normalized": "morbidity and mortality attributable to rothia bacteremia in neutropenic and nonneutropenic patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170308", "receivedate": "20170308", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13305946, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "PHHY2017US025874", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MITOXANTRONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MITOXANTRONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FILGRASTIM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FILGRASTIM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLADRIBINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLADRIBINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "76593", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA RECURRENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": "66", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Bacterial infection", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ABIDI MZ, LEDEBOER N, BANERJEE A, HARI P.. MORBIDITY AND MORTALITY ATTRIBUTABLE TO ROTHIA BACTEREMIA IN NEUTROPENIC AND NONNEUTROPENIC PATIENTS.. DIAGNOSTIC MICROBIOLOGY AND INFECTIOUS DISEASE. 2016;85(1):116-20", "literaturereference_normalized": "morbidity and mortality attributable to rothia bacteremia in neutropenic and nonneutropenic patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170228", "receivedate": "20170228", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13279109, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "US-TEVA-745395USA", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "77782", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." } ], "patientagegroup": null, "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Bacteraemia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Multiple organ dysfunction syndrome", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ABIDI MZ, LEDEBOER N, BANERJEE A, HARI P. MORBIDITY AND MORTALITY ATTRIBUTABLE TO ROTHIA BACTEREMIA IN NEUTROPENIC AND NONNEUTROPENIC PATIENTS. DIAGN-MICROBIOL-INFECT-DIS 2016;85(1):116-120.", "literaturereference_normalized": "morbidity and mortality attributable to rothia bacteremia in neutropenic and nonneutropenic patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170308", "receivedate": "20170308", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13305882, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170428" }, { "companynumb": "US-TARO PHARMACEUTICALS USA.,INC-2017SUN00059", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MITOXANTRONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MITOXANTRONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FILGRASTIM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FILGRASTIM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLADRIBINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLADRIBINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "76912", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." } ], "patientagegroup": null, "patientonsetage": "66", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Endocarditis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bacteraemia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Stomatococcal infection", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ABIDI MZ, LEDEBOER N, BANERJEE A, HARI P. MORBIDITY AND MORTALITY ATTRIBUTABLE TO ROTHIA BACTEREMIA IN NEUTROPENIC AND NONNEUTROPENIC PATIENTS. DIAGN MICROBIOL INFECT DIS. 2016;85(1):116-120", "literaturereference_normalized": "morbidity and mortality attributable to rothia bacteremia in neutropenic and nonneutropenic patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170310", "receivedate": "20170310", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13317882, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "US-APOTEX-2017AP007450", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLADRIBINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLADRIBINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CIPROFLOXACIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "076896", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN HYDROCHLORIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FILGRASTIM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FILGRASTIM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MITOXANTRONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MITOXANTRONE" } ], "patientagegroup": null, "patientonsetage": "66", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Endocarditis bacterial", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Stomatococcal infection", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ABIDI MZ, LEDEBOER N, BANERJEE A, HARI P. MORBIDITY AND MORTALITY ATTRIBUTABLE TO ROTHIA BACTEREMIA IN NEUTROPENIC AND NONNEUTROPENIC PATIENTS. DIAGNOSTIC MICROBIOLOGY AND INFECTIOUS DISEASE. 2016;85(1):116-120", "literaturereference_normalized": "morbidity and mortality attributable to rothia bacteremia in neutropenic and nonneutropenic patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170301", "receivedate": "20170301", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13285322, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "US-DRREDDYS-USA/USA/17/0088160", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "075593", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLADRIBINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLADRIBINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MITOXANTRONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MITOXANTRONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FILGRASTIM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FILGRASTIM" } ], "patientagegroup": null, "patientonsetage": "66", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Endocarditis", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Stomatococcal infection", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ABIDI M, LEDEBOER N, BANERJEE A, HARI P. MORBIDITY AND MORTALITY ATTRIBUTABLE TO ROTHIA BACTEREMIA IN NEUTROPENIC AND NONNEUTROPENIC PATIENTS. DIAGN MICROBIOL INFECT DIS. 2016;85(1):116-20.", "literaturereference_normalized": "morbidity and mortality attributable to rothia bacteremia in neutropenic and nonneutropenic patients", "qualification": "3", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20170402", "receivedate": "20170402", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13394260, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "PHHY2017US025875", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "76593", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BACTERAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MEROPENEM" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BACTERAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MEROPENEM." } ], "patientagegroup": null, "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Bacteraemia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Multiple organ dysfunction syndrome", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ABIDI MZ, LEDEBOER N, BANERJEE A, HARI P.. MORBIDITY AND MORTALITY ATTRIBUTABLE TO ROTHIA BACTEREMIA IN NEUTROPENIC AND NONNEUTROPENIC PATIENTS.. DIAGNOSTIC MICROBIOLOGY AND INFECTIOUS DISEASE. 2016;85(1):116-20", "literaturereference_normalized": "morbidity and mortality attributable to rothia bacteremia in neutropenic and nonneutropenic patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170228", "receivedate": "20170228", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13279111, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170428" }, { "companynumb": "US-MYLANLABS-2017M1011291", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "075817", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Multiple organ dysfunction syndrome", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Bacteraemia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ABIDI MZ, LEDEBOER N, BANERJEE A, HARI P. MORBIDITY AND MORTALITY ATTRIBUTABLE TO ROTHIA BACTEREMIA IN NEUTROPENIC AND NONNEUTROPENIC PATIENTS. DIAGN-MICROBIOL-INFECT-DIS 2016;85(1):116-120.", "literaturereference_normalized": "morbidity and mortality attributable to rothia bacteremia in neutropenic and nonneutropenic patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170227", "receivedate": "20170227", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13274463, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "US-DRREDDYS-USA/USA/17/0088153", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "075593", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." } ], "patientagegroup": null, "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Stomatococcal infection", "reactionmeddraversionpt": "20.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Streptococcus test positive", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenic colitis", "reactionmeddraversionpt": "20.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Multiple organ dysfunction syndrome", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ABIDI M, LEDEBOER N, BANERJEE A, HARI P. MORBIDITY AND MORTALITY ATTRIBUTABLE TO ROTHIA BACTEREMIA IN NEUTROPENIC AND NONNEUTROPENIC PATIENTS. DIAGN MICROBIOL INFECT DIS. 2016;85(1):116-20.", "literaturereference_normalized": "morbidity and mortality attributable to rothia bacteremia in neutropenic and nonneutropenic patients", "qualification": "3", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20170402", "receivedate": "20170402", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13394233, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" } ]

{ "abstract": "BACKGROUND\nDopamine agonists (DA) are the first-line therapy in prolactinomas, but they fail to decrease prolactin (PRL) levels and/or tumor size in some of these tumors, which are labeled as resistant prolactinomas (RP). To date, risk factors for DA resistance are not fully understood and management of DA-RP is not well established.\n\n\nMETHODS\nWe retrospectively recorded clinical, biochemical and radiological features, as well as management and outcome, of all cabergoline (CAB)-RP attended at the Endocrinology department of a tertiary hospital between 1995 and 2016. CAB resistance was defined as the failure to normalize PRL (biochemical resistance, BR) or reduce tumor size by at least 50% (morphological resistance, MR) with a CAB dose up to 2mg/week (or 3mg/week in cases where lower doses were not tested) for at least 3 months.\n\n\nRESULTS\nTen CAB-RP were found. The mean age of the cohort was 30.6 years and 50% of subjects were male. The average tumor size was 1.78cm (80% macroadenomas). The mean maximal dose of CAB was 3.8mg/week. Five patients showed isolated MR, four combined MR+BR and only one isolated BR. MR patients were more often males and older than MR+BR patients. Transsphenoidal surgery achieved normalization of PRL and/or disappearance of tumor in three of seven patients. At the end of follow up all patients had controlled PRL levels (with or without CAB) and most of them bore a visible although stable tumor.\n\n\nCONCLUSIONS\nIsolated MR and combined MR+BR are the most frequent patterns of DA resistance whereas isolated BR seems to be uncommon. Our data support a high tumor size but not male gender as a risk factor for DA resistance.", "affiliations": "Hospital Universitario Ramón y Cajal, Madrid, Spain. Electronic address: martaazul.2a@hotmail.com.;Endocrinology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain.;Endocrinology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain.;Endocrinology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain.;Endocrinology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain.", "authors": "Araujo-Castro|Marta|M|;Abad López|Ainhoa|A|;Aller Pardo|Javier|J|;Kanaan Kanaan|Laura|L|;Palacios García|Nuria|N|", "chemical_list": "D018491:Dopamine Agonists; D000077465:Cabergoline", "country": "Spain", "delete": false, "doi": "10.1016/j.endinu.2019.04.007", "fulltext": null, "fulltext_license": null, "issn_linking": "2530-0180", "issue": "67(3)", "journal": "Endocrinologia, diabetes y nutricion", "keywords": "Cabergolina; Cabergoline; Prolactinoma; Resistance; Resistencia", "medline_ta": "Endocrinol Diabetes Nutr (Engl Ed)", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000077465:Cabergoline; D018491:Dopamine Agonists; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D010911:Pituitary Neoplasms; D015175:Prolactinoma; D012189:Retrospective Studies", "nlm_unique_id": "101717565", "other_id": null, "pages": "194-204", "pmc": null, "pmid": "31201099", "pubdate": "2020-03", "publication_types": "D016428:Journal Article", "references": null, "title": "Phenotype and resistance patterns of 10 resistant prolactinomas.", "title_normalized": "phenotype and resistance patterns of 10 resistant prolactinomas" }

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PHENOTYPE AND RESISTANCE PATTERNS OF 10 RESISTANT PROLACTINOMAS.. ENDOCRINOL-DIABETES-NUTR.. 2020?67 (3):194-204.", "literaturereference_normalized": "phenotype and resistance patterns of 10 resistant prolactinomas", "qualification": "3", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": null, "receiptdate": "20200417", "receivedate": "20200417", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17678132, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200714" }, { "companynumb": "ES-ABBVIE-20K-144-3367499-00", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TESTOSTERONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021015", "drugbatchnumb": "NOT AVAILABLE", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HORMONE REPLACEMENT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TESTOSTERONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CABERGOLINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "NOT AVAILABLE", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROLACTIN-PRODUCING PITUITARY TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CABERGOLINE." } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARAUJO-CASTRO M, LOPEZ A, PARDO J, ET.AL. PHENOTYPE AND RESISTANCE PATTERNS OF 10 RESISTANT PROLACTINOMAS.. ENDOCRINOL-DIABETES-NUTR.. 2020?67 (3):194-204.", "literaturereference_normalized": "phenotype and resistance patterns of 10 resistant prolactinomas", "qualification": "3", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": null, "receiptdate": "20200417", "receivedate": "20200417", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17679345, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200714" } ]

{ "abstract": "When studying treatments for psychiatric or mental diseases in a placebo-controlled trial, we may consider use of the sequential parallel comparison design to reduce the number of patients needed through the reduction of the high placebo response rate. Under the assumption that the odds ratio of responses is constant between phases in the sequential parallel comparison design, we derive the conditional maximum likelihood estimator for the odds ratio. On the basis of the conditional likelihood, we further derive three asymptotic interval and an exact interval estimators for the odds ratio of responses. We employ Monte Carlo simulation to evaluate the performance of these interval estimators in a variety of situations. We find that the asymptotic interval and exact interval estimators developed here can all perform well. We use the double-blind, placebo-controlled study assessing the efficacy of a low dose of aripiprazole adjunctive to antidepressant therapy for treating patients with major depressive disorder to illustrate the use of these estimators.", "affiliations": "Department of Mathematics and Statistics, San Diego State University, San Diego, CA, USA.", "authors": "Lui|Kung-Jong|KJ|0000-0002-5413-2514", "chemical_list": "D000928:Antidepressive Agents; D010919:Placebos; D000068180:Aripiprazole", "country": "England", "delete": false, "doi": "10.1177/0962280218796255", "fulltext": null, "fulltext_license": null, "issn_linking": "0962-2802", "issue": "28(10-11)", "journal": "Statistical methods in medical research", "keywords": "Exact interval estimator; Mantel–Haenszel estimator; conditional likelihood; coverage probability; sequential parallel comparison design", "medline_ta": "Stat Methods Med Res", "mesh_terms": "D000928:Antidepressive Agents; D000068180:Aripiprazole; D003865:Depressive Disorder, Major; D004311:Double-Blind Method; D006801:Humans; D016013:Likelihood Functions; D009010:Monte Carlo Method; D009716:Numerical Analysis, Computer-Assisted; D016017:Odds Ratio; D010919:Placebos; D012107:Research Design; D018570:Risk Assessment; D018401:Sample Size", "nlm_unique_id": "9212457", "other_id": null, "pages": "3074-3085", "pmc": null, "pmid": "30156122", "pubdate": "2019", "publication_types": "D016428:Journal Article", "references": null, "title": "Asymptotic and exact interval estimators of the common odds ratio under the sequential parallel comparison design.", "title_normalized": "asymptotic and exact interval estimators of the common odds ratio under the sequential parallel comparison design" }

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{ "abstract": "Epidermodysplasia verruciformis (EV) is a rare dermatologic condition that is clinically characterized by flat, cutaneous, verrucous papules, pityriasis versicolor-like lesions, and similar lichenoid papules. There are 2 forms of EV: a classic inherited genodermatosis and a secondary acquired form. EV predisposes individuals to infections with certain types of human papillomavirus virus and subsequently increases the risk of cutaneous squamous cell carcinoma. The acquired form occurs in immunosuppressed patients, particularly in patients infected with HIV; however, it has also been described in patients who have undergone stem cell and solid organ transplantation. We report an additional case of renal transplantation and immunosuppressive therapy-associated acquired EV (AEV) in a 78-year-old man with multiple flesh-colored to violaceous, flat-topped papules distributed on the face and trunk clinically mimicking lichen planus. Biopsy was typical for that of EV, demonstrating enlarged keratinocytes with a blue-gray cytoplasm, a thickened granular layer, acanthosis, and hyperkeratosis. Herein, we discuss an unusual presentation of an AEV-mimicking lichen planus with review of the literature.", "affiliations": "Department of Pathology and Laboratory Medicine, Summa Health System- Akron, Akron, OH; and.;Department of Pathology and Laboratory Medicine, Summa Health System- Akron, Akron, OH; and.;Trillium Creek Dermatology and Surgery Center, Medina, OH.", "authors": "Henning|Ania|A|;Weaver|Joshua|J|;Reedy|Matthew|M|", "chemical_list": "D007166:Immunosuppressive Agents; D017255:Acitretin", "country": "United States", "delete": false, "doi": "10.1097/DAD.0000000000001696", "fulltext": null, "fulltext_license": null, "issn_linking": "0193-1091", "issue": "43(1)", "journal": "The American Journal of dermatopathology", "keywords": null, "medline_ta": "Am J Dermatopathol", "mesh_terms": "D017255:Acitretin; D000328:Adult; D000368:Aged; D001706:Biopsy; D003937:Diagnosis, Differential; D004819:Epidermodysplasia Verruciformis; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008010:Lichen Planus; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D055815:Young Adult", "nlm_unique_id": "7911005", "other_id": null, "pages": "71-74", "pmc": null, "pmid": "32568838", "pubdate": "2021-01-01", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Acquired Epidermodysplasia Verruciformis in the Setting of Renal Transplant.", "title_normalized": "acquired epidermodysplasia verruciformis in the setting of renal transplant" }

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Acquired Epidermodysplasia Verruciformis in the Setting of Renal Transplant.. 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Acquired Epidermodysplasia Verruciformis in the Setting of Renal Transplant. [Review].. 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{ "abstract": "Chronic hepatitis B virus (HBV) infection affects >10% of the general population and is the leading cause of liver cirrhosis and cancer in West Africa. Despite current recommendations, HBV is often not tested for in clinical routine in the region. We included all people living with HIV (PLWH) in care between March and July 2019 at Fann University Hospital in Dakar (Senegal) and proposed hepatitis B surface antigen (HBsAg) test to those never tested. All HBsAg-positive underwent HIV and HBV viral load (VL) and liver stiffness measurement. We evaluated, using logistic regression, potential associations between patient characteristics and (a) HBV testing uptake; (b) HIV/HBV co-infection among individual HBsAg tested. We determined the proportion of co-infected who had HBV DNA >20 IU/ml on ART and sequenced HBV polymerase in those with HBV replication.of 1076 PLWH in care, 689 (64.0%) had never had an HBsAg test prior to our HBV testing intervention. Women and individuals >40 years old were less likely to have been previously tested. After HBV testing intervention,107/884 (12.1%) PLWH were HBsAg-positive. Seven of 58 (12.1%) individuals newly diagnosed with HIV/HBV co-infection had a detectable HBV VL, of whom five were HIV-suppressed. Two patients on ART including 3TC and AZT as backbone showed the presence of the triple resistance mutation 180M/204I/80V. In this Senegalese urban HIV clinic, the majority of patients on ART had never been tested for HBV infection. One in ten co-infected individuals had a detectable HBV VL despite HIV suppression, and 8% were not receiving a TDF-containing regimen.", "affiliations": "Department of Infectious Diseases, Bern University Hospital, University of Bern, Bern, Switzerland.;Department of Infectious and Tropical Diseases, Fann University Hospital, Dakar, Senegal.;Department of Infectious and Tropical Diseases, Fann University Hospital, Dakar, Senegal.;Department of Infectious and Tropical Diseases, Fann University Hospital, Dakar, Senegal.;Department of Infectious and Tropical Diseases, Fann University Hospital, Dakar, Senegal.;Department of Infectious and Tropical Diseases, Fann University Hospital, Dakar, Senegal.;Institute of Infectious Diseases, University of Bern, Bern, Switzerland.;Institute of Infectious Diseases, University of Bern, Bern, Switzerland.;Department of Infectious and Tropical Diseases, Fann University Hospital, Dakar, Senegal.;Department of Infectious Diseases, Bern University Hospital, University of Bern, Bern, Switzerland.", "authors": "Ramírez Mena|Adrià|A|https://orcid.org/0000-0002-5724-4124;Tine|Judicaël M|JM|;Fortes|Louise|L|;Ndiaye|Ousseynou|O|;Ka|Daye|D|;Ngom|Ndeye Fatou|NF|;Ramette|Alban|A|;Bittel|Pascal|P|;Seydi|Moussa|M|;Wandeler|Gilles|G|;|||", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1111/jvh.13615", "fulltext": "\n==== Front\nJ Viral Hepat\nJ Viral Hepat\n10.1111/(ISSN)1365-2893\nJVH\nJournal of Viral Hepatitis\n1352-0504\n1365-2893\nJohn Wiley and Sons Inc. Hoboken\n\n34610183\n10.1111/jvh.13615\nJVH13615\nOriginal Article\nOriginal Articles\nHepatitis B screening practices and viral control among persons living with HIV in urban Senegal\nRAMÍREZ MENA et al.\nRamírez Mena Adrià https://orcid.org/0000-0002-5724-4124\n1 2 3 adria.ramirez@posteo.net\n\nTine Judicaël M. 2\nFortes Louise 2\nNdiaye Ousseynou 2\nKa Daye 2\nNgom Ndeye Fatou 2\nRamette Alban 4\nBittel Pascal 4\nSeydi Moussa 2\nWandeler Gilles 1 2 5\nfor SEN‐B\n1 Department of Infectious Diseases Bern University Hospital University of Bern Bern Switzerland\n2 Department of Infectious and Tropical Diseases Fann University Hospital Dakar Senegal\n3 Graduate School for Health Sciences University of Bern Switzerland\n4 Institute of Infectious Diseases University of Bern Bern Switzerland\n5 Institute of Social and Preventive Medicine University of Bern Switzerland\n* Correspondence\nAdrià Ramírez Mena, Graduate School for Health Sciences, University of Bern, Avenue de Milan, 14, 1007, Lausanne, Switzerland.\nEmail: adria.ramirez@posteo.net\n\n05 10 2021\n1 2022\n29 1 10.1111/jvh.v29.1 6068\n03 9 2021\n12 5 2021\n03 9 2021\n© 2021 The Authors. Journal of Viral Hepatitis published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.\n\nAbstract\n\nChronic hepatitis B virus (HBV) infection affects >10% of the general population and is the leading cause of liver cirrhosis and cancer in West Africa. Despite current recommendations, HBV is often not tested for in clinical routine in the region. We included all people living with HIV (PLWH) in care between March and July 2019 at Fann University Hospital in Dakar (Senegal) and proposed hepatitis B surface antigen (HBsAg) test to those never tested. All HBsAg‐positive underwent HIV and HBV viral load (VL) and liver stiffness measurement. We evaluated, using logistic regression, potential associations between patient characteristics and (a) HBV testing uptake; (b) HIV/HBV co‐infection among individual HBsAg tested. We determined the proportion of co‐infected who had HBV DNA >20 IU/ml on ART and sequenced HBV polymerase in those with HBV replication.of 1076 PLWH in care, 689 (64.0%) had never had an HBsAg test prior to our HBV testing intervention. Women and individuals >40 years old were less likely to have been previously tested. After HBV testing intervention,107/884 (12.1%) PLWH were HBsAg‐positive. Seven of 58 (12.1%) individuals newly diagnosed with HIV/HBV co‐infection had a detectable HBV VL, of whom five were HIV‐suppressed. Two patients on ART including 3TC and AZT as backbone showed the presence of the triple resistance mutation 180M/204I/80V. In this Senegalese urban HIV clinic, the majority of patients on ART had never been tested for HBV infection. One in ten co‐infected individuals had a detectable HBV VL despite HIV suppression, and 8% were not receiving a TDF‐containing regimen.\n\nhepatitis B\nHIV\nresistance\nscreening\nsub‐Saharan Africa\ntesting\nSchweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (SNSF)Universitat Bern source-schema-version-number2.0\ncover-dateJanuary 2022\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.1.7 mode:remove_FC converted:18.07.2022\nRamírez Mena A , Tine JM , Fortes L , et al. Hepatitis B screening practices and viral control among persons living with HIV in urban Senegal. J Viral Hepat. 2022;29 :60–68. 10.1111/jvh.13615 34610183\n\nFunding information\n\nThis study was supported by a Swiss National Science Foundation Professorship grant. (PP00P3_176944 to Gilles Wandeler).\n==== Body\npmc1 INTRODUCTION\n\nOver 10% of people living with HIV (PLWH) in West Africa also have chronic hepatitis B virus (HBV) infection, the leading cause of liver cirrhosis and cancer in the region. 1 HIV infection has a profound impact on the natural history of HBV, including the acceleration of the progression to end‐stage liver disease and the increase in liver‐related mortality. 2 , 3 Tenofovir‐containing antiretroviral therapy (ART) leads to HBV viral suppression in more than 80% of HIV/HBV‐co‐infected individuals and reduces the progression of liver fibrosis and the risk of hepatocellular carcinoma (HCC). 4 , 5 , 6 Considering its clinical benefits and high genetic barrier to resistance, tenofovir, either as tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF), should always be included in the ART regimen of HIV/HBV‐co‐infected individuals, provided there is no contraindication.\n\nDespite international recommendations, the uptake of systematic HBV testing among PLWH has been generally poor in sub‐Saharan Africa. 7 This is problematic for several reasons: As tenofovir should be included in the ART regimen in the presence of HBV infection, knowledge of the individual hepatitis B surface antigen (HBsAg) status is key in informing the prescription of optimal ART for each patient, including second‐line and third‐line treatment regimens. 8 HBV testing among PLWH is also required to identify those who will need a comprehensive liver disease assessment, including the measurement of liver fibrosis and HCC surveillance. In addition, the systematic testing for HBsAg allows health care providers to offer proper counselling on measures to reduce HBV transmission and screening of household members. 9\n\nWe aimed to investigate predictors of HBV testing among PLWH in care at a referral HIV outpatient clinic in Senegal and to evaluate their HBV infection status by implementing a simple and systematic HBV testing intervention. We hypothesized that detecting and characterizing HBV infection would allow the improvement of HBV management in this patient population.\n\n2 MATERIALS AND METHODS\n\n2.1 Study setting\n\nWe conducted a cross sectional study at the « Service des Maladies Infectieuses et Tropicales/Centre Régional de Recherche et de Formation à la Prise en Charge clinique de Fann» (SMIT/CRCF), an urban adult HIV treatment centre in Dakar, Sénégal. This clinic has been one of the several referral centres for HIV management in Senegal since 1998. Since the publication of the first ART recommendations in 2002, Senegal has been adapting its recommendations in accordance with WHO protocols. Until 2013, recommended initial ART combined two nucleos(t)ide reverse transcriptase inhibitors (NRTI), generally lamivudine (LAM) and zidovudine (AZT), and one non‐nucleoside reverse transcriptase inhibitor (NNRTI). In 2013 the Senegalese ART guidelines included the use of TDF alongside LAM or emtricitabine (FTC) as part of the preferred first‐line backbones, in line with WHO recommendations. 8 , 10 However, switching patients with virological suppression to a TDF‐based regimen was not a priority. As part of routine clinical care, all PLWH initiating ART undergo clinical and laboratory visits at day 1, 7, 14, 30, followed by quarterly visits. CD4 cell counts are measured every 6 months and HIV‐1 viral load (VL) annually. This study was part of a larger research programme, SEN‐B, which aims at evaluating the determinants of HBV ‘functional cure’ and liver‐related outcomes among HIV/HBV‐co‐infected and HBV mono‐infected individuals in Senegal.\n\n2.2 Study participants and data\n\nAll PLWH in routine clinical care at the SMIT/CRCF as of January 2019 were considered for participation in the study. We used the centralized database from the Programme National de la Lutte contre le SIDA and medical records to identify the past availability of HBsAg test results. Individuals without a recorded HBsAg test result were identified and offered voluntary testing for HBV at the next scheduled follow‐up visit during the study period (March‐July 2019). The following data were retrieved from the clinical chart of all individuals: (a) demographic and clinical characteristics: age, sex, marital status, employment category, date of first positive HIV test, date of ART initiation and date and result of HBV, (b) stage of HIV disease: WHO stage, CD4+ cell counts and HIV‐1 VL, and prior AIDS defining illnesses; (c) treatment history: prior and current ART and reason for treatment changes (eg treatment failure, adverse events).\n\n2.3 Study procedures and laboratory measurements\n\nHBsAg testing was performed using a one‐step lateral flow assay rapid test (NOVATest®). NOVATest® (Atlas Link Biotech–ISO 13485) One‐Step Hepatitis B Virus Surface Antibody (HBsAg) Test Kit is a CE‐marked (CE 2265), rapid immunochromatographic in vitro assay for the detection of HBsAg in human serum samples. In a validation study in Senegal using the Elecsys® HBsAg II test (Cobas e‐411, Roche Diagnostics) as gold standard, the sensitivity of NOVATest® was 89.5% and its specificity 100%. 11 All individuals with a positive HBsAg test result between March and July 2019 were offered additional laboratory and transient elastography measurements, and samples were stored for viral sequencing. We performed HIV‐1 RNA (lower limit of detection 20 cp/ml) and HBV DNA (lower limit of detection 20 IU/ml) viral load quantification using a commercial assay (COBAS®Ampliprep Taqman 96, v2.0, Roche Diagnostics GmbH). HBV sequencing was performed in samples of patients with HBV DNA >20 IU/ml using previously published methodologies. 12 In brief, polymerase was amplified using specific primer sets and PCR products were purified with the QIAquick PCR purification kit (Qiagen). The Sanger‐sequencing reaction was outsourced to a commercial service provider (Microsynth AG). Additional laboratory measurements included aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine and CD4+ cell count. We defined ALT as being elevated if ALT >35 IU for men and >25 IU for women, according to AASLD recommendations. 13 If the HBsAg test was positive, the ART regimen was reviewed and replaced by a TDF‐containing combination if not already prescribed.\n\nWe measured liver fibrosis in all HIV/HBV‐co‐infected individuals using transient elastography (Fibroscan®, Echosens). Liver stiffness measurements (LSM) were performed by a single investigator who received manufacturer‐recommended training. Results were expressed as the median (kPa) and the interquartile range (IQR) of all valid measurements. LSM was considered reliable when it included >10 valid measurements with a success rate >60% and IQR/M ≤ 0.30. 14 Significant liver fibrosis (Metavir stages F2–F4) was defined as LSM > 7.1 kPa and cirrhosis (Metavir stage F4) as LSM > 11 kPa, as per WHO thresholds. 15\n\n2.4 Data analysis\n\nCategorical variables were expressed as percentages with 95% confidence intervals (CI), and continuous variables as median values with IQR. Demographic and clinical characteristics were compared between individuals who had been previously tested and others using the Mann‐Whitney test or Kruskal–Wallis test for continuous variables and Pearson chi–square (χ2) test or Fisher exact test for categorical variables. Logistic regression was used to evaluate potential associations between patient characteristics and (a) HBV testing uptake among all PLWH and (b) HBV infection status among individual who underwent HBsAg testing. Multivariable models were adjusted for age, sex and any other variable with a p‐value < 0.05 in univariable analyses.\n\n2.5 Ethics\n\nThe study was approved by the Senegalese National Health Research Ethics Committee (CNERS) at the Health and Social Action Ministry of Senegal (0061/MSAS/DPRS/CNERS, 576/MSAS/DPRS/CNERS and PSS/BTMB/09611). All SEN‐B participants signed an informed consent.\n\n3 RESULTS\n\n3.1 Chronic hepatitis B virus testing during routine care\n\nOf 1076 PLWH in care for a median of 5.6 years (IQR 2.3–10.6) at the time of the HBV testing intervention, 689 (64.0%) did not have a documented HBsAg test in the past (Figure 1). Among 387 individuals previously tested, 49 (12.4%) were co‐infected with HBV. Demographic and clinical characteristics of PLWH by HBsAg testing status are shown in Table 1 and Table 2. Overall, 158/387 (41.0%) men and 229/689 (33.2%) women had been previously tested. In multivariable analysis, female patients (adjusted odds ratio (aOR: 0.70, 95% CI 0.50–0.98) and those aged >40 years (aOR: 0.55, 95% CI 0.39–0.78) were less likely to have been previously tested for HBV infection, whereas those who initiated ART after 2014 had increased odds of having a known HBV status (aOR: 2.96, 95% CI 2.12–4.15; Table 2 ).\n\nFIGURE 1 Study flow diagram. Abbreviations: HBsAg, hepatitis B virus antigen; HBV, hepatitis B virus; DNA, deoxyribonucleic acid; HIV, human immunodeficiency virus; RNA, ribonucleic acid\n\nTABLE 1 Demographic and clinical characteristics of PLWH, by HBsAg testing status\n\nCharacteristics\tHBsAg screening status\tP\t\nNever tested\n\nn = 689\n\n\tPreviously tested\n\nn = 387\n\n\t\nSex (n[%])\tMale\t227\t[33.0]\t158\t[40.8]\t0.02\t\nFemale\t460\t[68.0]\t229\t[59.2]\t\nUnknown\t2\t[0.3]\t0\t[0]\t\nAge, years\tMedian (IQR)\t47\t[39–55]\t45\t[34–53]\t<0.001\t\nEmployment status (n[%])\tEmployed\t468\t[84.8]\t299\t[77.3]\t<0.001\t\nStudent\t33\t[6.0]\t46\t[11.9]\t\nUnemployed\t50\t[7.3]\t15\t[3.9]\t\nUnknown\t138\t[20.0]\t27\t[7.0]\t\nWHO stage at presentation (n[%])\tI–II\t228\t[33.1]\t152\t[39.3]\t<0.001\t\nIII–IV\t345\t[50.1]\t215\t[55.6]\t\nUnknown\t116\t[16.8]\t20\t[5.1]\t\nPeriod of ART initiation, years (n[%])\t1998–2013\t411\t[59.7]\t132\t[34.1]\t<0.001\t\n2014–2019\t229\t[33.2]\t254\t[65.6]\t\nUnknown\t49\t[7.1]\t1\t[0.3]\t\nCD4 at ART initiation, cel/ul (n[%])\t<200\t287\t[41.7]\t187\t[48.3]\t<0.001\t\n200+\t165\t[24.0]\t129\t[33.3]\t\nUnknown\t237\t[34.4]\t71\t[18.5]\t\nTime on ART, years\tMedian (IQR)\t9,3\t[4.8–12.8]\t4,8\t[2.5–8.5]\t<0.001\t\nART line regimen (n[%])\t1st line\t507\t[73.6]\t334\t[86.3]\t<0.001\t\n2nd/3rd line\t117\t[17.0]\t47\t[12.1]\t\nUnknown\t65\t[9.4]\t6\t[1.6]\t\nAbbreviations: ART, Antiretroviral treatment; HBsAg, Hepatitis B virus surface antigen; IQR, interquartile range; WHO, world health organization.\n\nJohn Wiley & Sons, Ltd\n\nTABLE 2 Factors associated with HBV testing during routine HIV care\n\n\tn/N\tUnivariable analysis\tMultivariable analysis\t\nOR (95% CI)\tp\tOR (95% CI)\tp\t\nSex\tMale\t158/385\t1.00\t0.01\t1.00\t0.02\t\nFemale\t229/689\t0.72 (0.55–0.93)\t\t0.71 (0.54–0.94)\t\nAge group, years\t18–40\t149/339\t1.00\t<0.001\t1.00\t0.01\t\n>40\t237/730\t0.61 (0.47–0.80)\t\t0.69 (0.51–0.92)\t\nWHO stage at presentation (n[%])\tI–II\t152/380\t1.00\t0.62\t\t\t\nIII–IV\t215/560\t0.79 (0.57–1.09)\t\t\t\nCD4 at ART initiation, cells/mm3 (n[%])\t<200\t187/474\t1.00\t0.23\t\t\t\n200+\t129/294\t1.19 (0.89–1.61)\t\t\t\nPeriod of ART initiation, years (n[%])\t1998–2013\t170/632\t1.00\t<0.001\t1.00\t<0.001\t\n2014–2019\t213/387\t3.33 (2.55–4.34)\t\t3.02 (2.27–4.00)\t\nART line regimen\t1st line\t334/841\t1.00\t0.01\t1.00\t0.26\t\n2nd/3rd line\t47/164\t0.61 (0.42–0.88)\t\t0.80 (0.54–1.18)\t\nAbbreviations: ART, antiretroviral treatment; CI, confidence interval; OR, odds ratio; WHO, world health organization.\n\nJohn Wiley & Sons, Ltd\n\n3.2 Prevalence and risk factors of chronic hepatitis B virus infection\n\nOf 689 previously untested patients, 498 (72.3%) underwent an HBsAg test during the HBV testing intervention. Reasons for not testing were the lack of availability of testing kits or reagents in the laboratory at time of the visit, unwillingness to participate in the study or not attending the follow‐up visit, among others. The main demographic and clinical characteristics of individuals who were not tested during our intervention were similar to those of patients who were tested: they were predominantly women (68% vs. 66% among those tested, p = 0.63), aged above 40 years old (69% vs. 72%, p = 0.67) and presenting with less than 200 CD4 cells/µl (45% vs. 40%; p = 0.01). During the HBV testing intervention, 58/498 (11.7%) PLWH had a positive HBsAg test. Thus, the overall prevalence of HBV infection among PLWH in care at our clinic was 12.1% (107 of 884, 95% CI 9.9–14.3). The prevalence of HIV/HBV‐co‐infection was marginally higher among male participants compared to woman (13.6% vs. 11.2%, p = 0.02), whereas estimates were similar across age categories (Table 3). In multivariable analyses no significant associations were found between potential explanatory variables and HBV infection (Table 4).\n\nTABLE 3 Proportion of people living with HIV co–infected with HBV across sub‐groups\n\nCharacteristics\tHIV/HBV\tPrevalence\t\nn/N\t(%; 95% CI)\t\nAll\t107/884\t\t\nSex\t\nMale\t44/323\t\nFemale\t63/559\t\nAge group, years\t\n18–40\t33/281\t\n>40\t74/598\t\nWHO stage at presentation\t\nI–II\t43/304\t\nIII–IV\t49/463\t\nCD4 at ART initiation, cel/ul\t\n<200\t48/386\t\n200+\t30/238\t\nPeriod of ART initiation, years\t\n1998–2013\t53/481\t\n2014–2019\t45/347\t\nART line regimen\t\n1st line\t76/688\t\n2nd/3rd line\t18/130\t\nAbbreviations: ART, antiretroviral treatment; HBV, hepatitis B virus; HIV, human immunodeficiency virus; WHO, World Health Organisation.\n\nJohn Wiley & Sons, Ltd\n\nTABLE 4 Correlates for HIV/HBV co‐infection\n\n\tn/N\tUnivariable analysis\tMultivariable analysis\t\nOR (95% CI)\tp\tOR (95% CI)\tp\t\nSex\tMale\t44/323\t1.00\t0.3\t_\t\t\nFemale\t63/559\t0.81 (0.53–1.22)\t\t_\t\t\nAge group, years\t18–40\t33/281\t1.00\t0.79\t_\t\t\n>40\t74/598\t1.06 (0.61–1.81)\t\t_\t\t\nWHO stage at presentation\tI–II\t43/304\t1.00\t0.14\t_\t\t\nIII–IV\t49/463\t0.60 (0.36–1.01)\t\t_\t\t\nCD4 at ART initiation, cel/ul\t<200\t48/386\t1.00\t0.95\t_\t\t\n200+\t18/153\t0.98 (0.52–1.83)\t\t_\t\t\nPeriod of ART initiation, years\t1998–2013\t53/481\t1.00\t0.39\t_\t\t\n2014–2019\t45/347\t1.20 (0.79–1.84)\t\t_\t\t\nART line regimen initiation\t1st line\t76/688\t1.00\t0.36\t_\t\t\n2nd/3rd line\t18/130\t1.29 (0.74–2.24)\t\t_\t\t\nAbbreviations: ART, antiretroviral treatment; CI, confidence interval; OR, odds ratio; WHO, World Health Organisation.\n\nJohn Wiley & Sons, Ltd\n\n3.3 Biological and virological characterization of HIV/chronic hepatitis B virus ‐co‐infected individuals\n\nAmong 58 individuals who had a newly positive HBsAg test during the HBV testing intervention, 55.2% were women and the median age was 46 years (IQR 39–54). These participants were on ART for a median cumulative time of 7.7 years (IQR 3.0–11.0) and 30% presented to HIV care after 2014, when TDF became available in Senegal. At the time of HBV testing intervention, 54 (93.1%) patients were on a TDF‐containing regimen. Overall, 28/55 (51%) co‐infected individuals (3 individuals had missing creatinine values) had an eGFR (CKD‐EPI formula) below 90 ml/min/1.73m2, including three with values below 60 ml/min. One individual had significant liver fibrosis and one liver cirrhosis, whereas only one participant had an elevated ALT value (Figure 2). Among the 58 HIV/HBV‐co‐infected individuals, 7 (12.1%) had a detectable HBV VL, of whom 5 were HIV‐suppressed (Figure 1, Figure 2). HBV viral suppression was achieved in 40/47 (85.1%) individuals on TDF‐containing ART and in 1/4 (25.0%) without TDF. HBV reverse trancriptase sequencing was successful in 4 of 5 HIV/HBV‐co‐infected individuals with HBV DNA >20 IU/ml, and showed the presence of the triple resistance mutation 180 M/204I/80V in two patients who were treated with lamivudine as the only HBV‐active drug (Table 5). The patients without resistance mutations were both on a TDF‐containing regimen and had never been exposed to lamivudine monotherapy for HBV infection.\n\nFIGURE 2 Liver, renal and virological assessment of HIV/HBV‐co‐infected individuals screened during the study. Abbreviations: ALT, alanine aminotransferase; eGFR, estimated glomerular filtrate rate; CKD‐EPI, chronic kidney disease epidemiology collaboration equation; HBV, hepatitis B virus; DNA, deoxyribonucleic acid; HIV, human immunodeficiency virus; RNA, ribonucleic acid; IU, international units\n\nTABLE 5 HBV genotype and drug‐resistance patterns among HIV/HBV‐co‐infected individuals with HBV DNA viral load > 20 IU/ml during ART\n\nPatient(ID)\tSex\tAge (years)\tCD4 counts (cells/mm3)\tCurrent ART\tTime on ART (years)\tTransient elastography (kPa)\tALT (IU)\tHBV viral load (IU/ml)\tHIV viral load (cop/ml)\tHBV genotype\tResistance mutations\t\nID 1\tM\t42\t_\tTDF 3TC EFV\t5.8\t4.6\t15\t33\t< 20\ta\ta\t\nID 2\tM\t52\t213\tTDF 3TC EFV\t3.0\t4.8\t14\t46\t< 20\ta\ta\t\nID 3\tM\t54\t399\tAZT 3TC LPV/r\t18.5\t5.5\t10\t97\t554\tA1\tL180 M–M204I–L80V\t\nID 4\tF\t36\t336\tTDF 3TC NVP\t7.3\t5.3\t9\t369\t33.800\tA1\tnone\t\nID 5\tF\t45\t785\tAZT 3TC NVP\t12.1\t3.1\t16\t386\t< 20\tE\tL180 M–M204I–L80V\t\nID 6\tM\t54\t444\tTDF 3TC EFV\t10.3\t3.1\t12\t63.600\t< 20\ta\ta\t\nID 7\tM\t60\t321\tTDF 3TC LPV/r\t2.8\t5.8\t8\t> 10.000.000\t< 20\tE\tnone\t\nAbbreviations: 3TC, Lamivudine; ART, Antiretroviral treatment; EFV, Efavirenz; ETV, Entecavir; F, Female; HBV, Hepatitis B; ID, Identification; LdT, Telbivudine; LPV/r, Lopinavir/ritonavir; M, Male; NVP, Nevirapine; TDF, Tenofovir Disoproxil Fumarate. aSample non amplified.\n\nJohn Wiley & Sons, Ltd\n\n4 DISCUSSION\n\nIn this urban HIV clinic in Senegal, approximately two thirds of PLWH had not been tested for the presence of HBV infection during routine clinical care. Although testing rates increased in recent years, they remained sub‐optimal, especially among women and older individuals. During a one‐off HBV diagnostic intervention, we screened 72% of individuals without a previous test and undertook a detailed characterization of HIV/HBV‐co‐infected participants. The overall prevalence of HBV infection was 12.1% in our cohort, and the estimate was similar across all sub‐groups. Of 58 newly diagnosed cases of HBV infection, one‐half had some degree of renal dysfunction, two patients had significant liver fibrosis or cirrhosis, and 12% had detectable HBV DNA levels. Two of four HIV/HBV‐co‐infected individuals who were receiving LAM as the only HBV‐active drug had developed significant drug resistance, which underlines the need for the systematic HBsAg testing of PLWH in sub‐Saharan Africa.\n\nDespite the importance of HBV testing for the clinical management of individuals on ART, our study shows that even in tertiary care settings, HBV testing is not a priority in routine clinical care: only one third of PLWH on ART had been tested prior to our intervention and that proportion was lower in women and patients aged 40 and above. The observed gender disparity in access to HBV testing was consistent with previous findings from Zambia and Cameroun, where men were more likely to be HBsAg screened than women in primary and secondary care HIV clinics. 16 , 17 Given the risk of vertical transmission in women with poorly controlled HBV infection, HBV testing should especially be reinforced in women of childbearing age. 18 PLWH were more likely to be tested for HBV infection if enrolled into care after 2014, when Senegalese national guidelines adopted the WHO recommendations on HBV screening before ART initiation and the use of TDF as one of the recommended first‐line regimens. 8 , 10 As the number of PLWH on second‐line regimens is increasing in the region, it is crucial to identify those co‐infected with HBV to maintain TDF as a part of ART. 10 Lack of knowledge of HBV among health workers 19 , 20 as well as the lack of availability of reagents and limited funding for diagnostic tests by national programmes are some of the obstacles that need to be addressed in order to improve testing uptake in the region. 9\n\nOver 90% of newly diagnosed co‐infected individuals in our study were on a TDF‐based regimen for at least 3 years. These estimates are higher than those from similar studies in Cameroon and the Gambia, where only 60.5% and 11.5% of co‐infected individuals were on TDF, most likely due to differences in the timing of roll‐out of TDF in first‐line ART across the region. 16 , 21 Despite the use of ART including TDF, 9% of co‐infected individuals had an HBV VL >20 IU/ml at the time of assessment, the majority being HIV‐suppressed. Our results are in line with those from a small prospective study in Ivory Coast: among 86 HIV/HBV‐co‐infected patients on TDF‐containing ART, 94.2% had a suppressed HBV VL after a median of 35 months. 22 Whereas it remains unclear why a minority of patients experiences continuous HBV replication on TDF despite HIV suppression, a number of risk factors have been described, including sub‐optimal treatment adherence, severe immunosuppression and HBeAg status at ART initiation. 23 Importantly, only two patients on long‐term TDF‐containing ART had a LSM compatible with significant liver fibrosis or cirrhosis in our study. These findings add to the increasing body of literature from SSA showing that potent HBV treatment is associated with a long‐term reduction in liver fibrosis progression among HIV/HBV‐co‐infected individuals. 5 , 24\n\nOf four individuals newly diagnosed with chronic HBV infection who had never been exposed to TDF, two had HBV replication on a regimen including LAM and AZT. Sequencing of the polymerase showed the presence of LAM‐associated resistance mutations in both patients (one with genotype A1 and the other with genotype E). These findings underline the high likelihood of resistance development during LAM HBV monotherapy, as shown in previous studies in the region. In cohort analyses from Cameroun, Malawi and South Africa, the use of LAM without TDF was linked to the gradual emergence of resistance mutations in the HBV polymerase gene. 25 , 26 , 27 The proportion of individuals with detectable HBV VL on LAM monotherapy who developed resistance reached 88% in an HIV cohort from The Gambia. 20 Given the significant proportion of participants who were on a sub‐optimal ART regimen for HBV therapy and the related virological and clinical consequences, our data highlight the importance of the systematic HBsAg testing of all PLWH entering care and initiating ART.\n\nThe use of TDF has been associated with proximal renal tubulopathy, which is of special concern for HIV/HBV‐co‐infected individuals in SSA, given the lack of treatment alternatives. In one of the largest studies on renal function trajectories in PLWH in SSA to date, individuals on TDF were three times more likely to develop moderate or severe renal dysfunction compared to those on other NRTI, but the incidence of severe renal dysfunction events was low. 28 In our study, more than half of HIV/HBV‐co‐infected individuals showed some degree of renal dysfunction (eGFR < 90 ml/min/1.73m2) while on ART, but only 5% had an eGFR below 60 ml/min/1.73m2. HBV infection has been identified as a predictor of progressive renal impairment in PLWH. 29 In Zambia, PLWH co‐infected with HBV were twice as likely to have severe renal dysfunction as those who were HBV‐negative. 30 As life expectancy among African PLWH is increasing, their risk of developing cardio‐metabolic complications and associated renal dysfunction is higher. 31 Thus, data on long‐term renal outcomes from prospective cohorts of ageing PLWH co‐infected with HBV in SSA are urgently needed to inform future treatment guidelines and the potential benefit of replacing TDF by TAF. 32\n\nOur study is among the first to provide comprehensive HBV virological data from HIV/HBV‐co‐infected individuals in West Africa, and illustrates how a simple diagnostic intervention can help improve the control of HBV infection in a busy urban HIV clinic. Unfortunately, we were unable to include one quarter of individuals without a previous HBsAg test, mainly due to logistical reasons. As the demographic characteristics of individuals not included in the study did not differ significantly from those of our participants, and given the stable prevalence of HBV infection across sub‐populations, we do not anticipate a significant selection bias. Given that our analysis of renal dysfunction relied on a single creatinine measurement, we were not able to differentiate acute from chronic renal injury and may have over‐estimated the true burden of renal impairment in our cohort. Finally, we may have under‐estimated the prevalence of HBV treatment failure with emerging drug resistance as we were not able to sequence the virus of each individual with detectable VL during ART.\n\n5 CONCLUSIONS\n\nIn this urban West African referral HIV clinic, the majority of PLWH on ART never had an HBV test performed during routine care. Among newly diagnosed HBV‐co‐infected individuals, one in ten had a detectable HBV viral load despite HIV suppression, and 8% were not receiving a TDF‐containing regimen. Considering the increased risk of liver‐related complication in individuals with HBV replication and the beneficial impact of TDF on reducing their incidence, HBV testing should be performed routinely during HIV clinical care. The early diagnosis of HBV infection should trigger additional investigations, including the evaluation of liver fibrosis and the initiation of HCC screening among high‐risk patients. As the wider implementation of simple diagnostic interventions, such as HBsAg testing and reflex liver fibrosis evaluation, could help reduce liver‐related complications among PLWH in sub‐Saharan Africa, their feasibility and cost‐effectiveness should be urgently evaluated in large, prospective cohort settings.\n\nCONFLICT OF INTEREST\n\nThe authors have no competing interest to declare.\n\nAUTHOR CONTRIBUTIONS\n\nAR, JT and GW conceptualized and designed the research study. AR, JT, ON contributed to data collection and management. AR analysed the data and wrote the first draft of the manuscript. All authors critically reviewed the manuscript and approved its final version.\n\nACKNOWLEDGEMENTS\n\nWe thank the SEN‐B study staff and patients at the SMIT/CRCF. Special thanks to Aminata Diallo, Khady Ndow, Ndeye Amy and Astou Ndiaye for operational assistance. Open Access Funding provided by Universitat Bern.\n\nDATA AVAILABILITY STATEMENT\n\nThe data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.\n==== Refs\nREFERENCES\n\n1 Leumi S , Bigna JJ , Amougou MA , Ngouo A , Nyaga UF , Noubiap JJ . Global burden of hepatitis B infection in people living with human immunodeficiency virus: a systematic review and meta‐analysis. Clin Infect Dis. 2019;71 (11 ):2799–2806. 10.1093/cid/ciz1170\n2 Nikolopoulos GK , Paraskevis D , et al. Impact of hepatitis B virus infection on the progression of AIDS and mortality in HIV‐infected individuals: a cohort study and meta‐analysis. Clin Infect Dis. 2009;48 (12 ):1763–1771. 10.1086/599110 19435436\n3 Thio CL , Seaberg EC , Skolasky R , et al. HIV‐1, hepatitis B virus, and risk of liver‐related mortality in the Multicenter Cohort Study (MACS). 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Viruses. 2020;12 (6 ):634. 10.3390/v12060634\n28 Mulenga L , Musonda P , Mwango A , et al. Effect of baseline renal function on tenofovir‐containing antiretroviral therapy outcomes in Zambia. Clin Infect Dis. 2014;58 (10 ):1473–1480. 10.1093/cid/ciu117 24585558\n29 Mocroft A , Neuhaus J , Peters L , et al. Hepatitis B and C co‐infection are independent predictors of progressive kidney disease in HIV‐Positive, antiretroviral‐treated adults. PLoS One. 2012;7 (7 ):e40245. 10.1371/journal.pone.0040245 22911697\n30 Mweemba A , Zanolini A , Mulenga L , et al. Chronic hepatitis B virus coinfection is associated with renal impairment among Zambian HIV‐infected adults. Clin Infect Dis. 2014;59 (12 ):1757–1760. 10.1093/cid/ciu734 25228705\n31 Mtisi TJ , Ndhlovu CE , Maponga CC , Morse GD . Tenofovir‐associated kidney disease in Africans: a systematic review. AIDS Res Ther. 2019;16 (1 ):12. 10.1186/s12981-019-0227-1 31171021\n32 Surial B , Béguelin C , Chave J‐P , et al. Brief report: switching From TDF to TAF in HIV/HBV‐coinfected individuals with renal dysfunction‐a prospective cohort study. J Acquir Immune Defic Syndr. 2020;85 (2 ):227–232. 10.1097/QAI.0000000000002429 32925387\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1352-0504", "issue": null, "journal": "Journal of viral hepatitis", "keywords": "HIV; hepatitis B; resistance; screening; sub-Saharan Africa; testing", "medline_ta": "J Viral Hepat", "mesh_terms": null, "nlm_unique_id": "9435672", "other_id": null, "pages": null, "pmc": null, "pmid": "34610183", "pubdate": "2021-10-05", "publication_types": "D016428:Journal Article", "references": null, "title": "Hepatitis B screening practices and viral control among persons living with HIV in urban Senegal.", "title_normalized": "hepatitis b screening practices and viral control among persons living with hiv in urban senegal" }

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Hepatitis B screening practices and viral control among persons living with HIV in urban Senegal. 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Hepatitis B screening practices and viral control among persons living with HIV in urban Senegal. 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Hepatitis B screening practices and viral control among persons living with HIV in urban Senegal. 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Hepatitis B screening practices and viral control among persons living with HIV in urban Senegal. Journal of Viral Hepatitis. 2021;00:1-9", "literaturereference_normalized": "hepatitis b screening practices and viral control among persons living with hiv in urban senegal", "qualification": "3", "reportercountry": "CH" }, "primarysourcecountry": "CH", "receiptdate": "20211021", "receivedate": "20211021", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19984383, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" } ]

{ "abstract": "Primary hepatic angiosarcoma (PHA) is a rare mesenchymal liver tumor, accounting for 0.1-2% of primary liver malignancies. The clinical presentations of PHA are variable, from asymptomatic to liver failure or complicated with tumor rupture. The diagnosis of PHA is difficult due to the lack of specific clinical manifestation and investigation results, which can be confused with other liver tumors resulting in late diagnosis. However, there is currently a paucity of effective therapeutic approaches. We advocate early diagnosis with radiological imaging and histopathology because most of them are diagnosed in late-stage and carry a grave prognosis. Surgical resection remains the mainstay of treatment, which can significantly prolong survival. Chemotherapy, including transarterial chemoembolization, is an option for palliative treatment. Unfortunately, molecular treatment has limited efficacy and liver transplantation is also not recommended due to high rate of recurrence. We present a case series of four patients with biopsy-proven PHA which had distinct presentations and clinical courses.", "affiliations": "Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand.;Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand.", "authors": "Rujeerapaiboon|Natthapat|N|;Wetwittayakhlang|Panu|P|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.1159/000506928", "fulltext": "\n==== Front\nCase Rep Gastroenterol\nCase Rep Gastroenterol\nCRG\nCase Reports in Gastroenterology\n1662-0631 S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com \n\n10.1159/000506928\ncrg-0014-0137\nCase Series\nPrimary Hepatic Angiosarcoma: A Rare Liver Malignancy − Varying Manifestations but Grave Prognosis\nRujeerapaiboon Natthapat Wetwittayakhlang Panu * Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand\n*Panu Wetwittayakhlang, MD, Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, 15 Karnjanavanich Road, Hat Yai, Songkhla 90110 (Thailand), wet.panu@gmail.com, panu.we@psu.ac.th\nJan-Apr 2020 \n8 4 2020 \n8 4 2020 \n14 1 137 149\n9 1 2020 2 3 2020 2020 Copyright © 2020 by S. Karger AG, Basel2020This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Primary hepatic angiosarcoma (PHA) is a rare mesenchymal liver tumor, accounting for 0.1–2% of primary liver malignancies. The clinical presentations of PHA are variable, from asymptomatic to liver failure or complicated with tumor rupture. The diagnosis of PHA is difficult due to the lack of specific clinical manifestation and investigation results, which can be confused with other liver tumors resulting in late diagnosis. However, there is currently a paucity of effective therapeutic approaches. We advocate early diagnosis with radiological imaging and histopathology because most of them are diagnosed in late-stage and carry a grave prognosis. Surgical resection remains the mainstay of treatment, which can significantly prolong survival. Chemotherapy, including transarterial chemoembolization, is an option for palliative treatment. Unfortunately, molecular treatment has limited efficacy and liver transplantation is also not recommended due to high rate of recurrence. We present a case series of four patients with biopsy-proven PHA which had distinct presentations and clinical courses.\n\nKeywords\nPrimary hepatic angiosarcomaHepatic angiosarcomaIntra-tumoral hemorrhage\n==== Body\nIntroduction\nPrimary hepatic angiosarcoma (PHA) is a rare hepatic tumor, originating from endothelial and fibroblastic tissue, primarily made up of vessels and composed of abundant vasculature. It represents only 0.1–2% of all primary liver malignancies [1]. PHA commonly occurs in ages from 60 to 70 years. The clinical presentations are variable, from asymptomatic to liver failure; most patients have nonspecific symptoms at initial presentation that usually mimic other chronic liver diseases and are difficult to distinguish from other liver malignancies, resulting in late diagnosis and delayed treatment. These symptoms include abdominal pain, fatigue, weight loss, jaundice, and anorexia. Physical examination can reveal hepatomegaly, ascites, or jaundice [2]. Few patients present with hemoperitoneum secondary to tumor rupture, which was reported in 17–27% of cases [3, 4]. The differential diagnosis of PHA are hepatocellular carcinoma, cholangiocarcinoma, metastatic carcinoma of liver, and hepatic hemangioma. Furthermore, there is a lack of specific laboratory findings for diagnosis of PHA, include liver function test or tumor markers. Imaging study and pathological features remain the key to aid diagnosis. On computed tomography (CT), the dominant tumors usually show heterogenous enhancement, suggesting central necrosis or hemorrhage and delayed progressive enhancement [5, 6, 7]. Pathologically, PHA is composed of pleomorphic atypical mesenchymal cells with elongated nuclei, and the tumor exhibits its own disorganized anastomotic vascular channels. The areas of necrosis and hemorrhage are commonly reported in histological findings [3], when more specific immunohistochemical markers for PHA including ERG expression, CD34, CD31, and factor VIII can lead to definite diagnosis [8]. Unfortunately, PHA is associated with grave prognosis. Surgical resection remains a curative treatment; however, it is difficult to perform because 80% of patients have advanced stage at diagnosis. Chemotherapy and transcatheter arterial chemoembolization (TACE) are considered a palliative treatment. Liver transplant is not recommended due to a high rate of recurrence and rapid progression of tumor with survival after liver transplant less than 7 months. The majority of patients have medial survival less than 1 year, even after receiving treatment. The common causes of death are liver failure and hemoperitoneum from spontaneous tumor rupture [4, 9, 10].\n\nThere has been a paucity of data and significant challenges regarding the diagnosis, treatment, and prognosis of this tumor. Many physicians remain unaccustomed to the clinical features of PHA. We present the cases of four patients with biopsy-proven PHA, which had distinct presentations and clinical courses.\n\nCase Presentation\nCase 1\nAn 81-year-old man was admitted due to massive upper gastrointestinal hemorrhage for 2 h. He had epigastric pain and early satiety for 3 weeks. His past medical history was unremarkable except for heavy alcohol drinking, 1–2 bottles a day for over 30 years. He denied a history of exposure to thorotrast or vinyl chloride. Physical examination revealed mildly pale, icteric sclerae, hepatomegaly with a liver span of 14 cm, parotid gland enlargement and palmar erythema. Other examinations were unremarkable. Laboratory investigations on admission showed white blood cell (WBC) count 6,210/dL, hemoglobin (Hb) 5.8 g/dL, platelet count 283 × 103/dL, aspartate transaminase (AST) 116 U/L, alanine aminotransferase (ALT) 73 U/L, alkaline phosphatase (ALP) 192 U/L, albumin 2.7 g%, total bilirubin (TB) 5.74 mg%, direct bilirubin (DB) 5.3 mg%, prothrombin time (PT) 16.2 s (control 12.4), and international normalized ratio (INR) 1.23; serum alpha-fetoprotein (AFP) was within normal range.\n\nEsophagogastroduodenoscopy was performed and revealed a 3-cm large ulcer with elevated border and necrotic tissue in the antrum of stomach; no varix was seen. The tissue biopsy was performed to exclude malignant ulcer. Liver ultrasonography revealed a cirrhotic liver and diffused multiple echogenic nodules size 7–9 mm in both lobes with a large echogenic mass 3.3 cm in size with a halo. A further CT scan demonstrated multiple large infiltrative masses with few arterial enhancements, no venous washout, size 1–4 cm in both lobes, osteolytic foci at the thoracic spine level T10 and T11, and small subpleural nodule at the right lower lung. Liver biopsy was performed for definite diagnosis. The specimen consisted of a few pieces of gray tan irregular soft tissue and disclosed the angiosarcoma; immunohistochemical study showed positive staining for CD34 and factor VIII. The specimen of gastric ulcer biopsy also revealed metastasis of angiosarcoma.\n\nHe was treated with a paclitaxel dose of 175 mg/m2. Unfortunately, 5 days after receiving chemotherapy, he developed febrile neutropenia with septic shock. His relatives refused further treatment and invasive procedures, and he died in the following days.\n\nCase 2\nA 55-year-old woman with a medical history of type 2 diabetes mellitus, presented with right upper abdominal pain and significant weight loss for 5 months, and progressive jaundice for 2 months. She denied a history of carcinogen exposure. Physical examination showed hepatomegaly 4 cm below the right costal margin with a liver span of 15 cm. Liver examination described a rubbery to firm consistency, blunt edge, and smooth surface. Other findings were unremarkable except mild icteric sclerae. The complete blood count revealed: WBC 9,820/dL, Hb 12.0 g/dL, and platelet count 98 × 103/dL. The liver function test showed: AST 44 U/L, ALT 20 U/L, ALP 449 U/L, TB 3.81 mg%, DB 2.57 mg%. The serum AFP was 2.16 ng/mL (normal <7 mg/mL).\n\nMultiphase CT scan demonstrated diffused multiple arterial enhancing infiltrating nodules varying in size, scattered throughout the entire liver, with ascites and mesenteric fat reticulation suspicious of carcinomatosis peritonei.\n\nLaparoscopic liver biopsy was performed for diagnosis, and the specimen consisted of a piece of light brown irregular soft tissue. Histopathological findings showed the presence of diffused proliferation of abnormal small vessels with diffused hemorrhage. The abnormal vessels showed enlarged endothelial cells with nuclear atypia. Immunohistochemical study showed positive staining for CD34 and factor VIII in the endothelial cells. Histopathological study was consistent with PHA (Fig. 1).\n\nShe received a total of five cycles of paclitaxel with a 20% dose reduction. The following posttreatment CT scans showed progression of the disease with peritoneal metastasis, and she later decided to stop treatment. She survived for 19 months and 14 months after symptom onset and treatment initiation, respectively.\n\nCase 3\nA 47-year-old woman without past medical history was admitted due to acute right upper abdominal pain for 8 h and syncope prior to admission. She had a history of taking oral contraceptive pills 4–6 months per year, for 7 years. Physical examination revealed vital signs: BP 100/60 mm Hg, pulse rate 115/min. Her body mass index was 33.6 kg/m2. Abdomen examination showed marked tenderness at the right upper quadrant; the liver was palpated 8 cm below the costal margin with a liver span of 20 cm with mild tenderness, no splenomegaly, and no shifting dullness.\n\nLaboratory investigations showed: WBC count 8,200/dL, Hb 7.4 g/dL, and platelet count 592 × 103/dL, AST 34 U/L, ALT 23 U/L, ALP 335 U/L, TB 1.22 mg%, DB 0.73 mg%; coagulogram was in normal limit, AFP was 2.72 ng/mL.\n\nThe emergency CT scan revealed acute rupture of liver tumor by evidence of acute clot and acute hematoma. She was provisionally diagnosed with ruptured hepatic adenoma and underwent emergency hepatic embolization. The angiography finding revealed a large hepatic mass at the anterior aspect of the right hepatic lobe, receiving arterial supply from the anterior branch of the right branch of the hepatic artery. Eventually, embolization was performed to stop bleeding. The scheduled CT scan 2 weeks after embolization showed a larger diameter of hemorrhagic mass from 20.7 to 23.0 cm, lysed perihepatic hematoma, without distance metastasis (Fig. 2).\n\nFour weeks after embolization, she underwent extended right hepatectomy with wedge diaphragm and primary repair. The operation demonstrated a huge liver mass with intratumoral hemorrhage, displaced IVC, and mediastinum. The specimen consisted of a liver tumor size 28 × 20 × 14 cm and weighing 2,300 g. The tumor appeared to be a light-brownish rubbery mass with a massive hemorrhage. The histopathological finding was compatible with angiosarcoma (French system grade III) and free tumor margin. The immunochemical staining was positive for CD34 and factor VIII, consistent with PHA (Fig. 3).\n\nThe follow-up CT scan was performed after surgery, and it showed multiple new nodules about 0.5–2 cm in the left lobe liver, a heterogenous enhancing mass size 3.7 cm in the right subdiaphragmatic space; peritoneal thickening was also noted. Thus, the physicians planned to treat her with chemotherapy, doxorubicin. However, she refused chemotherapy treatment because of her poor clinical condition, and she passed away 4 months later.\n\nCase 4\nA 69-year-old previously heathy woman presented with left upper quadrant pain for 2 months. She described her intermittent colicky abdominal pain, each attack lasting 10 min. She also noticed a weight loss of 3 kg in a week. Physical examination showed palpated liver 4 cm below the right costal margin and 6 cm below the xyphoid; the surface of the liver appeared to be lobulated with firm consistency; no hepatic bruit was heard.\n\nThe laboratory investigation showed: WBC count 5,080/dL, Hb 10.5 g/dL, and platelet count 99 × 103/dL, AST 84 U/L, ALT 33 U/L, ALP 187 U/L, TB 2.47 mg%, DB 1.48 mg%, PT 20 s and INR 1.89. The serum tumor markers included AFP, CEA, and CA 19-9 and were within normal limits. The scheduled CT scan demonstrated numerous masses, and multiple nodules size 1–9 cm across the entire liver, an osteoblastic lesion at L4 vertebrae, multiple small nodules 2–8 mm in size at both lungs with surrounding ground glass, which is typical for hemorrhage (Fig. 4).\n\nFor a definite diagnosis, she underwent real-time sonographic guidance percutaneous tumor biopsy. The specimen consisted of light brown soft tissue. The histopathological finding revealed a malignant vascular tumor, immunochemistry staining positive for CD 34 and factor VIII. These findings are consistent with angiosarcoma.\n\nThe patient had planned to have chemotherapy. Unfortunately, 2 weeks after diagnosis, she was admitted to the hospital due to severe abdominal pain. Investigations revealed a ruptured tumor, evidence of disseminated intravascular coagulopathy, and liver failure. Thus, she denied invasive therapy and passed away 1 week later.\n\nThe clinical manifestation, tumor feature, and treatment outcome of the four patients are summarized in Table 1.\n\nDiscussion\nPHA is a liver tumor originating from endothelial and fibroblastic tissue, accounting for 0.1–2% of all primary liver malignancies [1]. Despite its rarity, PHA remains the most common malignant mesenchymal cell tumor of the liver [2]. PHA generally develops in the sixth to seventh decade of life and is predominantly found in males with a male-to-female ratio of 2–4:1 [11]. According to an epidemiological study from the United States, 25% of PHA were associated with known etiologies. Thorotrast application in angiography was linked to PHA in the past decade with the average latency period from exposure to onset of about 20 years. Vinyl chloride, in plastic fabrication, has also been shown to have an established association with PHA with the hazard ratio approximately 10- to 15-fold. Besides, other agents including arsenic androgen, anabolic steroids, cyclophosphamide, phenelzine, and copper are proposed as possible carcinogens [2, 9]. However, these cases are rare and lack explicit associations.\n\nThe presentations of PHA are variable, ranging from asymptomatic to acute liver failure. Most of the patients have nonspecific symptoms that mimic chronic liver diseases, with late diagnosis as the consequence. These symptoms include abdominal pain, fatigue, weight loss, and anorexia [2]. The reported physical examinations of PHA comprised hepatosplenomegaly, jaundice, ascites, and rarely hepatic bruit due to its vascular nature. Few patients, approximately 9%, present with symptoms secondary to metastasis. Hemoperitoneum is a fetal complication secondary to tumor rupture, which was reported in 17–27% [3, 4].\n\nMoreover, rare presentations of PHA in cases of acute liver failure, high-output heart failure, esophageal varices, hemothorax, and disseminated intravascular coagulopathy from Kasabach-Merritt syndrome have recently been reported [12].\n\nFor investigation, almost all patients (97%) undergo a nonspecific abnormal liver function test. Accretion of ALP is the most common abnormal finding. Hyperbilirubinemia may occur in cases of advanced disease. Cytopenia is common in PHA, with 54% of patients displaying thrombocytopenia. While anemia may reflect spontaneous tumor rupture or microangiopathic hemolytic anemia, there is no specific tumor marker corresponding to PHA [4].\n\nThe lack of specific clinical presentations and laboratory findings emphasizes the diagnostic value of radiological imaging. Conventional ultrasound has reported a limited yield in diagnostic evaluation. The mass typically demonstrated different echogenicity depending on necrosis or hemorrhage nature.\n\nOn imaging, similar findings appear on dynamic CT and magnetic resonance imaging (MRI). The dominant tumor usually showed heterogenous enhancement suggesting central necrosis, hemorrhage, and fibrotic change. Delayed progressive enhancement but incomplete venous and delayed phase of enhancing lesions is observed without a centripetal filling pattern. In comparison to hemangioma, the enhancing pattern of PHA is a peripheral rim with central septal-like or linear progression, while a hemangioma-enhancing pattern is centripetal nodular enhancement [5, 6, 7].\n\nOn T1-weighted MRI, the irregular high signal intensity of the dominant mass suggests the presence of hemorrhage. On T2-weighted images, there is increased signal intensity and a septum-like or rounded area of low intensity. The hyperintense signal indicates the area of hemorrhage or necrosis, while the hypointense signal represents hemosiderin deposition and fibrous solid portion. On dynamic contrast-enhanced MRI, the enhancement pattern shows the progressive enhancement of lesion as a dynamic CT scan [5, 6, 7].\n\nLastly, relevant angiographic findings comprise numerous mass lesions with fluffy staining and early pooling of contrast media that progressively increase over time. The most prevalent feature of the angiogram is intense peripheral stain late in the arterial phase.\n\nThe diagnosis of PHA remains problematic owing to lack of obvious clinical and investigation features, which are typically analogous with other vascular tumors. A definite diagnosis requires histopathology via liver biopsy. Many reports recommend open liver biopsy because of better visualization and easier hemostasis, whereas percutaneous biopsy, a simpler method, is a safer and faster procedure without significant complications [13]. Post-biopsy hemorrhage is the primary concern in PHA because of its vascularity. Bleeding occurrence was reported in 9%, which can be managed by blood transfusion and hepatic arterial angioembolization.\n\nPathologically, PHA consists of four characteristics; multiple nodules, large dominant mass, mixed mass with nodule, and diffusely infiltrating micronodular tumor. The tumor has a pale white-yellow-gray color, a spongy appearance, and an ill-defined margin [3].\n\nPHA is composed of pleomorphic atypical mesenchymal cells, polyhedral, and sometimes spindle-shaped [8]. Neoplastic cells contain prominent chromatin, atypical hyperchromic, and elongated nuclei with frequent mitoses. This tumor exhibits its own disorganized anastomosis vascular channels, ranging from dilated sinusoid or cavernous spaces to slit-like freely anastomosing vessels, formed by spindle-shaped cells [3]. Areas of necrosis, hemorrhage, and calcification are reported in 80% of specimens.\n\nThere are no specific immunochemistry markers. A recent report stated that the most sensitive and specific marker is ERG expression, with a 100% sensitivity, followed by CD34 (87.5%), CD31 (87.2%), and factor VIII (41.7%), respectively [8].\n\nFor the treatment of PHA, there is a paucity of effective therapeutic approaches. Surgical resection remains a promising treatment for PHA. Radiosurgery with R0 resection is the sole curative treatment. Adjuvant chemotherapy provides further survival benefit with reported median survival up to 17 months [10]. Liver transplantation is contraindicated in PHA owing to high recurrence and poor prognosis regardless of liver transplantation.\n\nChemotherapy is considered a palliative treatment in patients who are not surgical candidates. Many chemotherapy regimens have been demonstrated in various reports, none of which appear to be superior. Salvage chemotherapy with 5-fluorouracil/carboplatin/doxorubicin/ifosfamide improves survival in 50% of patients, based on its antiangiogenic properties. The limited efficacy of molecular treatment including bevacizumab, sorafenib, and sunitinib cannot be recommended. TACE is effective in patients with a dominant mass. Reports have shown that TACE with either lipiodol/cisplatin or lipiodol/mitomycin/Adriamycin is beneficial in 50% of patients [14, 15]. Radiotherapy is not a treatment option for PHA due to the intrinsic radio-resistant property of tumor cells.\n\nPHA carries a grave prognosis. Postdiagnosis median survival without treatment is approximately 1–6 months, with 3% surviving longer than 2 years [4, 9, 10]. For patients who underwent surgical resection either with or without adjuvant chemotherapy, the median survival is approximately 17 months [10]. Curative surgery is difficult to perform in more than 80% of cases because of the advanced stage at diagnosis [4]. The most common cause of death is liver failure, accounting for 50% of cases, followed by hemoperitoneum from spontaneous tumor rupture (25%). Other causes of death are metastasis disease, infection, renal failure, and heart failure (3%) [4, 10]. Distant metastasis makes up more than 60% of cases, which are diagnosed post-mortem. The most common site of metastasis is the lungs, spleen, and bone, respectively. Complications are reported for 17–27% of individuals [4].\n\nIn conclusion, PHA is a rare, hepatic, and malignant tumor, which physicians may not recognize as it mimics other liver tumors resulting in late diagnosis. Clinical presentations are variable from mild to severe symptoms, and fetal complications may be present. Spontaneous tumor rupture or liver failure may commonly occur. Diagnosis of the disease in the early stage with CT or MRI and histopathology provides survival benefit. However, prognosis is still poor despite chemotherapy treatment.\n\nStatement of Ethics\nInformed consent was obtained for this case series report. The names of the subjects are not mentioned in this case series, and no identifying image has been included for these cases.\n\nDisclosure Statement\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\nThere are no funding sources to report.\n\nAuthor Contributions\nN. Rujeerapaiboon wrote the manuscript, and P. Wetwittayakhlang wrote and supervised the writing of the manuscript and provided the clinical information of all cases. Both authors read and approved the final manuscript.\n\nAcknowledgements\nThe authors acknowledge Dr. Poowadon Wetwittayakhlung for providing histological pictures for these cases.\n\nFig. 1 Histopathological examination of tumor tissue in case 2. a Histopathological study (hematoxylin-eosin stain, ×40) showed the tumor cells (T) grow along sinusoids adjacent to hepatic cords (L). b The tumor cells appearabundant, poorly defined cell borders, pleomorphic with hyperchromatic nuclei. The abnormal vessels also showed enlarged endothelial cells with nuclear atypia (×400). The Immunohistochemical study showed positive staining for CD 34 (c) and factor VIII (d).\n\nFig. 2 Multiphase CT scan of liver in case 3 demonstrates a large hemorrhagic hepatic mass 15 × 20 × 23 cm in size with an enhanced solid part at the anterosuperior part on plain phase.\n\nFig. 3 Histopathological finding of primary hepatic angiosarcoma in case 3. a Histological examination of tumor tissue (hematoxylin-eosin stain, ×40) showed an area of the tumor tissue (T) infiltrated in the liver tissue (L). b The tumor cells present diffuse proliferation of abnormal small vessels and enlargement of endothelial cells with nuclear atypia (×400). The immunohistochemical study of the same tissue showed positive staining for CD 34 (c) and factor VIII marker (d), which indicated hepatic angiosarcoma.\n\nFig. 4 Multiphase CT scan of the liver in case 4 illustrates multiple scattered hypervascular infiltrative masses and nodules, about 1–9 cm in size in an almost entire enlarged liver. The masses have progressive enhancement on portal venous phase, and most of them have surrounding ground-glass opacity which is a typical finding for hemorrhage in angiosarcoma.\n\nTable 1 Summary of clinical features, tumor characteristics, treatments, and survival outcomes in the four cases\n\nCase\tAge, years\tSex\tClinical manifestations\tTumor characteristics\tExtrahepatic metastasis\tTumor rupture\tTreatment\tSurvival time from symptom onset\t\n1\t81\tM\tmassive upper GI bleeding, abdominal pain, jaundice\tmultiple infiltrative mass\tspine, pleura, stomach\tno\tpaclitaxel 20% dose reduction\t1.5 months\t\n2\t55\tF\tabdominal pain, jaundice, weight loss\tmultiple scattered nodules\tperitoneal\tno\tpaclitaxel 20% dose reduction\t19 months\t\n3\t47\tF\tintraperitoneal hemorrhage\tsingle dominant mass with hemorrhage\tnone\tyes\tsurgical resection\t6 months\t\n4\t69\tF\tabdominal pain, weight loss, hepatomegaly\tdiffuse multiple mass with hemorrhage\tspine, lungs\tyes\tbest supportive care\t2 months\n==== Refs\nReferences\n1 Mani H Van Thiel DH Mesenchymal tumors of the liver [viii.] Clin Liver Dis 2001 2 5 (1) 219 57 11218917 \n2 Zhu YP Chen YM Matro E Chen RB Jiang ZN Mou YP Primary hepatic angiosarcoma: A report of two cases and literature review World J Gastroenterol 2015 5 21 (19) 6088 96 26019478 \n3 Chaudhary P Bhadana U Singh RA Ahuja A Primary hepatic angiosarcoma Eur J Surg Oncol 2015 9 41 (9) 1137 43 26008857 \n4 Locker GY Doroshow JH Zwelling LA Chabner BA The clinical features of hepatic angiosarcoma: a report of four cases and a review of the English literature Medicine (Baltimore) 1979 1 58 (1) 48 64 368508 \n5 Koyama T Fletcher JG Johnson CD Kuo MS Notohara K Burgart LJ Primary hepatic angiosarcoma: findings at CT and MR imaging Radiology 2002 3 222 (3) 667 73 11867783 \n6 Pickhardt PJ Kitchin D Lubner MG Ganeshan DM Bhalla S Covey AM Primary hepatic angiosarcoma: multi-institutional comprehensive cancer centre review of multiphasic CT and MR imaging in 35 patients Eur Radiol 2015 2 25 (2) 315 22 25278246 \n7 Thapar S Rastogi A Ahuja A Sarin S Angiosarcoma of the liver: imaging of a rare salient entity J Radiol Case Rep 2014 8 8 (8) 24 32 25426242 \n8 Wang ZB Yuan J Chen W Wei LX Transcription factor ERG is a specific and sensitive diagnostic marker for hepatic angiosarcoma World J Gastroenterol 2014 4 20 (13) 3672 9 24707153 \n9 Timaran CH Grandas OH Bell JL Hepatic angiosarcoma: long-term survival after complete surgical removal Am Surg 2000 12 66 (12) 1153 7 11149588 \n10 Zheng YW Zhang XW Zhang JL Hui ZZ Du WJ Li RM Primary hepatic angiosarcoma and potential treatment options J Gastroenterol Hepatol 2014 5 29 (5) 906 11 24372769 \n11 Huang NC Wann SR Chang HT Lin SL Wang JS Guo HR Arsenic, vinyl chloride, viral hepatitis, and hepatic angiosarcoma: a hospital-based study and review of literature in Taiwan BMC Gastroenterol 2011 12 11 (1) 142 22200164 \n12 Massarweh S Munis A Karabakhtsian R Romond E Moss J Metastatic angiosarcoma and kasabach-merritt syndrome Rare Tumors 2014 6 6 (2) 5366 25002952 \n13 Kang TW Lee MW Choi D An C Kim MJ Joo I Safety of Percutaneous Biopsy for Hepatic Angiosarcoma: Results of a Multicenter Korean Survey J Vasc Interv Radiol 2016 6 27 (6) 846 51 27080009 \n14 Ozden I Bilge O Erkan M Cevikbaş U Acarli K Five years and 4 months of recurrence-free survival in hepatic angiosarcoma J Hepatobiliary Pancreat Surg 2003 10 (3) 250 2 14605984 \n15 Park YS Kim JH Kim KW Lee IS Yoon HK Ko GY Primary hepatic angiosarcoma: imaging findings and palliative treatment with transcatheter arterial chemoembolization or embolization Clin Radiol 2009 8 64 (8) 779 85 19589416\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1662-0631", "issue": "14(1)", "journal": "Case reports in gastroenterology", "keywords": "Hepatic angiosarcoma; Intra-tumoral hemorrhage; Primary hepatic angiosarcoma", "medline_ta": "Case Rep Gastroenterol", "mesh_terms": null, "nlm_unique_id": "101474819", "other_id": null, "pages": "137-149", "pmc": null, "pmid": "32355483", "pubdate": "2020", "publication_types": "D002363:Case Reports", "references": "19589416;11867783;368508;25278246;26008857;14605984;26019478;25426242;22200164;24707153;27080009;24372769;25002952;11218917;11149588", "title": "Primary Hepatic Angiosarcoma: A Rare Liver Malignancy - Varying Manifestations but Grave Prognosis.", "title_normalized": "primary hepatic angiosarcoma a rare liver malignancy varying manifestations but grave prognosis" }

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PRIMARY HEPATIC ANGIOSARCOMA: A RARE LIVER MALIGNANCY - VARYING MANIFESTATIONS BUT GRAVE PROGNOSIS. CASE REPORTS IN GASTROENTEROLOGY. 2020?14 (1):137-149", "literaturereference_normalized": "primary hepatic angiosarcoma a rare liver malignancy varying manifestations but grave prognosis", "qualification": "1", "reportercountry": "TH" }, "primarysourcecountry": "TH", "receiptdate": "20200611", "receivedate": "20200605", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17868059, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200714" }, { "companynumb": "TH-ACCORD-185093", "fulfillexpeditecriteria": "1", "occurcountry": "TH", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "205720", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": "175", "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANGIOSARCOMA METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "175", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL/PACLITAXEL LIPOSOME" } ], "patientagegroup": null, "patientonsetage": "81", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Febrile neutropenia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Septic shock", "reactionmeddraversionpt": "23.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "RUJEERAPAIBOON N, WETWITTAYAKHLANG P. PRIMARY HEPATIC ANGIOSARCOMA: A RARE LIVER MALIGNANCY-VARYING MANIFESTATIONS BUT GRAVE PROGNOSIS. CASE REPORTS IN GASTROENTEROLOGY. 2020?14(1):137-149. DOI: 10.1159/000506928.", "literaturereference_normalized": "primary hepatic angiosarcoma a rare liver malignancy varying manifestations but grave prognosis", "qualification": "1", "reportercountry": "TH" }, "primarysourcecountry": "TH", "receiptdate": "20200612", "receivedate": "20200612", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17889910, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200714" } ]

{ "abstract": "Pentostatin was used to treat 26 patients with advanced B-cell chronic lymphocytic leukemia resistant to conventional treatment. Twenty patients had progressive disease on previous regimens and six had had partial remission and then relapsed 3-34 months after previous chemotherapy. Eleven patients had previously been treated with three different regimens. 10 had been treated with two regimens, and five had been treated with one regimen. Pentostatin was administered at a dosage of 4 mg/m2 weekly for 3 weeks, then 4 mg/m2 every other week for 6 weeks and once a month for 6 months. Seven of 26 assessable patients (27%) achieved partial remission and five (19%) achieved clinical improvement. The median duration of partial remission until relapse or death was 210 days. Myelosuppression was minor and transient in responsive patients, indicating some degree of selective effect on lymphocytes. Except for one patient who died of cerebral hemorrhage during the first 6 weeks of treatment, no drug-related deaths were registered. Major toxic effects included nausea in 17 patients (mainly grade 1), infections in 15, and liver enzyme elevations in five. Thus, pentostatin is active, even in patients with advanced B-cell chronic lymphocytic leukemia that is refractory to multiple chemotherapy regimens. Response can be achieved with mild myelosuppression.", "affiliations": "Department of Internal Medicine V, University of Heidelberg, Federal Republic of Germany.", "authors": "Ho|A D|AD|;Thaler|J|J|;Stryckmans|P|P|;Coiffier|B|B|;Luciani|M|M|;Sonneveld|P|P|;Lechner|K|K|;Rodenhuis|S|S|;Peetermans|M E|ME|;deCataldo|F|F|", "chemical_list": "D015649:Pentostatin", "country": "United States", "delete": false, "doi": "10.1093/jnci/82.17.1416", "fulltext": null, "fulltext_license": null, "issn_linking": "0027-8874", "issue": "82(17)", "journal": "Journal of the National Cancer Institute", "keywords": null, "medline_ta": "J Natl Cancer Inst", "mesh_terms": "D000328:Adult; D000368:Aged; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D008875:Middle Aged; D015649:Pentostatin", "nlm_unique_id": "7503089", "other_id": null, "pages": "1416-20", "pmc": null, "pmid": "2388293", "pubdate": "1990-09-05", "publication_types": "D016428:Journal Article", "references": null, "title": "Pentostatin in refractory chronic lymphocytic leukemia: a phase II trial of the European Organization for Research and Treatment of Cancer.", "title_normalized": "pentostatin in refractory chronic lymphocytic leukemia a phase ii trial of the european organization for research and treatment of cancer" }

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JOURNAL OF THE NATIONAL CANCER INSTITUTE. 1990?82 (17):1416-1420", "literaturereference_normalized": "pentostatin in refractory chronic lymphocytic leukemia a phase ii trial of the european organization for research and treatment of cancer", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20200303", "receivedate": "20200303", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17493092, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "DE-PFIZER INC-2020076180", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PENTOSTATIN" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "020122", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 MG/M2, WEEKLY FOR 3 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PENTOSTATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PENTOSTATIN" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "020122", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 MG/M2, EVERY OTHER WEEK FOR 6 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PENTOSTATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PENTOSTATIN" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "020122", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 MG/M2, MONTHLY FOR 6 MONTHS", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "802", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PENTOSTATIN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Cerebral haemorrhage", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "HO, A.. PENTOSTATIN IN REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA: A PHASE II TRIAL OF THE EUROPEAN ORGANIZATION FOR RESEARCH AND TREATMENT OF CANCER. JOURNAL OF THE NATIONAL CANCER INSTITUTE. 1990?82 (17):1416-1420", "literaturereference_normalized": "pentostatin in refractory chronic lymphocytic leukemia a phase ii trial of the european organization for research and treatment of cancer", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20200303", "receivedate": "20200227", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17468113, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" } ]

{ "abstract": "Pneumonia is a well-recognized respiratory infection associated with substantial morbidity and mortality. Despite its effects on the respiratory system, pneumonia can cause or exacerbate cardiovascular complications through various mechanisms. The two main mechanisms that are described in this case report are hypoxia-induced pulmonary hypertension and the effect of sepsis on the cardiovascular system. Pulmonary hypertension (PH) is a disease characterized by raised pulmonary arterial pressure due to a progressive increase in pulmonary vascular resistance, inevitably leading to right ventricular (RV) afterload. For our case, the situation was complicated by sepsis, which further worsened the myocardial function causing left ventricular hypertrophy and left ventricular dysfunction. The main goal of this case report is to highlight the fact that cardiovascular events due to pneumonia are a potential complication even in young patients who are without any comorbidities. We present a case of a 14-year-old patient who presented with symptoms of cough, hemoptysis, fever, chest pain, and dyspnea. After the necessary investigations, he was diagnosed with severe pneumonia, sepsis, moderate PH, and left ventricular dysfunction. The treatment course was focused on stabilizing the patient by oxygen supplementation, treating the underlying cause with the use of antibiotics, and decreasing the already raised arterial pressures through vasodilator therapy. After the patient went through the proper course of treatment, there was a marked improvement in his general condition.Cardiac complications due to pneumonia are potential complications even in relatively young patients who have no noted comorbidities. Clinicians should be aware of these potentially fatal complications of pneumonia and appreciate the significance of this association for timely recognition, diagnosis, and management of these complications.", "affiliations": "Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, China.;Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, China.;Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, China.;Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang, China.;Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, China. shenht@sj-hospital.org.", "authors": "Gitonga|Elaine N|EN|;Wang|Junwu|J|;Yu|Shengwei|S|;Wu|Na|N|;Shen|Haitao|H|", "chemical_list": null, "country": "China", "delete": false, "doi": "10.21037/apm-20-1198", "fulltext": null, "fulltext_license": null, "issn_linking": "2224-5820", "issue": "9(5)", "journal": "Annals of palliative medicine", "keywords": "Pulmonary hypertension (PH); left ventricular dysfunction; sepsis; sepsis-induced cardiomyopathy; severe pneumonia", "medline_ta": "Ann Palliat Med", "mesh_terms": "D000293:Adolescent; D006801:Humans; D006976:Hypertension, Pulmonary; D008171:Lung Diseases; D008297:Male; D011014:Pneumonia; D018805:Sepsis; D018487:Ventricular Dysfunction, Left", "nlm_unique_id": "101585484", "other_id": null, "pages": "3629-3642", "pmc": null, "pmid": "33065802", "pubdate": "2020-09", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Left ventricular dysfunction and reversible pulmonary hypertension secondary to severe pneumonia in a background of sepsis: a case report and review of the literature.", "title_normalized": "left ventricular dysfunction and reversible pulmonary hypertension secondary to severe pneumonia in a background of sepsis a case report and review of the literature" }

[ { "companynumb": "CN-CHEPLA-C20212673", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CEFACLOR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFACLOR." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "GANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GANCICLOVIR." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BRUFEN" } ], "patientagegroup": null, "patientonsetage": "14", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Confusional state", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary hypertension", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "General physical health deterioration", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Orthopnoea", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GITONGA EN, WANG J, YU S, WU N, SHEN H. LEFT VENTRICULAR DYSFUNCTION AND REVERSIBLE PULMONARY HYPERTENSION SECONDARY TO SEVERE PNEUMONIA IN A BACKGROUND OF SEPSIS: A CASE REPORT AND REVIEW OF THE LITERATURE. ANNALS OF PALLIATIVE MEDICINE. 2020?9 (5):3629?3642. DOI:HTTP://DX.DOI.ORG/10.21037/APM?20?1198", "literaturereference_normalized": "left ventricular dysfunction and reversible pulmonary hypertension secondary to severe pneumonia in a background of sepsis a case report and review of the literature", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20210602", "receivedate": "20210602", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19357265, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]

{ "abstract": "It has been proposed that it is not necessary to adjust the dose of linezolid (LZD) in patients with reduced renal function. However, significantly lower platelet counts and hemoglobin levels have been reported in such patients compared to those in patients with normal renal function. This suggests that the appropriate dose and administration method for LZD are yet to be established in patients with renal dysfunction. The subjects in this study were patients with renal dysfunction who developed adverse effects of thrombocytopenia and anemia during treatment with LZD. We investigated the association of these adverse effects with the blood LZD concentration and the area under the concentration-time curve from zero to 24 h (AUC(0-24)), determined using a one-compartment Bayesian model (n = 20). The measured blood LZD concentration was significantly higher than the predicted concentration in a population pharmacokinetics approach (p < 0.01), and severe thrombocytopenia developed as the blood LZD concentration increased. The platelet count and hemoglobin level decreased as the AUC(0-24) of LZD increased in patients with renal dysfunction, and the correlations were significant: r = 0.593 and r = 0.783, respectively (p < 0.01). These findings suggest that LZD administered to patients with renal dysfunction may reach a high blood level and subsequently increase the AUC(0-24), which may then induce adverse effects of severe thrombocytopenia and anemia.", "affiliations": "Department of Pharmacy, Sasebo Chuo Hospital, Sasebo, Nagasaki, Japan. yas_tsuji@hakujyujikai.or.jp", "authors": "Tsuji|Yasuhiro|Y|;Hiraki|Yoichi|Y|;Matsumoto|Kana|K|;Mizoguchi|Akiko|A|;Kobayashi|Tsutomu|T|;Sadoh|Shinichi|S|;Morita|Kunihiko|K|;Kamimura|Hidetoshi|H|;Karube|Yoshiharu|Y|", "chemical_list": "D000081:Acetamides; D000890:Anti-Infective Agents; D006454:Hemoglobins; D023303:Oxazolidinones; D000069349:Linezolid", "country": "Netherlands", "delete": false, "doi": "10.1007/s10156-010-0080-6", "fulltext": null, "fulltext_license": null, "issn_linking": "1341-321X", "issue": "17(1)", "journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy", "keywords": null, "medline_ta": "J Infect Chemother", "mesh_terms": "D000081:Acetamides; D000368:Aged; D000740:Anemia; D000890:Anti-Infective Agents; D019540:Area Under Curve; D001499:Bayes Theorem; D004305:Dose-Response Relationship, Drug; D005260:Female; D006454:Hemoglobins; D006801:Humans; D000069349:Linezolid; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D008875:Middle Aged; D023303:Oxazolidinones; D012044:Regression Analysis; D051437:Renal Insufficiency; D013203:Staphylococcal Infections; D013921:Thrombocytopenia", "nlm_unique_id": "9608375", "other_id": null, "pages": "70-5", "pmc": null, "pmid": "20582446", "pubdate": "2011-02", "publication_types": "D016428:Journal Article", "references": null, "title": "Thrombocytopenia and anemia caused by a persistent high linezolid concentration in patients with renal dysfunction.", "title_normalized": "thrombocytopenia and anemia caused by a persistent high linezolid concentration in patients with renal dysfunction" }

[ { "companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2018-06687", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LINEZOLID" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "205517", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MG, EVERY 12 HOURS", "drugenddate": null, "drugenddateformat": null, "drugindication": "STAPHYLOCOCCAL INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LINEZOLID." } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug level increased", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatic function abnormal", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "TSUJI Y, HIRAKI Y, MATSUMOTO K, MIZOGUCHI A, ET AL.. THROMBOCYTOPENIA AND ANEMIA CAUSED BY A PERSISTENT HIGH LINEZOLID CONCENTRATION IN PATIENTS WITH RENAL DYSFUNCTION. J INFECT CHEMOTHER. 2011?17:70?75", "literaturereference_normalized": "thrombocytopenia and anemia caused by a persistent high linezolid concentration in patients with renal dysfunction", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180822", "receivedate": "20180822", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15306094, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" } ]

{ "abstract": "We present a case of hypertensive urgency in a diabetic patient with painful diabetic neuropathy on duloxetine treatment. The patient's blood pressure was high after taking 1-day dose of duloxetine and the patient was diagnosed with hypertensive urgency. The patient was managed with labetalol, leading to reduction in blood pressure. The patient's medication was switched to telmisartan and metoprolol, which leads to resolution of increased blood pressure. This case report is a possible case of hypertensive urgency after the initiation of duloxetine managed with antihypertensives and resolves with the discontinuation of the duloxetine.", "affiliations": "Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India.;Department of Pharmacology, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India.;Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India.;Department of Pharmacology, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India.", "authors": "Shukla|Ravindra|R|;Khasbage|Sameer|S|;Garg|Mahendra Kumar|MK|;Singh|Surjit|S|", "chemical_list": "D000700:Analgesics; D000959:Antihypertensive Agents; D000068736:Duloxetine Hydrochloride", "country": "India", "delete": false, "doi": "10.4103/ijp.IJP_370_19", "fulltext": "\n==== Front\nIndian J Pharmacol\nIndian J Pharmacol\nIJPharm\nIndian Journal of Pharmacology\n0253-7613 1998-3751 Wolters Kluwer - Medknow India \n\nIJPharm-52-213\n10.4103/ijp.IJP_370_19\nDrug Watch\nDuloxetine-induced hypertensive urgency in type 2 diabetes mellitus with diabetic neuropathy\nShukla Ravindra Khasbage Sameer 1 Garg Mahendra Kumar Singh Surjit 1 Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India\n1 Department of Pharmacology, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India\nAddress for correspondence: Dr. Surjit Singh, Department of Pharmacology, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India. E-mail: sehmby_ss@yahoo.com\nMay-Jun 2020 \n04 8 2020 \n52 3 213 215\n18 6 2019 05 8 2019 13 7 2020 Copyright: © 2020 Indian Journal of Pharmacology2020This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.We present a case of hypertensive urgency in a diabetic patient with painful diabetic neuropathy on duloxetine treatment. The patient's blood pressure was high after taking 1-day dose of duloxetine and the patient was diagnosed with hypertensive urgency. The patient was managed with labetalol, leading to reduction in blood pressure. The patient's medication was switched to telmisartan and metoprolol, which leads to resolution of increased blood pressure. This case report is a possible case of hypertensive urgency after the initiation of duloxetine managed with antihypertensives and resolves with the discontinuation of the duloxetine.\n\nDuloxetinehypertensive urgencypainful diabetic neuropathy\n==== Body\nIntroduction\nDuloxetine acts by inhibiting the selective reuptake of serotonin (5-hydroxytryptamine [5-HT]) and norepinephrine (NE) and is categorized as a selective serotonin and norepinephrine reuptake inhibitor (SNRI). Duloxetine acts by central pain inhibitory mechanisms, which is thought to be linked to its central nervous system (CNS) 5-HT and NE activity potential.[1] Both 5-HT and NE have significant neurotransmission activities in the brainstem and spinal cord's descending pain inhibitory pathways. Moreover, to decrease the peripheral transmission of pain signals to CNS, these neurotransmitters are thought to behave synergistically.[2] Here, we report a case of hypertensive urgency secondary use of duloxetine for painful diabetic neuropathy therapy and also discuss the appropriate clinical presentation and management. As the incidence of hypertensive emergency induced by duloxetine is uncommon, our goal is to increase awareness of this life-threatening adverse event. Till date, a single case report of duloxetine-induced hypertensive emergency has been published by Mermi and Atmaca.[3] US Food & Drug administration approved label mentions hypertensive crisis has a temporal relationship with duloxetine based on the individual safety case reports (ISCR). However, a causal relationship cannot be established.\n\nCase Report\nIn June 2019, a 62-year-old female of middle socioeconomic strata, resident of rural area of Jodhpur, with a diagnosis of type 2 diabetes mellitus with hypertension (HTN), presented in AIIMS outpatient department with complaints of burning pain and numbness on both the legs and feet. She was on treatment with standard antidiabetic medication including insulin glargine and gliclazide. The patient was stabilized on amlodipine for HTN, rosuvastatin for hyperlipidemia, and aspirin for primary prevention of cardiovascular diseases (CVD). Her BP was within normal limits and controlled with amlodipine. There was no history of alcohol intake or smoking. Diagnosis of painful diabetic neuropathy was made with the use of diabetic neuropathy symptom score and diabetes neuropathy examination score and she was enrolled in the randomized clinical trial entitled, “A Comparative Evaluation of Duloxetine and Gabapentin in Painful Diabetic Neuropathy,” and the Clinical Trial Registry of India (CTRI) number-CTRI/2018/10/015944. The patient was started on duloxetine 30 mg twice daily for over a period of 1½ month for painful diabetic neuropathy. Two days later, she presented in the emergency department with chief complaints of severe anxiety, nausea, and severe headache. There was no significant family history. There was a history of renal calculus 2 years back which was operated successfully. There was no history of chest pain, shortness of breath, palpitations, and abdominal or urinary complaints. There was no history of substance use and no history of labile HTN.\n\nOn examination, she was conscious and oriented. She was afebrile with pulse rate of 105 beats per min and blood pressure of 210/120 mmHg in supine position and with oxygen saturation of 93% on 2 L/min of oxygen flow. Other investigations such as liver function test and kidney function test were normal. 24-h urinary protein was 0.09 g/24 h, glycated hemoglobin was 9.2%, and low-density lipid cholesterol was 140 mg/dl. Arterial blood gases (ABG) were within normal limits. Laboratory and ABG findings are given in Table 1.\n\nTable 1 Laboratory findings and arterial blood analysis report\n\nLaboratory test\tResults\tNormal values\t\nRBC count (×106/ul)\t4.4\t4.1-5.1\t\nPlatelet count (×103/ul)\t50\t150-450\t\nHb (g/dl)\t12\t12.3-15.3\t\nHematocrit (%)\t40\t36.9 and 44.6\t\nWBC’s (cells/mcL)\t5500\t4,500-10,000\t\nMean corpuscular volume\t85\t80-96\t\nSodium level\t138\t135-145\t\nPotassium level\t3.9\t3.6-5.2\t\nLipid profile (Chol+TG+LDL-C+HDL-C) mg/dl\t220/195/42/139\t<200/<150/<100/40-60\t\nArterial blood gases\t\t\t\n pH\t7.38\t7.35-7.45\t\n Oxygen saturation (%)\t95\t94-100\t\n Bicarbonate level (mmol/L)\t24.5\t22-26\t\n PO2 (mmHg)\t81\t75-100\t\n PCO2 (mHg)\t31\t35-45\t\nChol=Total Cholesterol, TG=Triglyceride, LDL-C=Low-density lipid cholesterol, HDL-C=High-density lipid cholesterol, RBC=Red blood cell, Hb=Hemoglobin, WBC’s=White blood cell\n\nHypertensive urgency secondary to the use of duloxetine was suspected and the patient was immediately transferred to the intensive care unit for surveillance and further management of blood pressure. Diagnosis of duloxetine-induced hypertensive urgency was made. Duloxetine was stopped and the patient was administered labetalol 20 mg by i.v. infusion. Her blood pressure decreased to 170/110 mmHg, and with repeated doses, it further declined to 154/88 mmHg, along with resolution of headache.\n\nThe patient improved clinically and symptomatically. She was administered oral telmisartan 40 mg for the control of BP and tablet metoprolol 25 mg once daily was also included in her treatment regime. She was discharged on the next day with tablet telmisartan 40 mg once daily, along with metoprolol 25 mg for control of BP and pantoprazole and domperidone for acid reflux. The reaction was reported to the World Health Organization Uppsala Monitoring Centre (WHO-UMC) through VigiFlow software (unique ID: INIPC: 2019–35052). The consent of the patient was taken for publication of her case report in scientific journal and she has no objection with the publication of information.\n\nDiscussion\nThis case illustrates a possible case of duloxetine-induced hypertensive urgency. Hypertensive urgency is acute, life-threatening emergency, associated with marked rise in blood pressure, usually above 180/120 mmHg without the presence of acute end-organ damage. Most patients suffering from hypertensive urgency and emergency have uncontrolled or unknown chronic HTN. However, the disease may occur in people who are normotensive.[4] Assessment of hypertensive urgency and emergency includes certain history and physical examination points to be emphasized. Medical history should include history of past treatment, ruling out illicit drug use, CVD, neurological symptoms, and urinary complaints. Information about known clinical and medical conditions, such as thyroid disorders, systemic lupus erythematosus, systemic sclerosis, Cushing's syndrome, abdominal pain, dyspnea, and menstrual history, can be extremely helpful.\n\nIn general, blood pressure is reduced by approximately 10% in the 1st hour and fifteen percent over next 2-3 hours gradually. Antihypertensive drug of choice includes labetalol, nicardipine, clevidipine, esmolol, fenoldopam, hydralazine, and phentolamine.\n\nIt has been observed that there is greater rise in mean systolic and diastolic blood pressure in patients on tricyclic antidepressants (TCA), which may increase the probability of stage I HTN.[5] The second-generation antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and SNRIs are mainstay in the management of affective disorders such as anxiety, depression, and pain disorders such as neuropathic pain. Escitalopram results in a slight, but not clinically significant, reduction of BP, without dose–response effect.[4] Venlafaxine has also been reported to cause increase in BP. The probable cause of venlafaxine-induced HTN is the rise in NE concentrations and the increased peripheral noradrenergic neurotransmission. Sibutramine, an amphetamine-like SNRI, the probable mechanism of sibutramine-induced HTN in both normotensive and hypertensive patients, is the increased quantity of circulating NE in the body.\n\nUse of Naranjo's probability scale and WHO-UMC causality scale assessment indicated duloxetine as a possible cause of hypertensive urgency. The safe dose of duloxetine is 20 mg/day and should be slowly increased to maximum of 60 mg/day in single dose or divided every 12 h. Duloxetine was used at a higher dose of 120 mg/day for the management of diabetic peripheral neuropathy. 120 mg dose is no more effective than 60 mg/day, but the side effects are very common at 120 mg/day dose. A study done by Derby et al. predicted that on administration of duloxetine, prehypertensive patients may become hypertensive, but predose blood pressure levels can help in prediction of such events.[6] Overall, the study data suggest that the administration of supratherapeutic dosages of duloxetine up to 200 mg twice daily is usually not associated with serious, clinically relevant adverse events such as hypertensive emergencies.[6]\n\nIn subjects with preexisting HTN, hypertensive emergency and urgency with duloxetine has been rarely reported. Henceforth, in subjects with risk factors like known case of HTN or CVD, blood pressure monitoring is recommended, especially during initial months of treatment.\n\nConclusion\nIt can be concluded that hypertensive urgency can be caused by duloxetine. Therefore, clinicians should be cautious of likelihood of duloxetine-induced hypertensive urgency and should be vigilant to diagnose and report the incident.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n\nAcknowledgment\nWe also acknowledge the constant support and guidance provided by the National Coordinating Centre, IPC, Ghaziabad, Ministry of Health and Family Welfare, Government of India, from time to time.\n==== Refs\n1 Yaksh TL Pharmacology of spinal adrenergic systems which modulate spinal nociceptive processing Pharmacol Biochem Behav 1985 22 845 58 2861606 \n2 Zhuo M Gebhart GF Biphasic modulation of spinal nociceptive transmission from the medullary raphe nuclei in the rat J Neurophysiol 1997 78 746 58 9307109 \n3 Mermi O Atmaca M Duloxetine-induced hypertension: A case report Turk Psikiyatri Derg 2016 27 67 9 27369688 \n4 Hypertensive Emergencies: Uncontrolled Blood Pressure, Management of Hypertensive Emergencies Last accessed on 2019 Jun 11 Available from: https://emedicine.medscape.com/article/1952052-overview \n5 Licht CM de Geus EJ Seldenrijk A van Hout HP Zitman FG van Dyck R Depression is associated with decreased blood pressure, but antidepressant use increases the risk for hypertension Hypertension 2009 53 631 8 19237679 \n6 Derby MA Zhang L Chappell JC Gonzales CR Callaghan JT Leibowitz M The effects of supratherapeutic doses of duloxetine on blood pressure and pulse rate J Cardiovasc Pharmacol 2007 49 384 93 17577103\n\n", "fulltext_license": "CC BY-NC-SA", "issn_linking": "0253-7613", "issue": "52(3)", "journal": "Indian journal of pharmacology", "keywords": "Duloxetine; hypertensive urgency; painful diabetic neuropathy", "medline_ta": "Indian J Pharmacol", "mesh_terms": "D000700:Analgesics; D000959:Antihypertensive Agents; D001794:Blood Pressure; D003924:Diabetes Mellitus, Type 2; D003929:Diabetic Neuropathies; D000068736:Duloxetine Hydrochloride; D005260:Female; D006801:Humans; D006973:Hypertension; D008875:Middle Aged; D016896:Treatment Outcome", "nlm_unique_id": "7902477", "other_id": null, "pages": "213-215", "pmc": null, "pmid": "32874005", "pubdate": "2020", "publication_types": "D002363:Case Reports", "references": "27369688;19237679;2861606;9307109;17577103", "title": "Duloxetine-induced hypertensive urgency in type 2 diabetes mellitus with diabetic neuropathy.", "title_normalized": "duloxetine induced hypertensive urgency in type 2 diabetes mellitus with diabetic neuropathy" }

[ { "companynumb": "IN-LUPIN LIMITED-2020-09471", "fulfillexpeditecriteria": "2", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "090694", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MILLIGRAM, BID", "drugenddate": "2019", "drugenddateformat": "602", "drugindication": "Diabetic neuropathy", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": "2019", "drugstartdateformat": "602", "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": "1", "drugtreatmentdurationunit": "802", "medicinalproduct": "DULOXETINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Cardiovascular disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "INSULIN GLARGINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Type 2 diabetes mellitus", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN GLARGINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Hypertension", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ROSUVASTATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Hyperlipidaemia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ROSUVASTATIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "GLICLAZIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Type 2 diabetes mellitus", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GLICLAZIDE" } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypertensive urgency", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20190101" } }, "primarysource": { "literaturereference": "Shukla R, Khasbage S, Garg M, Singh S. Duloxetine-induced hypertensive urgency in type 2 diabetes mellitus with diabetic neuropathy. Indian journal of pharmacology. 2020;52(3):213-215", "literaturereference_normalized": "duloxetine induced hypertensive urgency in type 2 diabetes mellitus with diabetic neuropathy", "qualification": "3", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20211102", "receivedate": "20211102", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20023450, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20220303" } ]

{ "abstract": "OBJECTIVE\nTrimethylaminuria is a metabolic disorder characterized by excessive excretion of trimethylamine in body fluids following FMO3 gene mutations. Secondary forms of the disease may be due to consumption of trimethylamine precursor-rich foods or metabolism of some xenobiotics.\n\n\nMETHODS\nA HIV patient developed secondary trimethylaminuria following antiretroviral treatment. Riboflavin supplementation ameliorated his phenotype. 1 H-NMR confirmed increased urine level of TMA. Several genes involved in choline catabolism harboured missense mutations. Riboflavin supplement improved enzymatic activity of mutated enzymes promoting TMA clearance.\n\n\nCONCLUSIONS\nAntiretrovirals may increase the concentration of TMA precursors. The present study reports antiretroviral treatment as risk factor for such secondary trimethylaminuria. Riboflavin is an effective treatment.", "affiliations": "Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, Messina, Italy.;Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, Messina, Italy.;Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, Messina, Italy.;Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy.;Prevention and Research division, INAIL, Rome, Italy.;Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, Messina, Italy.;Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, Messina, Italy.", "authors": "Scimone|Concetta|C|;Alibrandi|Simona|S|;Donato|Luigi|L|;Giofrè|Salvatore V|SV|;Rao|Giacomo|G|;Sidoti|Antonina|A|https://orcid.org/0000-0001-9586-4394;D'Angelo|Rosalia|R|", "chemical_list": "D044966:Anti-Retroviral Agents; D008744:Methylamines; C023336:trimethylamine; D012256:Riboflavin", "country": "England", "delete": false, "doi": "10.1111/jcpt.13315", "fulltext": null, "fulltext_license": null, "issn_linking": "0269-4727", "issue": "46(2)", "journal": "Journal of clinical pharmacy and therapeutics", "keywords": "FMO3; antiretrovirals; choline; missense variants; riboflavin; trimethylamine; trimethylaminuria", "medline_ta": "J Clin Pharm Ther", "mesh_terms": "D000328:Adult; D044966:Anti-Retroviral Agents; D015658:HIV Infections; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008661:Metabolism, Inborn Errors; D008744:Methylamines; D012256:Riboflavin", "nlm_unique_id": "8704308", "other_id": null, "pages": "304-309", "pmc": null, "pmid": "33247860", "pubdate": "2021-04", "publication_types": "D002363:Case Reports", "references": null, "title": "Antiretroviral treatment leading to secondary trimethylaminuria: Genetic associations and successful management with riboflavin.", "title_normalized": "antiretroviral treatment leading to secondary trimethylaminuria genetic associations and successful management with riboflavin" }

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Antiretroviral treatment leading to secondary trimethylaminuria: Genetic associations and successful management with riboflavin. J-Clin-Pharm-Ther 2021;46(2):304-309.. J-Clin-Pharm-Ther. 2021;46(2):304-309", "literaturereference_normalized": "antiretroviral treatment leading to secondary trimethylaminuria genetic associations and successful management with riboflavin", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20211004", "receivedate": "20211004", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19911781, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" }, { "companynumb": "IT-VIIV HEALTHCARE LIMITED-IT2020GSK239421", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ABACAVIR 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"drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MILLIGRAM, ONCE A DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV infection", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMIVUDINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ABACAVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MILLIGRAM, ONCE A DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV infection", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ABACAVIR" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ATAZANAVIR" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MILLIGRAM, ONCE A DAY(100 MILLIGRAM, TID (3 TIMES DAILY) )", "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV infection", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ATAZANAVIR" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ATAZANAVIR" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MILLIGRAM, TWO TIMES A DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, 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Antiretroviral treatment leading to secondary trimethylaminuria: Genetic associations and successful management with riboflavin.. 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{ "abstract": "Acute lung injury (ALI) is a rare but life-threatening pulmonary complication of transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). The aim of this study was to characterize the common risk factors, clinical features, imaging findings, treatments, and outcomes of acute lung injury caused by TACE.\nA retrospective study was performed on all TACE-associated ALI cases that were diagnosed at authors' hospital from January 2015 to June 2018.\nThe study included 14 ALI cases where the mean age of patients was 60.9 ± 11.7 years (range 41-82 years), with a mean onset time of 2.4 ± 1.6 d after TACE. Of the 14 patients, 8 patients (57.1%) developed acute respiratory distress syndrome (ARDS). 7 patients (50%) had underlying chronic respiratory disease and hepatic arteriovenous fistula was detected in 6 patients (42.6%), both of which were significantly higher than control group (P < 0.05). Dyspnea (92.9%) was the most common symptoms. Pleural effusion (64.3%), diffuse pulmonary infiltration (42.9%), and accumulation of Lipiodol in lung field (42.9%) were frequent radiologic abnormalities. 11 patients (78.6%) achieved remission after treatment, and the 30-day mortality rate was approximately 21.4%. Patient's median survival time after the development of ALI was merely 4.3 months, which was obviously worse than control group (4.3 months vs. 13.5 months, P < 0.05).\nThis study illustrates that TACE-associated ALI is a rare pulmonary complication with a high mortality rate. We infer that pulmonary Lipiodol embolization might be one of the main causes of TACE-associated ALI. Thus, HCC patients who are at high risk should be closely evaluated and monitored during TACE to avoid such potentially fatal complication.", "affiliations": "Department of Respiratory Medicine, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.;Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.;Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.;Department of Respiratory Medicine, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.", "authors": "Fang|Liang-Jie|LJ|;Chen|Lu-Yan|LY|;Sun|Jun-Hui|JH|;Zhou|Jian-Ying|JY|https://orcid.org/0000-0002-8924-935X", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1155/2019/4307651", "fulltext": "\n==== Front\nAnal Cell Pathol (Amst)Anal Cell Pathol (Amst)ACPAnalytical Cellular Pathology (Amsterdam)2210-71772210-7185Hindawi 10.1155/2019/4307651Research ArticleClinical Characteristics and Outcomes of Acute Lung Injury Caused by Transcatheter Arterial Chemoembolization for Hepatocellular Carcinoma: A Retrospective Cohort Study from a Single Institution in China Fang Liang-jie \n1\nChen Lu-yan \n2\nSun Jun-hui \n2\nhttps://orcid.org/0000-0002-8924-935XZhou Jian-ying zjyhz@zju.edu.cn\n1\n\n1Department of Respiratory Medicine, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China\n2Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, ChinaAcademic Editor: Alfredo Procino\n\n2019 26 11 2019 2019 43076511 3 2019 25 9 2019 Copyright © 2019 Liang-jie Fang et al.2019This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\n Acute lung injury (ALI) is a rare but life-threatening pulmonary complication of transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). The aim of this study was to characterize the common risk factors, clinical features, imaging findings, treatments, and outcomes of acute lung injury caused by TACE. \n\nMethods\n A retrospective study was performed on all TACE-associated ALI cases that were diagnosed at authors' hospital from January 2015 to June 2018. \n\nResults\n The study included 14 ALI cases where the mean age of patients was 60.9 ± 11.7 years (range 41-82 years), with a mean onset time of 2.4 ± 1.6 d after TACE. Of the 14 patients, 8 patients (57.1%) developed acute respiratory distress syndrome (ARDS). 7 patients (50%) had underlying chronic respiratory disease and hepatic arteriovenous fistula was detected in 6 patients (42.6%), both of which were significantly higher than control group (P < 0.05). Dyspnea (92.9%) was the most common symptoms. Pleural effusion (64.3%), diffuse pulmonary infiltration (42.9%), and accumulation of Lipiodol in lung field (42.9%) were frequent radiologic abnormalities. 11 patients (78.6%) achieved remission after treatment, and the 30-day mortality rate was approximately 21.4%. Patient's median survival time after the development of ALI was merely 4.3 months, which was obviously worse than control group (4.3 months vs. 13.5 months, P < 0.05). \n\nConclusion\n This study illustrates that TACE-associated ALI is a rare pulmonary complication with a high mortality rate. We infer that pulmonary Lipiodol embolization might be one of the main causes of TACE-associated ALI. Thus, HCC patients who are at high risk should be closely evaluated and monitored during TACE to avoid such potentially fatal complication.\n\nMedical and Health Technology Program of Zhejiang Province2016RCA013\n==== Body\n1. Introduction\nHepatocellular carcinoma (HCC), the most common primary hepatic malignancy, is a leading cause of cancer-related death in the world, and more than 80% of the cases occur in Asia due to the prevalence of chronic hepatitis [1, 2]. Transcatheter arterial chemoembolization (TACE), a palliative therapy, first reported in the 1970s, has been widely used in treatment of HCC to prolong survival time, especially when tumors are not surgically respectable [3]. The rationale for TACE is based on the embolization of tumor vessels which predominantly supplied by hepatic arterial blood. Conventional TACE uses an emulsion of Lipiodol-chemotherapeutic agent, whereas TACE with drug-eluting beads (DEB-TACE) uses beads loaded with a chemotherapeutic agent such as doxorubicin. Both two regimens have been shown to achieve a significant survival benefit according to previous researches [4, 5].\n\nAcute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a type of respiratory failure characterized as the acutely development, bilateral pulmonary infiltrates and severe hypoxemia. ALI/ARDS could be caused by varied etiology, including sepsis, pancreatitis, trauma, pneumonia, and aspiration. Its death rate can reach to 35-50% [6]. Recently, as the prevalence of TACE, increasing clinical cases about post-TACE pulmonary complication had been reported and vast majority resulted in disastrous consequences [7–11]. Now, it is gradually accepted that ALI/ARDS caused by TACE is a rare but fatal complication, mainly thought to be related to chemical injury subsequent to the migration of the infused Lipiodol or chemotherapeutic agent to the lung vasculature. However, so far, most of our knowledge about this complication is based on case reports. Its clinical characteristics and outcomes have not been fully investigated by researchers.\n\nThus, this study aimed at retrospectively analyzing the common risk factors, clinical features, imaging findings, treatments, and outcomes of TACE-associated ALI. This information will be useful for precise evaluation, early recognition, and management in clinical practice.\n\n2. Materials and Methods\n2.1. Ethics Statement\nThe institutional ethical committee approved our research protocol. All the patients or their relatives provided written informed consent and understood that their hospital data would be used for research.\n\n2.2. Study Patients and Diagnostic Criteria\nThis study was a retrospective analysis conducted at the First Affiliated Hospital of Zhejiang University. 14 HCC patients with TACE-associated ALI, diagnosed from January 2015 to June 2018, were retrospectively analyzed. Patients, who developed pulmonary complication but no evidence of ALI, were selected as control group. Information was obtained regarding the following clinical parameters: demographic data, symptom, laboratory examination, radiographic presentation, treatment, follow-up, and outcome.\n\nDiagnosis of HCC was made by pathological confirmation (postoperative pathological test or needle biopsy) and typical radiographic evidence (significantly enhanced tumor in the arterial phase and rapidly cleared contrast agents in the portal venous phase). Pulmonary complication defined as the presence of respiratory symptoms (such as cough, sputum, and dyspnea) and abnormalities in chest imaging after TACE. ALI was confirmed according to the standard American-European Consensus Conference (AECC) definition as the development of acute, bilateral pulmonary infiltrates and hypoxemia (ALI: SpO2/FiO2 < 300; ADRS: SpO2/FiO2 < 200) in the absence of clinical signs of the left atrial hypertension as the main explanation for pulmonary edema.\n\n2.3. TACE Therapy\nPuncture with the Seldinger technique was routinely performed with a 5 F catheter being placed into the celiac aorta. Further catheterization was performed in the feeding artery of the intrahepatic tumor after angiography. Next, the intrahepatic tumor was treated with TACE therapy in which iodized oil emulsion or drug-eluting beads loaded with a chemotherapeutic agent were injected into the tumor artery before 300-500 μm particles to completely embolize the tumor feeding artery.\n\n2.4. Laboratory Parameters, Treatments, and Outcome Assessments\nOnce acute respiratory symptom developed after TACE, patient's laboratory examinations including blood gas analysis, CRP, D-dimer, myocardium zymogram level, and sputum or blood culture were tested according to the manufacturer's instructions. Chest computed tomography (CT) was performed using 16-slice or 64-slice systems (Toshiba Aquilion 16 CT Scanner; Brilliance iCT and 64-channel systems). Two experienced radiologists evaluated the CT images, and consensus was achieved by negotiation.\n\nPatients, diagnosed with TACE-associated ALI, were treated with oxygen therapy, antibiotic therapy, systemic corticosteroids, and respiratory support with mechanical ventilation depending on their etiology and the severity of disease.\n\n2.5. Statistical Analysis\nContinuous variables were presented as mean ± standard deviation and were performed by Student's t-test. Categorical variables were presented as frequencies and percentages (n (%)). Fisher's exact test was used to compare categorical variables. The survival curves were calculated by the Kaplan-Meier method. Survival differences were evaluated using log-rank test. P values < 0.05 were considered statistically significant. All statistical analyses were performed with SPSS v19.0 for Windows (IBM, USA).\n\n3. Results\n3.1. General Clinical Characteristics\nDuring the study period (January 2015 to June 2018), we identified 32 patients with pulmonary complication after TACE and 14 patients (10 female and 4 male) met the diagnostic criteria of ALI were included. The remaining 18 patients served as control group. The demographic features for those 14 patients were presented in Table 1. Briefly, the mean age of those 14 patients was 60.9 ± 11.7 years (range 41-82 years). Cirrhosis was the most common underlying disease (n = 10, 71.4%), followed by respiratory disease (n = 7, 50%), diabetes (n = 1, 7.1%), and hypertension (n = 1, 7.1%). The mean tumor diameter was 8.9 ± 3.6 cm. 10 patients (71.4%) were found to have portal vein tumor thrombus, and hepatic arteriovenous fistula was detected in 6 patients (42.9%). Among the 14 cases, 12 patients received conventional TACE therapy with mean dose of 9.6 ± 4.2 mL infused Lipiodol and another 2 patients received DEB-TACE therapy. Compared to control group, the combination of chronic respiratory disease or hepatic arteriovenous fistula were significantly common in patients with ALI (P < 0.05), which could be considered as risk factors for the development of ALI following TACE.\n\n3.2. Clinical Features\nThe clinical features of TACE-associated ALI were presented in Table 2. The mean time of ALI onset after TACE was 2.4 ± 1.6 d. Of the 14 patients, 8 patients (57.1%) developed ARDS. Dyspnea was the most common presenting symptom, occurring in 13 patients (92.9%), followed by cough (n = 10, 71.4%), fever (n = 4, 28.6%), hemoptysis (n = 2, 14.3%), and chest pain (n = 1, 7.1%). An increase in D-dimer was observed in most of the patients. Blood culture was performed in 4 febrile patients. Klebsiella pneumoniae was isolated from blood culture in 2 patients with an obvious increase in inflammatory markers such as C-reactive protein and white blood cell. The sputum and blood culture in other patients were negative.\n\nAll patients received chest CT scans after the onset of respiratory symptom. Pleural effusion was a frequent finding, which was detected in 9 cases (64.3%). The diffuse pulmonary infiltration (Figures 1(a), 1(b), 2(a), and 2(b)) and accumulation of Lipiodol in lung field (Figures 1(c), 1(d), 2(c), and 2(d)) were regarded as relatively specific findings, which are observed in 6 patients (42.9%). Other associated findings included multiple pulmonary consolidations and ground-glass opacity occurred in 35.7% and 21.4% of the patients, respectively.\n\n3.3. Etiology, Treatments, and Outcomes\nIn current research, we concluded that pulmonary Lipiodol embolization might be one of the main causes of TACE-induced ALI since 6 patients (42.9%) presented with diffuse pulmonary infiltration and obvious accumulation of Lipiodol on chest CT with a negative result in sputum or blood culture. In addition, patients whose blood culture detected Klebsiella pneumoniae were finally diagnosed as having liver abscess and bloodstream infection. Hence, sepsis induced by TACE ought to be another important reason for ALI. However, causes for the remaining 6 cases were unclear.\n\nAfter a diagnosis of TACE-associated ALI was established, all the patients received oxygen therapy immediately. Other combined treatments including empirical antibiotic therapy (85.7%) and corticosteroids (42.9%) were listed in Table 2. Due to exacerbation of severe hypoxemia, 2 patients were referred to intensive care unit (ICU) for mechanical ventilation and finally died of multiple organ failure or bloodstream infection two weeks later. Another patient with ARDS refused to invasive ventilation and transferred to local hospital, resulting in a death of respiratory failure. Overall, 11 patients achieved remission after treatment and the 30-day mortality rate of TACE-associated ALI was approximately 21.4%.\n\nLong-term follow-up was available for survivors (Table 3). Due to deterioration of physical condition, merely 4 patients (36.4%) were able to withstand further antitumor therapy including TACE or surgery, while other 7 patients (63.6%) were given best supportive care. The proportion of antitumor therapy in ALI group was significantly lower than that in control group (36.4% vs. 83.3%, P < 0.05). Accordingly, the patient's median survival time after the development of ALI was only 4.3 months, which was obviously worse than non-ALI group (4.3 months vs. 13.5 months, P < 0.05) (Figure 3). It suggested that the development of ALI could significantly impair the long-term survival of the patients with HCC.\n\n4. Discussion\nTACE is a widely accepted palliative treatment for patients with advanced HCC. Despite the great advantages of being less invasive and relatively safe, TACE still has multiple side effects [12, 13]. In the present research, we retrospectively analyzed 14 HCC patients who were diagnosed with TACE-associated ALI, revealing a high mortality rate (21.4%) and severe impairment of patient's long-term survival. We found that HCC patients with combined chronic respiratory disease or hepatic arteriovenous fistula were more prone to develop ALI after TACE. Vast majority of patients presented dyspnea, elevated D-dimer, diffuse pulmonary infiltration, and accumulation of Lipiodol on chest CT. Hence, we considered that pulmonary Lipiodol embolism was one of the main causes of TACE-associated ALI. Nevertheless, this study still had some potential limitations. It was a retrospective analysis conducted in a single medical center. The number of ALI cases was relatively small, so the result required further confirmation by large sample clinical studies. In addition, etiological conclusions mainly based on the clinical data analysis, lacking of pathological support.\n\nTo date, the mechanisms underlying symptomatic pulmonary injury associated with TACE are not well understood. The most likely mechanism is chemical injury caused by infused Lipiodol or administered medicine. Generally, the procedure of TACE involves mechanical occlusion of selective hepatic artery, supplying HCC with emulsion of Lipiodol-chemotherapeutic agent or beads loaded with a chemotherapeutic agent such as doxorubicin. Early studies had observed that 131I-labeled Lipiodol could be detected in the lung when delivered to the hepatic artery of patients with hepatic cancer [14, 15]. Now, increasing evidence supports that pulmonary oil embolism is closely related to the development of ALI/ARDS [16, 17]. Hatamaru et al. reported a case of TACE-associated ARDS due to pulmonary Lipiodol embolism, which confirmed the presence of fat droplets in the pulmonary arteriolar lumen via pathological autopsy [16]. In current study, nearly half of the cases presented diffuse pulmonary infiltration and accumulation of Lipiodol on chest CT but without evidence of infection, which were consistent with findings from other studies [18]. Concerning the underlying molecular mechanisms, it attributed to enzymatic digestion of Lipiodol by lipase and formation of free fatty acid, which is toxic to alveolar-capillary membrane. To date, several risk factors including a large hypervascular HCC (>10 cm) with AV shunts, large-volume Lipiodol infusion (>14.5 mL), and transinferior phrenic artery embolization have been identified for pulmonary Lipiodol embolism after TACE [13, 19, 20]. Thus, recommendations suggest that the maximum safe Lipiodol dose is about 15 to 20 mL or approximately 0.25 mL/kg total body weight.\n\nAlthough extremely rare, other chemotherapeutic agent may also possess potential for induction of ALI/ARDS when applies in TACE. Recently, acute lung injury following TACE of doxorubicin-loaded LC beads was reported by Khan et al. [8]. Kumasawa et al. described a TACE case using miriplatin with agents developed ARDS 5 days following therapy, presenting as cough, dyspnea, and pulmonary infiltration in chest imaging [7]. In our study, the definite causes of 6 cases were still unclear. We speculated that the etiology of some cases was implicated to chemotherapeutic drug-induced lung injury. In addition, our study revealed 2 ALI patients caused by bloodstream infection, indicating that sepsis secondary to TACE should not be completely ignored, especially in patient with fever and an obvious increase of inflammatory markers.\n\nThe optimal management strategy for TACE-associated ALI remains unknown. Oxygenation, systemic corticosteroids, and lung protective ventilation are the primary options and treatments varied according to etiological analysis and the severity of symptoms. Intravenous methylprednisolone might be effective to reduce the inflammatory response, oxidative stress involved in ARDS, and chemical pneumonitis induced by chemotherapeutic agent. It achieved success in 6 cases presented in our research. Nevertheless, the 30-day mortality rate of TACE-associated ALI was still as high as 21.4%. For there are no proven effective therapies, its prevention is quite essential. Precise evaluation, early recognition, and management are critically important during TACE.\n\nIn this study, patient's median survival time after the development of ALI was merely 4.3 months, which was significantly worse than non-ALI group. We believed that it closely related to lack of effective antineoplastic therapy since only 36.4% of the patients in ALI group were able to continue further antitumor therapy while the proportion in control group can reach to 83.3%. We inferred that the development of ALI accelerated deterioration of physical condition, leading to a great difficulty for achievement of further antitumor treatment, finally resulting in a poor prognosis.\n\nIn summary, this study characterized clinical features and outcomes of ALI caused by TACE, presenting as a lower occurrence rate but a higher mortality. Moreover, the development of ALI could significantly impair the long-term survival of the patients with HCC. Thus, physicians should be fully aware of and avoid this potential fatal complication during TACE.\n\nAcknowledgments\nThis work was supported by grants from the Medical and Health Technology Program of Zhejiang Province, China (no. 2016RCA013).\n\nData Availability\nThe data used to support the findings of this study are included within the article.\n\nConflicts of Interest\nNone of the authors have a conflict of interests regarding this paper.\n\nFigure 1 An 82-year-old man with HCC developed ARDS 24 h after the performance of TACE. The chest CT demonstrated diffuse pulmonary infiltration and bilateral pleural effusion (a, b). In addition, an obvious accumulation of Lipiodol (red arrows) was observed in the right lung lobe (c, d).\n\nFigure 2 Chest CT findings in a 60-year-old man with an underlying disease of COPD. He suffered from dyspnea and hemoptysis 10 h after TACE for HCC. Chest CT showed diffuse pulmonary infiltration in bilateral lung fields (a, b) and accumulation of Lipiodol (red arrows) located in bilateral lung lower lobes (c, d).\n\nFigure 3 Survival curve of hepatocellular carcinoma patients with TACE-associated pulmonary complications. In ALI group, patient's median survival time was 4.3 months, which was obviously worse than non-ALI group (4.3 months vs. 13.5 months, P < 0.05).\n\nTable 1 Demographic and baseline characteristics of patients with HCC.\n\nClinical characteristics\tALI (n = 14)\tNon-ALI# (n = 18)\t\nP value∗\t\nMean age (years)\t60.9 ± 11.7\t55.7 ± 5.9\t0.1112\t\nSex, n (%)\t\t\t0.7035\t\n Male\t10 (71.4)\t14 (77.8)\t\t\n Female\t4 (28.6)\t4 (22.2)\t\t\nCause of HCC, n (%)\t\t\t1.000\t\n Hepatitis B virus\t13 (92.9)\t16 (88.9)\t\t\n Alcoholic liver disease\t1 (7.1)\t2 (11.1)\t\t\nUnderlying disease, n (%)\t\t\t\t\n Cirrhosis\t10 (71.4)\t12 (66.7)\t0.4192\t\n Chronic respiratory disease\t7 (50)\t2 (11.1)\t0.0225\t\n Diabetes\t1 (7.1)\t2 (11.1)\t\t\n Hypertension\t1 (7.1)\t3 (16.7)\t\t\nChild-Pugh classification, n (%)\t\t\t1.000\t\n Child class A\t8 (57.1)\t11 (61.1)\t\t\n Child class B\t6 (42.9)\t7 (38.9)\t\t\nMean tumor diameter (cm)\t8.9 ± 3.6\t8.0 ± 3.3\t0.4677\t\nPortal vein tumor thrombus, n (%)\t\t\t1.000\t\n Presence\t10 (71.4)\t13 (72.2)\t\t\n Absence\t4 (28.6)\t5 (27.8)\t\t\nHepatic arteriovenous fistula, n (%)\t\t\t0.0265\t\n Presence\t6 (42.9)\t1 (5.6)\t\t\n Absence\t8 (57.1)\t17 (94.4)\t\t\nTherapeutic regimen\t\t\t1.000\t\n Conventional TACE\t13\t16\t\t\n DEB-TACE\t1\t2\t\t\nMean Lipiodol dose (mL)\t9.6 ± 4.2\t8.5 ± 3.6\t0.4651\t\n\n#Patients with pulmonary complication but no evidence of ALI; ∗significance level set at P < 0.05.\n\nTable 2 The clinical characteristics of HCC patients with TACE-associated ALI.\n\nClinical characteristics\tNo. of patients\tProportion (%)\t\nMean time to onset (days)\t2.4 ± 1.6\t\t\nClinical symptom\t\t\t\n Dyspnea\t13\t92.9\t\n Cough\t10\t71.4\t\n Fever\t4\t28.4\t\n Hemoptysis\t2\t14.3\t\n Chest pain\t1\t7.1\t\nLaboratory examination\t\t\t\n ALI (SpO2/FiO2: 200-300)\t6\t42.9\t\n ARDS (SpO2/FiO2: <200)\t8\t57.1\t\n CRP (mg/L)\t79.8 ± 54.2\t\t\n D-dimer (μg/mL)\t8032 ± 4631\t\t\n Positive blood culture\t2\t14.3\t\nRadiographic finding\t\t\t\n Pleural effusion\t9\t64.3\t\n Diffuse pulmonary infiltration\t6\t42.9\t\n Accumulation of Lipiodol in lung field\t6\t42.9\t\n Multiple pulmonary consolidations\t5\t35.7\t\n Multiple ground-glass opacity\t3\t21.4\t\nPossible etiology\t\t\t\n Pulmonary Lipiodol embolization\t6\t42.9\t\n Sepsis\t2\t14.3\t\n Unknown\t6\t42.9\t\nTreatment\t\t\t\n Oxygenation\t14\t100\t\n Empirical antibiotic therapy\t12\t85.7\t\n Systemic corticosteroids\t6\t42.9\t\n Mechanical ventilation\t2\t14.3\t\nTable 3 The outcomes of HCC patients with TACE-associated ALI.\n\n\tALI (n = 14)\tNon-ALI (n = 18)\t\nP value∗\t\n30-day mortality rate, n (%)\t3 (21.4)\t0 (0)\t\t\nCause of death\t\t\t\t\n Multiple organ failure\t1 (7.1)\t\t\t\n Bloodstream infection\t1 (7.1)\t\t\t\n Respiratory failure\t1 (7.1)\t\t\t\nAntitumor treatment after remission, n (%)\t\t\t0.0169\t\n TACE and surgery\t4 (36.4)\t15 (83.3)\t\t\n Best supportive care\t7 (63.6)\t3 (16.7)\t\t\nMedian survival time after ALI (months)\t4.3\t13.5\t0.0215\t\n\n∗Significance level set at P < 0.05.\n==== Refs\n1 Bray F. Ferlay J. Soerjomataram I. Siegel R. L. Torre L. A. Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA: a Cancer Journal for Clinicians 2018 68 6 394 424 10.3322/caac.21492 2-s2.0-85053395052 30207593 \n2 Zhu R. X. Seto W. K. Lai C. L. Yuen M. F. Epidemiology of hepatocellular carcinoma in the Asia-pacific region Gut Liver 2016 10 3 332 339 10.5009/gnl15257 2-s2.0-84969268030 27114433 \n3 Takayasu K. Transarterial chemoembolization for hepatocellular carcinoma over three decades: current progress and perspective Japanese Journal of Clinical Oncology 2012 42 4 247 255 10.1093/jjco/hys020 2-s2.0-84859260030 22407946 \n4 Lo C. M. Ngan H. Tso W. K. Randomized controlled trial of transarterial Lipiodol chemoembolization for unresectable hepatocellular carcinoma Hepatology 2002 35 5 1164 1171 10.1053/jhep.2002.33156 2-s2.0-0036237822 11981766 \n5 Facciorusso A. Di Maso M. Muscatiello N. Drug-eluting beads versus conventional chemoembolization for the treatment of unresectable hepatocellular carcinoma: a meta-analysis Digestive and Liver Disease 2016 48 6 571 577 10.1016/j.dld.2016.02.005 2-s2.0-84959534450 26965785 \n6 El Kenz H. Van der Linden P. Transfusion-related acute lung injury European Journal of Anaesthesiology 2014 31 7 345 350 10.1097/EJA.0000000000000015 2-s2.0-84905448552 24892308 \n7 Kumasawa F. Miura T. Takahashi T. A case of miriplatin-induced lung injury Journal of Infection and Chemotherapy 2016 22 7 486 489 10.1016/j.jiac.2016.01.003 2-s2.0-84956928131 26867794 \n8 Khan I. Vasudevan V. Nallagatla S. Arjomand F. Ali R. Acute lung injury following transcatheter hepatic arterial chemoembolization of doxorubicin-loaded LC beads in a patient with hepatocellular carcinoma Lung India 2012 29 2 169 172 10.4103/0970-2113.95335 2-s2.0-84860484989 22628935 \n9 Wu G. C. Perng W. C. Chen C. W. Chian C. F. Peng C. K. Su W. L. Acute respiratory distress syndrome after transcatheter arterial chemoembolization of hepatocellular carcinomas The American Journal of the Medical Sciences 2009 338 5 357 360 10.1097/MAJ.0b013e3181b15625 2-s2.0-73649131284 19826242 \n10 Nhu Q. M. Knowles H. Pockros P. J. Frenette C. T. An unexpected pulmonary complication following transcatheter arterial chemoembolization of a small hepatocellular carcinoma Journal of Clinical Gastroenterology 2016 50 6 524 525 10.1097/MCG.0000000000000524 2-s2.0-84962127998 27035078 \n11 Naorungroj T. Naksanguan T. Chinthammitr Y. Pulmonary Lipiodol embolism after transcatheter arterial chemoembolization for hepatocellular carcinoma: a case report and literature review Journal of the Medical Association of Thailand 2013 96 2 270 275 \n12 Sakamoto I. Aso N. Nagaoki K. Complications associated with transcatheter arterial embolization for hepatic tumors Radiographics 1998 18 3 605 619 10.1148/radiographics.18.3.9599386 2-s2.0-0032065854 9599386 \n13 Nhu Q. M. Knowles H. Pockros P. J. Frenette C. T. Pulmonary complications of transcatheter arterial chemoembolization for hepatocellular carcinoma World Journal of Respirology 2016 6 3 69 75 10.5320/WJR.v6.i3.69 27904836 \n14 Raoul J. L. Bourguet P. Bretagne J. F. Hepatic artery injection of I-131-labeled Lipiodol. Part I. Biodistribution study results in patients with hepatocellular carcinoma and liver metastases Radiology 1988 168 2 541 545 10.1148/radiology.168.2.2839866 2-s2.0-0023711325 2839866 \n15 Nakajo M. Kobayashi H. Shimabukuro K. Biodistribution and in vivo kinetics of iodine-131 Lipiodol infused via the hepatic artery of patients with hepatic cancer Journal of Nuclear Medicine 1988 29 3 1066 1077 2836573 \n16 Hatamaru K. Azuma S. Akamatsu T. 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Risk factors for the development of pulmonary oil embolism after transcatheter arterial chemoembolization of hepatic tumors Anti-Cancer Drugs 2014 25 8 976 981 10.1097/CAD.0000000000000113 2-s2.0-84905440168 24736105 \n20 Lin M. T. Kuo P. H. Pulmonary Lipiodol embolism after transcatheter arterial chemoembolization for hepatocellular carcinoma JRSM Short Reports 2010 8 3 1 6 10.1258/shorts.2009.090352\n\n", "fulltext_license": "CC BY", "issn_linking": "2210-7177", "issue": "2019()", "journal": "Analytical cellular pathology (Amsterdam)", "keywords": null, "medline_ta": "Anal Cell Pathol (Amst)", "mesh_terms": "D055371:Acute Lung Injury; D006528:Carcinoma, Hepatocellular; D016461:Chemoembolization, Therapeutic; D002681:China; D005260:Female; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome", "nlm_unique_id": "101541993", "other_id": null, "pages": "4307651", "pmc": null, "pmid": "31886119", "pubdate": "2019", "publication_types": "D016428:Journal Article", "references": "24892308;19826242;23590054;2839866;24736105;2836573;22628935;11981766;27035078;30263910;6254413;9599386;26867794;25632211;21103098;26965785;22407946;30207593;27904836;27114433", "title": "Clinical Characteristics and Outcomes of Acute Lung Injury Caused by Transcatheter Arterial Chemoembolization for Hepatocellular Carcinoma: A Retrospective Cohort Study from a Single Institution in China.", "title_normalized": "clinical characteristics and outcomes of acute lung injury caused by transcatheter arterial chemoembolization for hepatocellular carcinoma a retrospective cohort study from a single institution in china" }

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CLINICAL CHARACTERISTICS AND OUTCOMES OF ACUTE LUNG INJURY CAUSED BY TRANSCATHETER ARTERIAL CHEMOEMBOLIZATION FOR HEPATOCELLULAR CARCINOMA: A RETROSPECTIVE COHORT STUDY FROM A SINGLE INSTITUTION IN CHINA. ANAL CELL PATHOL. 2019 NOV 26? 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CLINICAL CHARACTERISTICS AND OUTCOMES OF ACUTE LUNG INJURY CAUSED BY TRANSCATHETER ARTERIAL CHEMOEMBOLIZATION FOR HEPATOCELLULAR CARCINOMA: A RETROSPECTIVE COHORT STUDY FROM A SINGLE INSTITUTION IN CHINA. ANAL CELL PATHOL. 2019 NOV 26? 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CLINICAL CHARACTERISTICS AND OUTCOMES OF ACUTE LUNG INJURY CAUSED BY TRANSCATHETER ARTERIAL CHEMOEMBOLIZATION FOR HEPATOCELLULAR CARCINOMA: A RETROSPECTIVE COHORT STUDY FROM A SINGLE INSTITUTION IN CHINA. ANAL CELL PATHOL. 2019 NOV 26? 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CLINICAL CHARACTERISTICS AND OUTCOMES OF ACUTE LUNG INJURY CAUSED BY TRANSCATHETER ARTERIAL CHEMOEMBOLIZATION FOR HEPATOCELLULAR CARCINOMA: A RETROSPECTIVE COHORT STUDY FROM A SINGLE INSTITUTION IN CHINA. ANAL CELL PATHOL. 2019 NOV 26? DOI: 10.1155/2019/4307651", "literaturereference_normalized": "clinical characteristics and outcomes of acute lung injury caused by transcatheter arterial chemoembolization for hepatocellular carcinoma a retrospective cohort study from a single institution in china", "qualification": "1", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20200107", "receivedate": "20200107", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17243513, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" } ]

{ "abstract": "Intra-arterial chemotherapy (IAC) has become a mainstay in the management of retinoblastoma, especially in advanced or refractory disease. However, IAC is not without complications, and chemotherapy toxic effects can lead to partial or complete choroidal ischemia, often causing vision loss.\nThis is a case report.\nA 4-month-old girl with bilateral retinoblastoma was treated with secondary IAC (melphalan 5 mg) for recurrent tumor following intravenous chemotherapy. One month later, complete tumor control was achieved. However, she demonstrated broad choroidal ischemia in the nasal and temporal quadrants but sparing of the watershed zone superior and inferior to the optic disc and in the papillomacular region. Fluorescein angiography revealed poor perfusion of the choriocapillaris with visibility of the large choroidal vessels in the nasal and temporal areas but preserved perfusion of the watershed zone. The watershed zone remained intact on the 10-month follow-up, and the final visual acuity was fix and follow without strabismus.\nThe pathophysiology of choroidal ischemia is not well understood, but the fortuitous watershed zone preservation in this case could represent uneven distribution of the chemotherapeutic drug, resulting in partial chemo-dilution of the medication in the watershed region, which represents the final downstream overlapping choroidal perfusion from both medial and lateral posterior ciliary arteries.", "affiliations": "Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.;Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.;Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.;Department of Neurovascular and Endovascular Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.;Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.", "authors": "Ancona-Lezama|David Arturo|DA|;Dalvin|Lauren A|LA|;Lucio-Alvarez|J Antonio|JA|;Jabbour|Pascal|P|;Shields|Carol L|CL|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.1159/000490856", "fulltext": null, "fulltext_license": null, "issn_linking": "2296-4657", "issue": "5(3)", "journal": "Ocular oncology and pathology", "keywords": "Choroidal ischemia; Intra-arterial chemotherapy; Retina; Retinoblastoma; Watershed zone", "medline_ta": "Ocul Oncol Pathol", "mesh_terms": null, "nlm_unique_id": "101656139", "other_id": null, "pages": "190-194", "pmc": null, "pmid": "31049327", "pubdate": "2019-04", "publication_types": "D016428:Journal Article", "references": "14985286;21670326;21746972;22137042;22427570;24656794;2582998;27881397;6701929;6832901;8148333", "title": "Choroidal Ischemia Sparing the Watershed Zone following Intra-Arterial Chemotherapy for Retinoblastoma.", "title_normalized": "choroidal ischemia sparing the watershed zone following intra arterial chemotherapy for retinoblastoma" }

[ { "companynumb": "US-DRREDDYS-USA/USA/19/0110456", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CONGENITAL RETINOBLASTOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".05", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CONGENITAL RETINOBLASTOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "203655", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INFUSION", "drugenddate": null, "drugenddateformat": null, "drugindication": "CONGENITAL RETINOBLASTOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN HYDROCHLORIDE FOR INJECTION" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CONGENITAL RETINOBLASTOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "18.6", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." } ], "patientagegroup": null, "patientonsetage": "4", "patientonsetageunit": "802", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Ischaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Retinal depigmentation", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ocular toxicity", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Strabismus", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ANCONA-LEZAMA D, DALVIN L, LUCIO-ALVAREZ J, JABBOUR P, SHIELDS C. CHOROIDAL ISCHEMIA SPARING THE WATERSHED ZONE FOLLOWING INTRA-ARTERIAL CHEMOTHERAPY FOR RETINOBLASTOMA. OCULAR ONCOLOGY AND PATHOLOGY. 2019?5(3):190-194. DOI:10.1159/000490856", "literaturereference_normalized": "choroidal ischemia sparing the watershed zone following intra arterial chemotherapy for retinoblastoma", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190524", "receivedate": "20190524", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16350950, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" } ]

{ "abstract": "The purpose of this study is to determine the frequency and severity of acute allergic-like reactions to gadolinium-based contrast media (GBCM) in children before, during, and after the transition from gadopentetate dimeglumine to gadoterate meglumine as our primary clinical GBCM.\n\n\n\nInstitutional review board approval was obtained for this Health Insurance Portability and Accountability Act-compliant retrospective investigation. Allergic-like reactions to GBCM in pediatric patients were retrospectively assessed from January 2009 to January 2017, which included a departmental change of GBCM from gadopentetate dimeglumine to gadoterate meglumine. Allergic-like reactions were identified from departmental and hospital databases. The number of doses of GBCM was obtained from billing data. Allergic-like reaction frequencies for each GBCM were calculated and compared using the chi-squared test.\n\n\n\nA total of 32,365 administrations of GBCM occurred during the study period (327 for gadofosveset trisodium; 672 for gadoxetate disodium; 12,012 for gadoterate meglumine; and 19,354 for gadopentetate dimeglumine). Allergic-like reactions occurred after 21 (0.06%) administrations. Reaction frequencies were not significantly different among the GBCM (0.3% gadofosveset trisodium; 0% gadoxetate disodium, 0.06% gadoterate meglumine, 0.08% gadopentetate dimeglumine; P > 0.05). Ten (47.6%) reactions were mild, 10 (47.6%) were moderate, and 1 (4.8%) was severe. The overall reaction frequency peaked during the 6-month transition period from gadopentetate dimeglumine to gadoterate meglumine (0.20%), compared with 0.07% pretransition (P = 0.048) and 0.04% posttransition (P = 0.0095).\n\n\n\nAllergic-like reactions to GBCM in children are rare. Gadoterate meglumine has a reaction frequency that does not significantly differ from other GBCMs. During the transition from gadopentetate dimeglumine to gadoterate meglumine, an increase in the frequency of reported allergic-like reactions was observed, likely reflective of the Weber effect.", "affiliations": "From the Cincinnati Children's Hospital Medical Center, Cincinnati, OH.", "authors": "Forbes-Amrhein|Monica M|MM|;Dillman|Jonathan R|JR|;Trout|Andrew T|AT|;Koch|Bernadette L|BL|;Dickerson|Julie M|JM|;Giordano|Richard M|RM|;Towbin|Alexander J|AJ|", "chemical_list": "D003287:Contrast Media; D009942:Organometallic Compounds; D008536:Meglumine; D005682:Gadolinium; D019786:Gadolinium DTPA; C109932:gadofosveset trisodium", "country": "United States", "delete": false, "doi": "10.1097/RLI.0000000000000444", "fulltext": null, "fulltext_license": null, "issn_linking": "0020-9996", "issue": "53(5)", "journal": "Investigative radiology", "keywords": null, "medline_ta": "Invest Radiol", "mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003287:Contrast Media; D004342:Drug Hypersensitivity; D005260:Female; D005682:Gadolinium; D019786:Gadolinium DTPA; D006801:Humans; D008297:Male; D008536:Meglumine; D009820:Ohio; D009942:Organometallic Compounds; D012189:Retrospective Studies; D012720:Severity of Illness Index", "nlm_unique_id": "0045377", "other_id": null, "pages": "313-318", "pmc": null, "pmid": "29337841", "pubdate": "2018-05", "publication_types": "D016428:Journal Article", "references": null, "title": "Frequency and Severity of Acute Allergic-Like Reactions to Intravenously Administered Gadolinium-Based Contrast Media in Children.", "title_normalized": "frequency and severity of acute allergic like reactions to intravenously administered gadolinium based contrast media in children" }

[ { "companynumb": "US-BAYER-2018-069626", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "GADOPENTETATE DIMEGLUMINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "019596", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "UNK, ONCE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GADOPENTETATE DIMEGLUMINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pruritus", "reactionmeddraversionpt": "21.0", "reactionoutcome": null }, { "reactionmeddrapt": "Urticaria", "reactionmeddraversionpt": "21.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "FORBES-AMRHEIN M M? DILLMAN J R? TROUT A T? KOCH B L? DICKERSON J M? GIORDANO R M? TOWBIN A J. FREQUENCY AND SEVERITY OF ACUTE ALLERGIC-LIKE REACTIONS TO INTRAVENOUSLY ADMINISTERED GADOLINIUM-BASED CONTRAST MEDIA IN CHILDREN. INVESTIGATIVE RADIOLOGY. 2018?53, 5:313-318", "literaturereference_normalized": "frequency and severity of acute allergic like reactions to intravenously administered gadolinium based contrast media in children", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180417", "receivedate": "20180417", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14769357, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180711" }, { "companynumb": "US-GUERBET-US-20180061", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LIGHT ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPOFOL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MIDAZOLAM HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LIGHT ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIDAZOLAM" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "GADOTERATE MEGLUMINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NUCLEAR MAGNETIC RESONANCE IMAGING", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOTAREM" } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Bronchospasm", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "FORBES-AMRHEIN M. FREQUENCY AND SEVERITY OF ACUTE ALLERGIC-LIKE REACTIONS TO INTRAVENOUSLY ADMINISTERED GADOLINIUM-BASED CONTRAST MEDIA IN CHILDREN. INVESTIGATIVE RADIOLOGY. 2017 NOV 18?.", "literaturereference_normalized": "frequency and severity of acute allergic like reactions to intravenously administered gadolinium based contrast media in children", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180323", "receivedate": "20180323", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14674531, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" } ]

{ "abstract": "OBJECTIVE\nTo examine the safety of therapeutic-dose anticoagulation during catheter-directed thrombolysis (CDT) for acute pulmonary embolism (PE).\n\n\nMETHODS\nA retrospective review of 156 consecutive cases (age, 56.6 ± 15.4 years; 85 males) of CDT with alteplase for acute PE (symptoms, <14 days) between 2009 and 2019 was performed. All patients received full-dose anticoagulation before, during, and after thrombolysis with low-molecular-weight heparin (LMWH) (n = 45) or unfractionated heparin (n = 111) infusion. Massive PE was diagnosed in 21 of 156 patients at presentation; submassive PE was diagnosed in 135 of 156 patients at presentation. The Simplified Pulmonary Embolism Severity Index was ≥1 in 69 of 156 patients.\n\n\nRESULTS\nThere were 4 mild (2.6%), 3 moderate (1.9%), and 3 severe (1.9%) hemorrhagic complications (Global Use of Strategies to Open Occluded Arteries), 1 of which (0.6%) was intracranial. No significant differences in hemorrhagic complication rates (P = .3, P = 1.0, and P = .6, respectively) or general complication rates (Society of Interventional Radiology [SIR] minor, P = .2; SIR major, P = .7) were noted between the LMWH and heparin groups. Mean pulmonary arterial pressure for the entire cohort improved from 28.9 ± 7.6 mmHg to 20.4 ± 6.5 mmHg (P < .001), whereas the Miller score improved from 19.3 ± 4.6 to 7.3 ± 3.9 (P < .001). The average infusion duration was 26 ± 11.9 hours over 2.3 ± 0.6 total visits to the angiography lab, during which a mean of 27.85 ± 14.2 mg of tissue plasminogen activator were infused.\n\n\nCONCLUSIONS\nTherapeutic anticoagulation during CDT for PE appears to be safe. The current study did not find a significant difference between LMWH and heparin infusion with respect to hemorrhagic and general complication rates.", "affiliations": "Department of Vascular and Interventional Radiology, Christiana Care Health System, 4755 Ogletown Stanton Rd, Ste 1e20, Newark, DE 19713. Electronic address: Agraif@christianacare.org.;Department of Vascular and Interventional Radiology, Christiana Care Health System, 4755 Ogletown Stanton Rd, Ste 1e20, Newark, DE 19713.;Department of Vascular and Interventional Radiology, Christiana Care Health System, 4755 Ogletown Stanton Rd, Ste 1e20, Newark, DE 19713.;Department of Vascular and Interventional Radiology, Christiana Care Health System, 4755 Ogletown Stanton Rd, Ste 1e20, Newark, DE 19713.;Department of Vascular and Interventional Radiology, Christiana Care Health System, 4755 Ogletown Stanton Rd, Ste 1e20, Newark, DE 19713.;Department of Vascular and Interventional Radiology, Christiana Care Health System, 4755 Ogletown Stanton Rd, Ste 1e20, Newark, DE 19713.", "authors": "Graif|Assaf|A|;Kimbiris|George|G|;Grilli|Christopher J|CJ|;Agriantonis|Demetrios J|DJ|;Putnam|Samuel G|SG|;Leung|Daniel A|DA|", "chemical_list": "D000925:Anticoagulants; D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight", "country": "United States", "delete": false, "doi": "10.1016/j.jvir.2019.12.003", "fulltext": null, "fulltext_license": null, "issn_linking": "1051-0443", "issue": "31(4)", "journal": "Journal of vascular and interventional radiology : JVIR", "keywords": null, "medline_ta": "J Vasc Interv Radiol", "mesh_terms": "D000328:Adult; D000368:Aged; D000925:Anticoagulants; D005260:Female; D005343:Fibrinolytic Agents; D006470:Hemorrhage; D006495:Heparin, Low-Molecular-Weight; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D061214:Patient Safety; D011655:Pulmonary Embolism; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D015912:Thrombolytic Therapy; D013997:Time Factors; D016896:Treatment Outcome", "nlm_unique_id": "9203369", "other_id": null, "pages": "537-543", "pmc": null, "pmid": "31959518", "pubdate": "2020-04", "publication_types": "D003160:Comparative Study; D016428:Journal Article", "references": null, "title": "Safety of Therapeutic Anticoagulation with Low-Molecular-Weight Heparin or Unfractionated Heparin Infusion during Catheter-Directed Thrombolysis for Acute Pulmonary Embolism.", "title_normalized": "safety of therapeutic anticoagulation with low molecular weight heparin or unfractionated heparin infusion during catheter directed thrombolysis for acute pulmonary embolism" }

[ { "companynumb": "US-ROCHE-2540161", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ALTEPLASE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "103172", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY EMBOLISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALTEPLASE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haematemesis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haematoma", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GRAIF A, KIMBIRIS G, GRILLI C, AGRIANTONIS D, PUTNAM S, LEUNG D ET AL SAFETY OF THERAPEUTIC ANTICOAGULATION WITH LOW-MOLECULAR-WEIGHT HEPARIN OR UNFRACTIONATED HEPARIN INFUSION DURING CATHETER-DIRECTED THROMBOLYSIS FOR ACUTE PULMONARY EMBOLISM. JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY 2020?:-.", "literaturereference_normalized": "safety of therapeutic anticoagulation with low molecular weight heparin or unfractionated heparin infusion during catheter directed thrombolysis for acute pulmonary embolism", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200204", "receivedate": "20200204", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17364148, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" } ]

{ "abstract": "In sugammadex-induced anaphylaxis, sugammadex and/or sugammadex-rocuronium complex have possible allergenic epitope.\n\n\n\nWe report a case of sugammadex-induced anaphylaxis during general anesthesia in a 60-year-old male undergoing orthopedic hand surgery, manifesting as profound hypotension and urticaria. The timing of onset was closely associated with sugammadex administration. The patient recovered after extensive therapy including fluid, epinephrine, other vasopressors, steroid, and antihistamine administration. By intradermal skin test which was done at four weeks after anaphylaxis, we confirmed positive reactions to both sugammadex and sugammadex-rocuronium complex.\n\n\n\nThis is a rare case of sugammadex-induced anaphylaxis that both sugammadex and sugammadex-rocuronium complex were confirmed as allergenic epitopes.", "affiliations": "Department of Anesthesiology and Pain Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Department of Anesthesiology and Pain Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Department of Anesthesiology and Pain Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Department of Anesthesiology and Pain Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.", "authors": "Choi|Shu Chung|SC|;Han|Sangbin|S|;Kwak|Jueun|J|;Lee|Ji Yung|JY|", "chemical_list": "D004338:Drug Combinations; D003473:Neuromuscular Nondepolarizing Agents; D000077122:Sugammadex; D000077123:Rocuronium", "country": "Korea (South)", "delete": false, "doi": "10.4097/kja.19344", "fulltext": "\n==== Front\nKorean J Anesthesiol\nKorean J Anesthesiol\nKJA\nKorean Journal of Anesthesiology\n2005-6419 2005-7563 Korean Society of Anesthesiologists \n\n10.4097/kja.19344\nkja-19344\nCase Report\nAnaphylaxis induced by sugammadex and sugammadex-rocuronium complex -a case report-\nSugammadex-induced anaphylaxishttp://orcid.org/0000-0001-6565-2112Choi Shu Chung http://orcid.org/0000-0002-0203-0751Han Sangbin http://orcid.org/0000-0001-9034-3645Kwak Jueun http://orcid.org/0000-0001-9123-1135Lee Ji Yung \nDepartment of Anesthesiology and Pain Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea\nCorresponding author: Ji Yung Lee, M.D., Ph.D. Department of Anesthesiology and Pain Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 10 63-ro, Yeoungdeungpo-gu, Seoul 07345, Korea Tel: +82-2-3779-1268 Fax: +82-2-783-0368 Email: anesthalee@naver.com\n8 2020 \n17 10 2019 \n73 4 342 346\n13 8 2019 9 10 2019 14 10 2019 Copyright © The Korean Society of Anesthesiologists, 20202020This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nIn sugammadex-induced anaphylaxis, sugammadex and/or sugammadex-rocuronium complex have possible allergenic epitope. \n\nCase\nWe report a case of sugammadex-induced anaphylaxis during general anesthesia in a 60-year-old male undergoing orthopedic hand surgery, manifesting as profound hypotension and urticaria. The timing of onset was closely associated with sugammadex administration. The patient recovered after extensive therapy including fluid, epinephrine, other vasopressors, steroid, and antihistamine administration. By intradermal skin test which was done at four weeks after anaphylaxis, we confirmed positive reactions to both sugammadex and sugammadex-rocuronium complex. \n\nConclusions\nThis is a rare case of sugammadex-induced anaphylaxis that both sugammadex and sugammadex-rocuronium complex were confirmed as allergenic epitopes.\n\nAnaphylaxisGeneral anesthesiaHypotensionRocuroniumSkin testSugammadexUrticaria\n==== Body\nSince the introduction of sugammadex into clinical practice, several cases of sugammadex-induced anaphylaxis have been reported [1-3]. Sugammadex is a synthetic γ-cyclodextrin that can reverse neuromuscular blockade induced by rocuronium and vecuronium in adults undergoing surgery. Its usage was approved by the US Food and Drug Administration in 2015, which was later compared to its approval in Europe in 2008. Such delay in approval seemed to be partly due to lack of data regarding its adverse reactions including hypersensitivity. We have experienced sugammadex-induced anaphylaxis and confirmed that the patient was reactive to both sugammadex and sugammadex-rocuronium complex by the intradermal skin test. Only one case report has documented the similar reactivity shown in our case [4]. But, in the reports that tested the sugammadex-rocuronium complex, methods to make the complex were different from each other [2,4,5]. Therefore, we would like to consider the skin test method with case review. Written informed consent was obtained from the patient for publication of this case report and accompanying images.\n\nCase Report\nThis study was approved by St.Mary's Hospital, The Catholic University of Korea (SC19ZESE0137).\n\nA 60-year-old male (weight: 64 kg, height: 159 cm) was scheduled for emergency incision, drainage, and flap coverage on soft tissue infection of the right hand. He had amputation of the right index finger at another hospital 26 years ago, and had middle finger amputation and flap coverage in our orthopedic department seven years ago. Both surgeries were performed under general anesthesia without exposure to sugammadex. He had hypertension that was not treated. He did not have allergy history.\n\nAfter he entered the operating room with anxiety, blood pressure (BP) 220/118 mmHg, heart rate 55 beats per minute (bpm), and O2 saturation by pulse oximetry 97% at room air were measured. Because a long time operation was scheduled and the patient refused regional anesthesia, we decided to perform general anesthesia. Within 5 min after we injected midazolam 3 mg and nicardipine 0.5 mg, he became comfortable and his BP decreased to 155/99 mmHg. After preoxygenation, general anesthesia was induced with propofol 120 mg and succinylcholine 70 mg using rapid sequence technique with supplemental remifentanil infusion. Following endotracheal intubation, we maintained anesthesia with inhalational gas mixture of oxygen (FiO2 0.4)-air-desflurane (6 vol%), supplementary remifentanil infusion at a rate of 0.03–0.07 μg/kg/min, and neuromuscular blocking agent rocuronium (EsmeronⓇ, MSD, the Netherlands) 40 mg. At 30 min after the operation, only a biopsy was performed and the operation was terminated because the malignancy was strongly suspected. Total anesthetic duration was 40 min. We discontinued the administration of all anesthetics. Sugammadex (Bridion®, MSD, the Netherlands) 200 mg was used to antagonize neuromuscular blockade at a train of four count of two monitored with a peripheral nerve stimulator (TOF watch®, Organon, Ireland). The patient started to breathe spontaneously while BP increased up to 207/119 mmHg concurrently that was treated with nicardipine 0.5 mg again. About 3 min after extubation while we prepared to transport the patient, his BP decreased suddenly to 78/38 mmHg. After 10 mg of ephedrine and 100 μg of phenylephrine injection to compensate suspicious nicardipine overdose, BP rose to 93/48 mmHg. He was transferred to the post anesthetic care unit (PACU).\n\nDuring transport, he complained of itching sense at the buttock area. Just after arrival at the PACU, we found urticarial rashes on the neck, chest, and buttock. Soon, he became rapidly hypotensive (66/41 mmHg) and tachycardic (104–105 bpm). In turn, he developed generalized urticaria over the whole body. An anaphylactic shock was strongly suspected on the basis of hemodynamic data and skin manifestation. We rapidly elevated his both legs, increased fluid infusion rate, and started infusion of epinephrine. We added norepinephrine to increase BP effectively. Also, methylprednisolone 125 mg, hydrocortisone 100 mg, and pheniramine 4 mg were given intravenously. Portable echocardiography showed no abnormal wall motion except dehydration. Arterial blood gas analysis was normal. After 30 min, his condition improved with a stable vital sign. After we explained anaphylaxis to the patient, he was transported to the intensive care unit for overnight observation. His serum mast cell tryptase level was 2.4 μg/L at 12 h and 5.8 μg/L at 36 h post-event (reference value: < 11.0 μg/L). His levels of immunoglobulins E, G, A, and M were normal.\n\nAfter one month from anaphylaxis, he was scheduled for an elective operation on the right first and third metacarpal bone resection. His hypertension was treated with atenolol. The plan of regional anesthesia was denied by the patient. After informed consent, an intradermal skin test was performed under general anesthesia. We anesthetized the patient in the same manner as prior anesthesia, but we used vecuronium (instead of rocuronium) and anticholinesterase (neostigmine 1.5 mg) with anticholinergics (glycopyrrolate 0.4 mg).\n\nFor the intradermal test, we prepared dilutions of test drugs: nicardipine 1 mg/ml (diluted 1 : 100), rocuronium 10 mg/ml (diluted 1 : 100), and sugammadex 100 mg/ml (diluted 1 : 100, 1 : 1000). We also prepared a mixture of rocuronium and sugammadex to test the sugammadex-rocuronium complex. Sugammadex (1 : 500 dilution) was mixed with the same volume of rocuronium (1 : 50 dilution). Thus, the final dilutions of the two drugs were 1 : 1000 and 1 : 100, respectively. This complex is known to have very few free sugammadex molecules. We used histamine (0.01%) as positive control and normal saline as negative control. Intradermal testing was conducted according to standard protocol on the patient’s volar forearm with a 25 G needle, resulting in a 5 mm wheal, 30 mm apart from each other. After 20 min, we evaluated the intradermal skin test results.\n\nThe skin tests were positive to 1 : 100 (20 × 10 mm wheal, 44 × 38 mm flare) and 1 : 1000 (14 × 9 mm wheal, 43 × 47 mm flare) dilutions of sugammadex. Sugammadex-rocuronium complex site also showed a positive reaction (24 × 10 mm wheal, 50 × 35 mm flare) (Fig. 1). Reactions to normal saline, nicardipine, and rocuronium were negative. There was no systemic allergic reaction during the test.\n\nHe received one more general anesthesia for vitrectomy due to retinal detachment. We avoided the use of sugammadex again. Currently he is on treatment of primary cancer of skin appendage, lung cancer, and bone metastasis. \n\nDiscussion\nAlthough the overall incidence of hypersensitivity seems to be low at 0.22% and the incidence of anaphylaxis is as low as 0.059% in subjects who receive sugammadex under general anesthesia [6], signs and symptoms of reported cases are very severe to anesthesiologists and patients [7]. Clinically, skin rash and hypotension were most commonly presented. The very strong probability of sugammadex-induced anaphylaxis in most cases is based on time correlations between drug administration and appearance of symptoms and signs. In our case, the use of nicardipine to control hypertension and successive hypotension made us hesitate to diagnose anaphylaxis shortly, because nicardipine and sugammadex were injected at almost the same time. Persistent hypotension and skin manifestation were very helpful for the diagnosis of anaphylaxis.\n\nFor diagnosis of anaphylaxis, plasma histamine and serum tryptase may be helpful [8,9]. For plasma histamine assay, sampling time is important because it is increased for 15–60 min after the appearance of anaphylaxis. Also, special handling is required for sampling and manipulation, such as obtaining blood through wide-bore needle, keeping sample cold at all times, immediate centrifuging, and prompt freezing of the plasma [8]. On the other hand, serum and plasma tryptase levels are increased 15 min–3 h after the appearance of anaphylaxis and ordinary sampling way is required. Measurement of both plasma histamine and tryptase can increase the diagnostic accuracy. To our regret, the proper sampling time for detection of plasma histamine and serum tryptase had passed. Histamine assay was omitted and tryptase levels were normal in the sample taken late. It is true that an elevated acute serum tryptase is highly predictive of IgE-mediated anaphylaxis. However, normal tryptase level does not preclude anaphylaxis according to its sensitivity, specificity, positive predictive value, or negative predictive value [10].\n\nThe skin test is superior to the analysis of histamine and tryptase for the diagnosis of anaphylaxis. In the cases of sugammadex-induced anaphylaxis, concurrent positive reactions to sugammadex and sugammadex-rocuronium complex have been rarely reported [2,4]. In some cases including this report, the skin tests for sugammadex and sugammadex-rocuronium complex were performed at the same time from the beginning [4,5]. In other cases, the skin test for the sugammadex-rocuronium complex was performed later to find out the possible allergenic antigen after negative reaction to sugammadex [2,11]. Nakanishi et al. [4] mixed equal volumes of sugammadex 100 mg/ml and rocuronium 10 mg/ml and made a serial dilution (1 : 10, 1 : 100, and 1 : 1000), yielding the ratio of sugammadex to rocuronium in the mixture 2.8 : 1 on a molar basis. By skin prick test, their patient was positive to sugammadex and undiluted rocuronium-sugammadex mixture. The authors suggested that a larger amount of free sugammadex molecules in the mixture seemed to elicit a positive skin reaction. In another case, Sadleir et al. [5] mixed equal volumes of 1 : 500 sugammadex and 1 : 50 rocuronium to make sugammadex 1 : 1000, rocuronium 1 : 100, respectively, resulting in a final concentration of 0.1 mg/ml for each drug. In that way, they expected very few free sugammadex molecules present in the mixture because the ratio of sugammadex to rocuronium in the mixture was 1 : 3.6 on a molar basis. Their patient was reactive to sugammadex, but not reactive to sugammadex-rocuronium complex. The authors suggested that the allergenic epitope of sugammadex was occupied by the binding of two molecules or it might have undergone conformational change that it could not bind to IgE. Ho et al. [2] have mixed equal volumes of rocuronium at 1 : 500 dilution (0.02 mg/ml) with sugammadex 1 : 50 (2 mg/ml). Their patient had a negative reaction to sugammadex, but a positive reaction to the sugammadex-rocuronium complex and sugammadex-vecuronium complex. In our case, although we used the method described by Sadleir et al. [5], different results were obtained. Our patient had a positive reaction to both sugammadex and sugammadex-rocuronium complex, suggesting that both of sugammadex and sugammadex encapsulating rocuronium expressed possible antigenic epitope. Like the case of anaphylaxis to sugammadex showing that γ-cyclodextrin in sugammadex was the causative allergen by skin test [12], the unchanged part common to sugammadex and sugammadex-rocuronium complex might have acted as allergen. It is extremely rare for both sugammadex and sugammadex-rocuronium complex to be identified as allergens in one patient [4]. However, as shown in this case, the anaphylactic symptoms were not more severe than other cases caused by only sugammadex or only sugammadex-rocuronium complex.\n\nThe dose of sugammadex that caused anaphylaxis was varied from 0.75 to 4 mg/kg [1,11]. Although the administered dose per body weight varies from patient to patient, many anesthesiologists administered 200 mg of sugammadex in the patients regardless of body weight, resulting in various concentrations of free sugammadex [2-4]. The sugammadex dose we used in this case was 200 mg (about 3.13 mg/kg, body weight). This was more than the recommended dose which was 2 mg/kg of sugammadex at TOF 2/4. Thus, more free sugammadex molecules would have existed in the patient’s blood at high levels, which might be involved in inducing anaphylaxis. There are two reports about sugammadex and hypersensitivity incidence in healthy non-anesthetized subjects. de Kam et al. [13] have reported that hypersensitivity or anaphylactic reaction to sugammadex is dose-dependent while Min et al. [14] have concluded that hypersensitivity incidence is similar across sugammadex doses. Although these two experimental conditions were different from clinical anesthesia, severe hypersensitivity reactions occurred clearly after a high dose of 16 mg/kg. In clinical situations, it is difficult to determine the correlation between sugammadex dose or concentration and anaphylaxis incidence based on the data obtained so far.\n\nFor skin test after anaphylaxis, we have to wait 4–6 weeks because of temporary loss of cutaneous activity following anaphylaxis. Clinicians need a minimum of two weeks after anaphylaxis to perform skin test so that there is sufficient time to restore the cutaneous reactivity. However, inconclusive results might be possible [15].\n\nTo treat anaphylaxis, most physicians use adrenaline, steroids, antihistamines, and bronchodilators in case of bronchospasm [9,15]. Our first choice of drug was epinephrine, the first-line therapy in anaphylaxis guidelines. We had to replace volume by leg-up position and rapid fluid infusion, added norepinephrine, and administered steroids and antihistamines. Fortunately, no patient has died after sugammadex-induced anaphylaxis from all the case reports. Typically, clinical features of sugammadex anaphylaxis appeared when the patient was already extubated, being transferred to ward bed, or PACU [8]. This very busy time point is almost consistent with the report that symptoms are all expressed within 4 min [7]. Anesthesiologists should pay constant attention in blood pressure when using sugammadex because extreme hypotension is the first sign in most cases. It seems that there is no difference in the degree of symptom between anaphylaxis induced by sugammadex and that induced by the sugammadex-rocuronium complex [1-5,8].\n\nA limitation of this case study is that a specific method to make the sugammadex-rocuronium complex for skin test is not established, yet. Also, the method of skin test varies from author to author.\n\nSugammadex-induced anaphylaxis is emerging as its usage is increased. Clinical presentation and timing of onset related to sugammadex administration are important clues for early diagnosis of sugammadex-induced anaphylaxis. After starting initial standard therapy for anaphylaxis, sampling for plasma histamine and serum tryptase evaluation within an appropriate time might be helpful. For precise diagnosis, it is important to perform a skin test for suspicious allergen, including sugammadex and sugammadex-rocuronium complex. However, the exact way to make inclusion complex is not established yet. Thus, when reporting this case of sugammadex anaphylaxis showing positive reactions to both sugammadex and sugammadex-rocuronium complex, simultaneous skin test for sugammadex and sugammadex-rocuronium complex would be helpful for further detection of an allergenic part.\n\nConflicts of Interest\n\nNo potential conflict of interest relevant to this article was reported.\n\nAuthor Contributions\n\nShuChung Choi (Writing – original draft)\n\nSangBin Han (Resources)\n\nJuEun Kwak (Investigation)\n\nJiYung Lee (Writing – review & editing)\n\nFig. 1. Intradermal skin test with suspicious allergen drugs. Sugammadex at both dilutions of 1 : 100 and 1 : 1000 showed positive reaction (5,6). The sugammadex-rocuronium complex also showed positive reaction (7). The red lines are the contour of flare and the blue lines are the contour of wheal. 1: normal saline as negative control, 2: histamine 0.01% as positive control, 3: nicardipine 1 : 100 dilution; 4: rocuronium 1 : 100 dilution, 5: sugammadex 1 : 100 dilution, 6: sugammadex 1 : 1000 dilution, 7: sugammadex-rocuronium complex.\n==== Refs\nReferences\n1 O’Donnell R Hammond J Soltanifar S A confirmed case of sugammadex-induced anaphylaxis in a UK hospital BMJ Case Rep 2017 2017 bcr2017220197 \n2 Ho G Clarke RC Sadleir PH Platt PR The first case report of anaphylaxis caused by the inclusion complex of rocuronium and sugammadex A A Case Rep 2016 7 190 2 27552242 \n3 Yoo JH Kim SI Ok SY Park SY Cho A Han YM Suspected anaphylactic reaction associated with sugammadex: a case report Korean J Anesthesiol 2016 69 413 6 27482323 \n4 Nakanishi T Ishida K Utada K Yamaguchi M Matsumoto M Anaphylaxis to sugammadex diagnosed by skin prick testing using both sugammadex and a sugammadex-rocuronium mixture Anaesth Intensive Care 2016 44 122 4 26673602 \n5 Sadleir PH Russell T Clarke RC Maycock E Platt PR Intraoperative anaphylaxis to sugammadex and a protocol for intradermal skin testing Anaesth Intensive Care 2014 42 93 6 24471669 \n6 Miyazaki Y Sunaga H Kida K Hobo S Inoue N Muto M Incidence of anaphylaxis associated with sugammadex Anesth Analg 2018 126 1505 8 29064876 \n7 Tsur A Kalansky A Hypersensitivity associated with sugammadex administration: a systematic review Anaesthesia 2014 69 1251 7 24848211 \n8 Takazawa T Mitsuhata H Mertes PM Sugammadex and rocuronium‑induced anaphylaxis J Anesth 2016 30 290 7 26646837 \n9 Hsu Blatman KS Hepner DL Current knowledge and management of hypersensitivity to perioperative drugs and radiocontrast media J Allergy Clin Immunol Pract 2017 5 587 92 28483312 \n10 Krishna MT York M Chin T Gnanakumaran G Heslegrave J Derbridge C Multi-centre retrospective analysis of anaphylaxis during general anaesthesia in the United Kingdom: aetiology and diagnostic performance of acute serum tryptase Clin Exp Immunol 2014 178 399 404 25070464 \n11 Okuno A Matsuki Y Tabata M Shigemi K A suspected case of coronary vasospasm induced by anaphylactic shock caused by rocuronium-sugammadex complex J Clin Anesth 2018 48 7 29660702 \n12 Hotta E Tamagawa-Mineoka R Masuda K Taura M Nakagawa Y Kanehisa FA Anaphylaxis caused by γ-cyclodextrin in sugammadex Allergol Int 2016 65 356 8 27062217 \n13 de Kam PJ Nolte H Good S Yunan M Williams-Herman DE Burggraaf J Sugammadex hypersensitivity and underlying mechanisms: a randomised study of healthy non-anaesthetised volunteers Br J Anaesth 2018 121 758 67 30236238 \n14 Min KC Bondiskey P Schulz V Woo T Assaid C Yu W Hypersensitivity incidence after sugammadex administration in healthy subjects: a randomised controlled trial Br J Anaesth 2018 121 749 57 30236237 \n15 Jimenez-Rodriguez TW Garcia-Neuer M Alenazy LA Castells M Anaphylaxis in the 21st century: phenotypes, endotypes, and biomarkers J Asthma Allergy 2018 11 121 42 29950872\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2005-6419", "issue": "73(4)", "journal": "Korean journal of anesthesiology", "keywords": "Anaphylaxis; General anesthesia; Hypotension; Rocuronium; Skin test; Sugammadex; Urticaria", "medline_ta": "Korean J Anesthesiol", "mesh_terms": "D000707:Anaphylaxis; D004338:Drug Combinations; D006801:Humans; D007431:Intraoperative Complications; D008297:Male; D008875:Middle Aged; D003473:Neuromuscular Nondepolarizing Agents; D000077123:Rocuronium; D000077122:Sugammadex", "nlm_unique_id": "101502451", "other_id": null, "pages": "342-346", "pmc": null, "pmid": "31619026", "pubdate": "2020-08", "publication_types": "D002363:Case Reports", "references": "30236238;28483312;26646837;29950872;25070464;27552242;29064876;27482323;27062217;30236237;24471669;26673602;29660702;24848211;28501827", "title": "Anaphylaxis induced by sugammadex and sugammadex-rocuronium complex -a case report.", "title_normalized": "anaphylaxis induced by sugammadex and sugammadex rocuronium complex a case report" }

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"activesubstance": { "activesubstancename": "ROCURONIUM BROMIDE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GENERAL ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESMERON" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SUGAMMADEX" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ORTHOPAEDIC PROCEDURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SUGAMMADEX" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "NICARDIPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.5 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NICARDIPINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ROCURONIUM BROMIDE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUROMUSCULAR BLOCKING THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESMERON" }, { "actiondrug": null, "activesubstance": null, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (6 VOL%)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DESFLURANE/OXYGEN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SUGAMMADEX" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUROMUSCULAR BLOCKADE REVERSAL", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SUGAMMADEX" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MIDAZOLAM HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIDAZOLAM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "120 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GENERAL ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "120", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPOFOL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SUGAMMADEX" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GENERAL ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SUGAMMADEX" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "REMIFENTANIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (RATE OF 0.03-0.07 UG/KG/MIN)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "REMIFENTANIL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ROCURONIUM BROMIDE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ORTHOPAEDIC PROCEDURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESMERON" } ], "patientagegroup": null, "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "64", "reaction": [ { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Urticaria", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Anaphylactic reaction", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHOI, S.. ANAPHYLAXIS INDUCED BY SUGAMMADEX AND SUGAMMADEX- ROCURONIUM COMPLEX: A CASE REPORT. KOREAN JOURNAL OF ANESTHESIOLOGY. 2019?10.4097/KJA.19344", "literaturereference_normalized": "anaphylaxis induced by sugammadex and sugammadex rocuronium complex a case report", "qualification": "1", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20191127", "receivedate": "20191029", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16969906, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" } ]

{ "abstract": "Drug toxicity is traditionally treated by reducing the amount of the drug absorbed, enhancing elimination, and providing supportive care. Once the drug has been absorbed, there are few methods that help decrease morbidity and mortality caused by a toxic drug level. Albumin infusion is a new approach that changes that, as it can rapidly reverse a toxic drug level back to a therapeutic level. It is believed with most drugs that the toxic effects are related to the total amount of the free drug. In this method, albumin binds to the free drug and acts as a reservoir or depot from which the drug is slowly released to the free form, thereby limiting the effects of drug toxicity. In this case report, an elderly female patient who experienced phenytoin toxicity was treated with albumin infusion, after which her phenytoin level returned to a therapeutic level with corresponding improvements in her symptoms. Based on our calculations, it was predicted that a small amount of albumin would reverse the patient's toxic symptoms. With this approach, the patient's toxic symptoms improved when free phenytoin levels dropped from 15 to 8 μmol/L. Albumin infusion is a promising new therapy that can rapidly reverse a toxic drug level back to a therapeutic level by binding the free drug to albumin.", "affiliations": "Alberta Health Services, Calgary, AB, Canada.", "authors": "Tatlow|Dean|D|;Poothencheri|Sreeja|S|;Bhangal|Ranjit|R|;Tatlow|Corinne|C|", "chemical_list": "D000418:Albumins; D000927:Anticonvulsants; D010672:Phenytoin", "country": "Australia", "delete": false, "doi": "10.1111/1440-1681.12358", "fulltext": null, "fulltext_license": null, "issn_linking": "0305-1870", "issue": "42(4)", "journal": "Clinical and experimental pharmacology & physiology", "keywords": "chemotherapy; drug toxicity; phenytoin; treatment", "medline_ta": "Clin Exp Pharmacol Physiol", "mesh_terms": "D000369:Aged, 80 and over; D000418:Albumins; D000927:Anticonvulsants; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008954:Models, Biological; D010672:Phenytoin; D011041:Poisoning; D011485:Protein Binding; D013997:Time Factors; D016896:Treatment Outcome", "nlm_unique_id": "0425076", "other_id": null, "pages": "389-93", "pmc": null, "pmid": "25586596", "pubdate": "2015-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Novel method for rapid reversal of drug toxicity: a case report.", "title_normalized": "novel method for rapid reversal of drug toxicity a case report" }

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NOVEL METHOD FOR RAPID REVERSAL OF DRUG TOXICITY: A CASE REPORT.. 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{ "abstract": "BACKGROUND\nWe aimed to evaluate the efficiency and safety of cis/carboplatin plus gemcitabine, which was previously used for mesothelioma but with no recorded proof of its efficiency, compared with cis/carboplatin plus pemetrexed, which is known to be effective in mesothelioma, in comparable historical groups of malignant pleural mesothelioma.\n\n\nMETHODS\nOne hundred and sixteen patients received cis/carboplatin plus pemetrexed (group 1), while 30 patients received cis/carboplatin plus gemcitabine (group 2) between June 1999 and June 2012. The two groups were compared in terms of median survival and adverse events to chemotherapy.\n\n\nRESULTS\nThe mean ages of groups 1 and 2 were 60.7 and 60.8 years, respectively. Most of the patients (78.1%) had epithelial type tumors, and 47% of the patients had stage IV disease. There was no difference between the two groups in terms of age, gender, asbestos exposure, histology, stage, Karnofsky performance status, presence of pleurodesis, prophylactic radiotherapy, second-line chemotherapy and median hemoglobin and serum albumin levels. The median survival time from diagnosis to death or the last day of follow up with a 95% confidence interval was 12 ± 0.95 months (95% CI: 10.15-13.85) for group 1 and 11.0 ± 1.09 months (95% CI: 8.85-13.15) for group 2 (Log-Rank: 0.142; p = 0.706). The median survival time from treatment to death or the last day of follow-up with a 95% confidence interval was 11.0 ± 0.99 months (95% CI: 9.06-12.94) for group 1 and 11.0 ± 1.52 months (95% CI: 8.02-13.97) for group 2 (Log-Rank: 0.584; p = 0.445). The stage and Karnofsky performance status were found to be significant variables on median survival time by univariate analysis. After adjusting for the stage and Karnofsky performance status, the chemotherapy schema was not impressive on median survival time (OR: 0.837; 95% CI: 0.548-1.277; p = 0.409). The progression free survival was 7.0 ± 0.61 months for group I and 6.0 ± 1.56 months for group II (Log-Rank: 0.522; p = 0.470). The treatment was generally well tolerated, and the side effects were similar in both groups.\n\n\nCONCLUSIONS\nThe study indicates that platinum-based gemcitabine is effective and a safe schema in malignant pleural mesothelioma. Further research should include large randomized phase III trials comparing these agents.", "affiliations": "Lung and Pleural Cancers Research and Clinical Center, Eskisehir Osmangazi University, Eskisehir, Turkey. guntuluak@gmail.com.;Lung and Pleural Cancers Research and Clinical Center, Eskisehir Osmangazi University, Eskisehir, Turkey.;Department of Chest Diseases, Eskisehir Osmangazi University, Medical Faculty, Eskisehir, Turkey.;Lung and Pleural Cancers Research and Clinical Center, Eskisehir Osmangazi University, Eskisehir, Turkey.", "authors": "Ak|Guntulu|G|;Metintas|Selma|S|;Akarsu|Muhittin|M|;Metintas|Muzaffer|M|", "chemical_list": "D009944:Organoplatinum Compounds; D000068437:Pemetrexed; D003841:Deoxycytidine; C056507:gemcitabine", "country": "England", "delete": false, "doi": "10.1186/s12885-015-1519-z", "fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 26156324151910.1186/s12885-015-1519-zResearch ArticleThe effectiveness and safety of platinum-based pemetrexed and platinum-based gemcitabine treatment in patients with malignant pleural mesothelioma Ak Guntulu +90 222 239 2979 / 7049-7052guntuluak@gmail.com 12Metintas Selma 13Akarsu Muhittin 2Metintas Muzaffer 121 Lung and Pleural Cancers Research and Clinical Center, Eskisehir Osmangazi University, Eskisehir, Turkey 2 Department of Chest Diseases, Eskisehir Osmangazi University, Medical Faculty, Eskisehir, Turkey 3 Department of Public Health, Eskisehir Osmangazi University, Medical Faculty, Eskisehir, Turkey 9 7 2015 9 7 2015 2015 15 51012 1 2015 26 6 2015 © Ak et al. 2015This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nWe aimed to evaluate the efficiency and safety of cis/carboplatin plus gemcitabine, which was previously used for mesothelioma but with no recorded proof of its efficiency, compared with cis/carboplatin plus pemetrexed, which is known to be effective in mesothelioma, in comparable historical groups of malignant pleural mesothelioma.\n\nMethods\nOne hundred and sixteen patients received cis/carboplatin plus pemetrexed (group 1), while 30 patients received cis/carboplatin plus gemcitabine (group 2) between June 1999 and June 2012. The two groups were compared in terms of median survival and adverse events to chemotherapy.\n\nResults\nThe mean ages of groups 1 and 2 were 60.7 and 60.8 years, respectively. Most of the patients (78.1 %) had epithelial type tumors, and 47 % of the patients had stage IV disease. There was no difference between the two groups in terms of age, gender, asbestos exposure, histology, stage, Karnofsky performance status, presence of pleurodesis, prophylactic radiotherapy, second–line chemotherapy and median hemoglobin and serum albumin levels. The median survival time from diagnosis to death or the last day of follow up with a 95 % confidence interval was 12 ± 0.95 months (95 % CI: 10.15–13.85) for group 1 and 11.0 ± 1.09 months (95 % CI: 8.85–13.15) for group 2 (Log-Rank: 0.142; p = 0.706). The median survival time from treatment to death or the last day of follow-up with a 95 % confidence interval was 11.0 ± 0.99 months (95 % CI: 9.06–12.94) for group 1 and 11.0 ± 1.52 months (95 % CI: 8.02–13.97) for group 2 (Log-Rank: 0.584; p = 0.445). The stage and Karnofsky performance status were found to be significant variables on median survival time by univariate analysis. After adjusting for the stage and Karnofsky performance status, the chemotherapy schema was not impressive on median survival time (OR: 0.837; 95 % CI: 0.548–1.277; p = 0.409). The progression free survival was 7.0 ± 0.61 months for group I and 6.0 ± 1.56 months for group II (Log-Rank: 0.522; p = 0.470). The treatment was generally well tolerated, and the side effects were similar in both groups.\n\nConclusions\nThe study indicates that platinum-based gemcitabine is effective and a safe schema in malignant pleural mesothelioma. Further research should include large randomized phase III trials comparing these agents.\n\nissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nMalignant pleural mesothelioma (MPM) is an aggressive tumor and remains a significant worldwide health problem because of its poor prognosis and increasing incidence [1]. Most of the patients have advanced disease at diagnosis and are not eligible for multimodality treatment. Platinum–based chemotherapy is the most effective systemic therapy in patients with advanced stage disease. Currently, following a randomized phase III study, the combination of cisplatin and pemetrexed is widely used for the systemic treatment of advanced disease [2]. Another randomized phase III study of cisplatin and raltitrexed in MPM showed similar results [3]. However, there is currently no universally accepted standard chemotherapeutic regimen for MPM.\n\nThe combination of cisplatin and gemcitabine was widely used for MPM throughout the world before the combination of antifolates and platinum compounds. Some studies reported that the combination of platinum and gemcitabine is also a reasonable first–line option for the systemic therapy of MPM because of its acceptable toxicity profile, good response and survival rates, and symptom-relieving effects [4–11]. Although gemcitabine in combination with cisplatin or carboplatin shows definite activity in MPM, given the lack of phase III evidence, the use of gemcitabine as a first–line therapy is not supported. Gemcitabine in combination with platinum or alone is being used in the clinic as a second–line regimen for MPM.\n\nThere are few studies compared the two regimens. They showed that platinum – based doublets might represent similar therapeutic activity in MPM [12–14]. Pemetrexed is an expensive agent, and when it is used, folic acid and vitamin B12 supplementation are required to reduce the toxicity. In our study, we aimed to evaluate the efficiency and safety of cis/carboplatin plus gemcitabine compared with cis/carboplatin plus pemetrexed, in comparable historical groups of malignant pleural mesothelioma.\n\nMethods\nPatients\nBetween June 1999 and June 2012, a total of 343 patients were histologically diagnosed with MPM at the Chest Disease Department of Eskisehir Osmangazi University Hospital in Turkey. After diagnosis, the best supportive care, chemotherapy, surgery, radiotherapy or combination therapies were given to the patients in the Pulmonary Oncology Unit of the Chest Disease Department. The study was approved by the Ethical Committee of Eskisehir Osmangazi University (number: 08.03.2000/242), and all of the patients provided written informed consent. A total of 146 patients, who had platinum compounds in combination with gemcitabine or pemetrexed, were enrolled in this study. The study inclusion criteria were as follows: no prior therapy except local radiotherapy to the entry site; measurable or evaluable disease; KPS of 70–100; age greater than 18 years; and adequate bone marrow (leukocytes ≥ 3000 / μL, granulocytes ≥ 1500 / μL, hemoglobin ≥ 10 g / dL, and platelets ≥ 100,000 μL), renal (creatinine ≤ 1.5 mg / dL or creatinine clearance ≥ 60 mL / min), hepatic (total bilirubin within normal institutional limits and AST and ALT ≤ 2.5 X upper limit of normal), and coagulation (prothrombin time international normalized ratio ≤ 1.5) functions were required. All of the patients provided written informed consent before chemotherapy according to our institutional guidelines. One hundred and ninety-seven patients were excluded from the study: 81 patients had only the best supportive care; 62 patients had surgical treatment; 22 patients received different chemotherapeutic regimens as first–line treatment; 2 patients died due to reasons unrelated to MPM or chemotherapy (pulmonary embolism and pneumonia); 20 patients were not be able to evaluate for a chemotherapy response; and 10 patients were not followed.\n\nClinical data, including age, gender, history of asbestos exposure, histology, stage, Karnofsky Performance Status (KPS), treatment history, side effects, response to chemotherapy, pleurodesis, prophylactic radiotherapy, second–line chemotherapy, baseline hemoglobin, baseline serum albumin and survival characteristics were collected for all the patients. All of the patients were staged according to the International Mesothelioma Interest Group (IMIG) staging system [15]. The tumor response was evaluated using a modified Response Evaluation Criteria in Solid Tumors (RECIST) [16].\n\nTreatment\nThe patients were classified into two groups according to their chemotherapy regimen: 116 patients received cis/carboplatin and pemetrexed (group 1), and 30 patients received cis/carboplatin and gemcitabine (group 2). The two groups were compared in terms of epidemiological, clinical and survival characteristics. The side effects of chemotherapy were also recorded.\n\nIn the pulmonary oncology unit of our clinic, cis/carboplatin and gemcitabine regimen was used as a first – line chemotherapy regimen until October 2005. Cis/carboplatin and pemetrexed has been used since October 2005. Gemcitabine 1250 mg/m2 was given intravenously on days 1 and 8 of a 21-day cycle, followed by intravenous cisplatin 75 mg/m2 or carboplatin 300 mg/m2 on day 1. Pemetrexed 500 mg/m2 was given intravenously on day one, followed by cisplatin 80 mg/m2 or carboplatin 300 mg/m2, intravenously on day 1, which was repeated every 21 days. Before the administration of pemetrexed, folic acid, vitamin B12, and dexamethasone supplementation were provided. Antiemetic therapy with 5-hydroxytryptamine antagonists and dexamethasone was given intravenously on day 1 and, thereafter, orally for 3 to 5 days. Chemotherapy was given for 4 to 6 cycles or until disease progression, unacceptable adverse events, or patient unwillingness to chemotherapy. Additionally, the use of any second-line chemotherapy was recorded. Adverse events were graded according to the World Health Organization (WHO) criteria and were assessed before chemotherapy [17]. All the side effects of chemotherapy were recorded. Dose adjustments for adverse events were based on a stepwise reduction schedule.\n\nA history and physical examination, complete blood count and differential, chemistry panel, electrocardiogram, chest radiograph, and chest and abdominal computed tomography (CT) scans were performed at baseline. Bone scans and brain magnetic resonance imaging were performed only if clinically indicated. Thereafter, the history and physical examination were performed every 21 days. The complete blood count and differential and chemistry panel were performed weekly. The tumor response to chemotherapy was evaluated by computed tomography (CT) scans, obtained every two or three cycles of chemotherapy. Thereafter, CT scans were performed at 3 monthly intervals until disease progression.\n\nStatistical analysis\nData were collected, analyzed, and evaluated in the Lung and Pleural Cancers Research and Clinical Center of Eskisehir Osmangazi University. All of the analyses were performed using a statistical software (SPSS, version 11.5). The characteristics of the patients, according to their chemotherapy schedule, were compared using a t-test for continuous variables and Pearson X2 test or Fisher’s Exact test for frequency. The median hemoglobin and serum albumin levels were compared using Mann–Whitney U test. The median survival times and progression – free survival with 95 % confidence intervals (CI) were estimated for each group. The survival curves were generated using the Kaplan – Meier method. All of the patients were followed until death or for a minimum period of 1 year. The median survival times were compared between the chemotherapy groups using both an unadjusted and a stratified (by stage, histology, KPS) log-rank test. The Cox proportional hazards regression models were fit to assess the effect of treatment, stage, histology, KPS, and other potential prognostic factors of survival. The interactions between treatments and stratification factors were explored using the Cox model. The significance level was considered to be 5 % (p < 0.05), and the approach used was bilateral.\n\nResults\nOne hundred and sixteen patients received cis/carboplatin plus pemetrexed (group 1) between October 2005 and June 2012, and 30 patients received cis/carboplatin plus gemcitabine (group 2) between June 1999 and September 2005. The mean ages of groups 1 and 2 were 60.7 and 60.8 years, respectively. The female ratios of groups 1 and 2 were 50 % and 53 %, respectively. Most of the patients (98 %) were exposed to asbestos for a major part of their life. Most of the patients (78.1 %) had epithelial type tumors, and approximately half of them had stage IV disease (47 %).\n\nThere was no difference between the two groups in terms of age, sex, asbestos exposure, KPS, histological cell type, stage, presence of pleurodesis, prophylactic radiotherapy, second–line chemotherapy and baseline hemoglobin and serum albumin levels (Table 1). These results showed that they were comparable groups.Table 1 Patient demographics and clinical characteristics\n\nDemographics or clinical characteristics\tCis/carboplatin and pemetrexed (n = 116)\tCis/carboplatin and gemcitabine (n = 30)\tp value\t\nMean age, years\t60.7 ± 10.9\t60.8 ± 9.9\t0.945\t\nMale: Female\t58 : 58\t14 : 16\t0.745\t\nAsbestos exposure, n (%)\t113 (97.4)\t29 (96.7)\t0.827\t\nMean Karnofsky Performance Status\t85.7 ± 9.9\t80.3 ± 8.7\t0.062\t\nHistology, n (%)\t\t\t\t\nEpithelial\t92 (79.3)\t22 (73.3)\t1.00\t\nSarcomatous\t9 (7.8)\t2 (6.7)\t\nMixed\t12 (10.3)\t5 (16.7)\t\nUnidentified\t3 (2.6)\t1 (3.3)\t\nStage, n (%)\t\t\t\t\nI\t6 (5.2)\t2 (6.7)\t0.662\t\nII\t12 (10.4)\t2 (6.7)\t\nIII\t41 (35.7)\t14 (46.7)\t\nIV\t56 (48.7)\t12 (40.0)\t\nPleurodesis, n (%)\t41 (35.3)\t10 (33.3)\t0.837\t\nProphylactic radiotherapy, n (%)\t22 (19.0)\t2 (6.7)\t0.083\t\nSecond–line chemotherapy, n (%)\t36 (31.0)\t8 (26.7)\t0.642\t\nMedian baseline hemoglobin, g / dL\t12.5\t12.3\t0.679\t\nMedian baseline serum albumin, g / dL\t3.8\t3.6\t0.336\t\n\n\nThere was no significant difference between the objective response rates to chemotherapy in the two treatment groups: 32.7 % for group I, and 36.7 % for group II (p = 0.700). The complete response rates were 3.4 % vs. 6.7 %, while the partial response rates were 29.3 % vs. 30.0 % in groups I and II, respectively. Stable disease occurred in 39.7 % and 30 % of the patients in groups I and II, respectively. The one-year survival rate for group I was 58.6 % and 56.6 % for group II; the 2–year survival rate for group I was 20.7 % and 13.3 % for group II; the 3 – year survival rate was 9.5 % for group I and 10 % for group II.\n\nThe median survival time from diagnosis to death or the last day of follow-up with a 95 % confidence interval was 12.0 ± 0.95 months (95 % CI: 10.15–13.85) for group 1 and 11.0 ± 1.09 months (95 % CI: 8.85–13.15) for group 2. The median survival time of the two groups was not different (Log-Rank: 0.142; p = 0.706). The median survival time from treatment to death or the last day of follow-up with a 95 % confidence interval was 11.0 ± 0.99 months (95 % CI: 9.06–12.94) for group 1 and 11.0 ± 1.52 months (95 % CI: 8.02–13.97) for group 2 (Log-Rank: 0.584; p = 0.445) (Fig. 1).Fig. 1 Median survival by treatment groups\n\n\n\nStage and KPS were found as significant variables of median survival time by univariate analysis in the two groups (p = 0.002 and p = 0.045, respectively). After adjusting for stage and KPS, the chemotherapy regimen was not impressive on median survival time (OR: 0.837; 95 % CI: 0.548–1.277; p = 0.409).\n\nThe progression free survival was 7.0 ± 0.61 months (95 % CI: 5.079–8.20) for group I and 6.0 ± 1.56 months (95 % CI: 2.94–9.06) for group II (Log-Rank: 0.522; p = 0.470) (Fig. 2).Fig. 2 Progression – free survival by treatment groups\n\n\n\nThe treatment was generally well tolerated, and the side effects were similar in both the groups (Table 2).Table 2 Grade III and IV toxicities according to treatment groups\n\nToxicity\tGroup I\tGroup II\tP*\t\nn (%)\tn (%)\t\nNeutropenia\t19 (16.3)\t3 (10.0)\t0.568\t\nAnemia\t4 (3.4)\t1 (3.3)\t1.000\t\nThrombocytopenia\t6 (5.1)\t4 (13.3)\t0.123\t\nNause / vomiting\t8 (6.9)\t5 (16.6)\t0.142\t\nNephrotoxicity\t5 (4.3)\t-\t0.584\t\nFebrile neutropenia\t2 (1.7)\t2 (6.6)\t0.187\t\nGroup I: cis/carboplatin + pemetrexed; Group II: cis/carboplatin + gemcitabine; a: Only the worst WHO grade was reported for each patient\n\n*: Fisher’s Exact Test\n\n\n\nDiscussion\nThere is currently no widely accepted therapy for MPM. The necessity for more effective treatments for patients with mesothelioma is obvious. A number of novel agents have been assessed to date. Several classes of drugs are being explored, including those that affect DNA transcription, cell-cycle progression, angiogenesis, and immune tolerance. Several ongoing or recently completed phase II and III trials using novel agents such as vorinostat, everolimus, CBP501, MORAb-009, NGR-hTNF, WT1 vaccine, bevacizumab, cediranib, and thalidomide have been conducted [18]. Although some of those targeted therapies have seemed to be promising, none of these agents have been implemented in daily practice. Therefore, most efforts are directed towards improving standard first-line therapy with antifolates and platinum compounds, or developing effective second-line treatments.\n\nPlatinum–based chemotherapy seems to be the most effective systemic therapy in patients with advanced stage disease. Platinum based gemcitabine was widely used in the late 1990s and 2000s as a part of phase studies in MPM because of the synergy between gemcitabine and platinum compounds [4–11]. In those studies, 9.6 to 13 months of overall survival time and 12 % to 48 % of the response rates were reported [4–11]. Variable activity has been observed with gemcitabine and platinum compounds in those studies because of small sample size, heterogeneity in prognostic factors, and different response measurements. Additionally, the symptom control was better than the control arm in some of these studies [4, 6, 7, 10]. Although the results have been variable, the response rate and survival data of the studies have been encouraging in advanced stage mesothelioma. While some physicians recommend only supportive care for mesothelioma, platin-based gemcitabine has become a widely used regimen in front-line chemotherapy for mesothelioma in some clinics. We used platin-based gemcitabine before pemetrexed, between June 1999 and September 2005, for mesothelioma in our clinic in Turkey.\n\nTwo large randomized phase III trials with combinations of antifolate and cisplatin have demonstrated a survival advantage with this combination compared with single agent cisplatin [2, 3]. In the trial comparing cisplatin plus pemetrexed to cisplatin alone, the response rate with the combination was 41 % in comparison to 17 % with cisplatin [2]. The median survival time was 12.1 months with the combination regimen. In the other phase III study with raltitrexed, the response rate was 23 %, with a median survival time of 11.4 months [3]. Following the study of Vogelzang et al., platin-based pemetrexed was approved by the FDA as a first-line treatment in mesothelioma. Thereafter, within several years, platinum and antifolate, especially pemetrexed, has been established as a standard of care in front-line chemotherapy for mesothelioma worldwide. Physicians have some concern about these studies. Neither cisplatin-based pemetrexed nor raltitrexed were compared with another doublet. Both studies used only cisplatin in the control arm. Interestingly, there is not much interest in raltitrexed. First, they are expensive agents, especially pemetrexed. When increasing incidence of mesothelioma is taken into account, pemetrexed is not cost effective for most of the patients especially in developing countries. Additionally, supplementation of folic acid and vitamin B12 is needed to reduce the toxicity of pemetrexed.\n\nAlthough, following the study of Vogelzang et al. in 2003, cisplatin-based pemetrexed has been established as first-line chemotherapy for mesothelioma in most of the world, gemcitabine and cisplatin is still accepted as an effective treatment regimen in phase II studies [19, 20].\n\nThere is not sufficient number of study compared platinum based doublets such as pemetrexed, raltitrexed, gemcitabine and vinorelbine with one another. We hypothesize that those doublets that are platin plus pemetrexed and platin plus gemcitabine may be comparable in terms of efficacy and safety, based on previous phase II studies of gemcitabine. The good response rate and median survival time observed in our study suggest that the combination of platin plus gemcitabine may have similar effects compared to pemetrexed plus cisplatin.\n\nLee et al. reviewed platinum analogs with either gemcitabine or pemetrexed in 81 mesothelioma patients, retrospectively [12]. They reported similar overall survival and 1– and 2–year survival rates with both regimens. However, in their study, the survival was better in the group that was able to receive second–line systemic therapy. Another study comparing gemcitabine plus cisplatin and pemetrexed plus carboplatin came from Cairo by Habib et al [13]. They set up a randomized phase II study that included 40 patients with mesothelioma. In their study, the response was superior in the pemetrexed group (78.9 % vs. 47.6 %). However, cumulative survival at 1.5 years was similar in the two groups. Additionally, patients included in the pemetrexed group were younger than the patients in the gemcitabine group (49 years old vs. 62 years old; p < 0.001). Age is a significant prognostic factor in mesothelioma and may be responsible for the good response to pemetrexed. Another small study, including total 30 patients, did not show a significant difference in terms of response rate and overall survival time between the two groups [14].\n\nIn the current study, the regimens were well tolerated with no toxic deaths. The frequencies and severity of toxicities experienced with platin plus gemcitabine or pemetrexed regimens appear to be comparable to those found in the literature.\n\nConclusions\nIn conclusion, the study indicates that platinum-based gemcitabine is effective and a safe schema in malignant pleural mesothelioma. To provide a more cost-effective treatment approach for advanced MPM, further research should include randomized controlled phase III trials comparing platinum doublets plus antifolate and platinum doublets plus gemcitabine or vinorelbine.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nGA participated in the design of the study, collected the data and drafted the manuscript. SM participated in the design of the study and performed the statistical analysis. MA helped to collect the data. MM participated in its design and helped to draft the manuscript. All authors read and approved the final manuscript.\n==== Refs\nReferences\n1. Ray M Kindler HL Malignant pleural mesothelioma: an update on biomarkers and treatment Chest 2009 136 888 96 10.1378/chest.08-2665 19736192 \n2. Vogelzang NJ Rusthoven JJ Symanowski J Denham C Kaukel E Ruffie P Gatzemeier U Boyer M Emri S Manegold C Niyikiza C Paoletti P Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma J Clin Oncol 2003 21 2636 44 10.1200/JCO.2003.11.136 12860938 \n3. van Meerbeeck JP Gaafar R Manegold C van Klaveren RJ van Marck EA Vincent M Legrand C Bottomley A Debruyne C Giaccone G Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: an intergroup study of the European Organization for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada J Clin Oncol 2005 23 6881 9 10.1200/JCO.20005.14.589 16192580 \n4. Byrne MJ Davidson JA Musk AW Dewar J van Hazel G Buck M de Klerk NH Robinson BW Cisplatin and gemcitabine treatment for malignant mesothelioma: a phase II study J Clin Oncol 1999 17 25 30 10458214 \n5. Van Haarst JMW Baas P Manegold C Schouwink JH Burgers JA de Bruin HG Mooi WJ van Klaveren RJ de Jonge MJ van Meerbeeck JP Multicentre phase II study of gemcitabine and cisplatin in malignant pleural mesothelioma Br J Cancer 2002 86 342 5 10.1038/sj.bjc.6600118 11875695 \n6. Nowak AK Byrne MJ Williamson R Ryan G Segal A Fielding D Mitchell P Musk AW Robinson BW Multicentre phase II study of cisplatin and gemcitabine for malignant mesothelioma Br J Cancer 2002 87 491 6 10.1038/sj.bjc.6600505 12189542 \n7. Favaretto AG Aversa SML Paccagnella A Manzini VP Palmisano V Oniga F Stefani M Rea F Bortolotti L Loreggian L Monfardini S Gemcitabine combined with carboplatin in patients with malignant pleural mesothelioma Cancer 2003 97 2791 7 10.1002/cncr.11405 12767092 \n8. Schutte W Blankenburg T Lauerwald K Schreiber J Bork I Wollscgkaeger B Treutler D Schneider CP Bonner R A multicenter phase II study of gemcitabine and oxaliplatin for malignant pleural mesothelioma Clin Lung Cancer 2003 4 294 7 10.3816/CLC.2003.n.009 14609447 \n9. Castagneto B Zai S Dongiovanni D Muzio A Bretti S Numico G Botta M Cisplatin and gemcitabine in malignant pleural mesothelioma: a phase II study Am J Clin Oncol 2005 28 223 6 10.1097/01.coc.0000144852.75613.56 15923792 \n10. Utkan G Buyukcelik A Yalcin B Akbulut H Demirkazik A Dincol D Onur H Goren D Mousa U Senler FC Icli F Divided dose of cisplatin combined with gemcitabine in malignant mesothelioma Lung Cancer 2006 53 367 74 10.1016/j.lungcan.2006.04.014 16828196 \n11. Kalmadi SR Rankin C Kraut MJ Jacobs AD Petrylak DP Adelstein DJ Keohan ML Taub RN Borden EC Gemcitabine and cisplatin in unresectable malignant mesothelioma of the pleura: a phase II study of the Southwest Oncology Group (SWOG 9810) Lung Cancer 2008 60 259 63 10.1016/j.lungcan.2007.09.018 18006112 \n12. Lee CW Murray N Anderson H Rao SC Bishop W Outcomes with first-line platinum-based combination chemotherapy for malignant pleural mesothelioma: a review of practice in British Columbia Lung Cancer 2009 64 308 13 10.1016/j.lungcan.2008.09.008 19004520 \n13. Habib EE Fahmy ES Chemotherapy management of malignant pleural mesothelioma: a phase II study comparing two popular chemotherapy regimens Clin Transl Oncol 2013 15 965 8 10.1007/s12094-013-1015-3 23408040 \n14. Shukuya T Takahashi T Imai H Tokito T Ono A Akamatsu H Taira T Kenmotsu H Naito T Murakami H Endo M Yamamoto N Comparison of cisplatin plus pemetrexed and cisplatin plus gemcitabine for the treatment of malignant pleural mesothelioma in Japanese patients Respir Investig 2014 52 101 6 10.1016/j.resinv.2013.07.002 24636265 \n15. Rusch VW A proposed new international TNM staging system for malignant pleural mesothelioma. From the International Mesothelioma Interest Group Chest 1995 108 1122 8 10.1378/chest.108.4.1122 7555126 \n16. Byrne MJ Nowak AK Modified RECIST criteria for assessment of response in malignant pleural mesothelioma Ann Oncol 2004 15 257 60 10.1093/annonc/mdh059 14760119 \n17. Miller AB Hoogstraten B Staquet M Winkler A Reporting results of cancer treatment Cancer 1981 47 207 14 10.1002/1097-0142(19810101)47:1<207::AID-CNCR2820470134>3.0.CO;2-6 7459811 \n18. Zauder MG Krug LM Novel therapies in phase II and III trials for malignant pleural mesothelioma J Natl Compr Canc Netw 2012 10 42 7 22223868 \n19. Kindler HL Karrison TG Gandara DR Lu C Krug LM Stevenson JP Janne PA Quinn DI Koczywas MN Brahmer JR Albain KS Taber DA Armato SG Vogelzang NJ Chen HX Stadler WM Vokes EE Multicenter, double-blind, placebo-controlled, randomized phase II trial of gemcitabine/cisplatin plus bevacizumab or placebo in patients with malignant mesothelioma J Clin Oncol 2012 30 2509 15 10.1200/JCO.2011.41.5869 22665541 \n20. Arrieta O Lopez-Macias D Mendoza-Garcia VO Bacon-Foseca L Munoz-Montano W Macedo-Perez EO Muniz-Hernandez S Blake-Cerda M Corona-Cruz JF A phase II trial of prolonged, continuous infusion of low-dose gemcitabine plus cisplatin in patients with advanced malignant pleural mesothelioma Cancer Chemother Pharmacol 2014 73 975 82 10.1007/s00280-014-2429-5 24687408\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2407", "issue": "15()", "journal": "BMC cancer", "keywords": null, "medline_ta": "BMC Cancer", "mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D003841:Deoxycytidine; D005260:Female; D006801:Humans; D017567:Karnofsky Performance Status; D008175:Lung Neoplasms; D008297:Male; D008654:Mesothelioma; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D009944:Organoplatinum Compounds; D000068437:Pemetrexed; D010997:Pleural Neoplasms; D016019:Survival Analysis", "nlm_unique_id": "100967800", "other_id": null, "pages": "510", "pmc": null, "pmid": "26156324", "pubdate": "2015-07-09", "publication_types": "D016430:Clinical Trial; D016428:Journal Article", "references": "18006112;24636265;15923792;7555126;22223868;16192580;19736192;24687408;11875695;22665541;19004520;23408040;14760119;16828196;7459811;14609447;10458214;12860938;12189542;12767092", "title": "The effectiveness and safety of platinum-based pemetrexed and platinum-based gemcitabine treatment in patients with malignant pleural mesothelioma.", "title_normalized": "the effectiveness and safety of platinum based pemetrexed and platinum based gemcitabine treatment in patients with malignant pleural mesothelioma" }

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{ "abstract": "Mesalazine is a well-established 1st line treatment for inflammatory bowel disease (IBD). Cardiotoxicity following 5-aminosalicyclic-acid therapy remains a rare yet serious complication and can often be challenging to distinguish from myocarditis presenting as an extra-intestinal manifestation of IBD.\nWe present a case of a 22-year-old man with a background of ulcerative colitis commenced on a mesalazine preparation for disease progression. He presented to our hospital 12 days following drug initiation with acute chest pain, peak troponin-T of 242 ng/L, dynamic electrocardiogram changes, and severe left ventricular systolic dysfunction on transthoracic echocardiogram. The clinical diagnosis of myopericarditis was suspected and mesalazine was stopped shortly after. Outpatient cardiac magnetic resonance performed 2 weeks following mesalazine cessation demonstrated a recovery of cardiac function with associated symptom and biochemical resolution.\nClinicians should be aware of this potentially fatal adverse effect of a commonly prescribed medication. Symptoms of myocarditis often occur within the early stages of mesalazine initiation, which aids the clinical diagnosis. The mainstay of treatment is to simply discontinue the drug with rapid resolution of symptoms seen without any permanent or long-term cardiac dysfunction. Close liaison with the gastroenterology team is key, as 2nd line IBD therapies are often required for the ongoing management of the patient's colitis.", "affiliations": "Cardiology Department, South Warwickshire NHS Foundation Trust, Lakin Road, Warwick CV34 5BW, UK.", "authors": "Shergill|Simran|S|0000-0003-4761-7297", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1093/ehjcr/ytaa508", "fulltext": "\n==== Front\nEur Heart J Case Rep\nEur Heart J Case Rep\nehjcr\nEuropean Heart Journal: Case Reports\n2514-2119\nOxford University Press\n\n10.1093/ehjcr/ytaa508\nytaa508\nCase Report\nAcademicSubjects/MED00200\nMesalazine-induced myopericarditis: a case report\nhttp://orcid.org/0000-0003-4761-7297\nShergill Simran\nDias Andre Handling Editor\nCambronero-Cortinas Esther Editor\nArcari Luca Editor\nNgo Linh Editor\nThomson Ross Editor\nCardiology Department, South Warwickshire NHS Foundation Trust, Lakin Road, Warwick CV34 5BW, UK\nCorresponding author. Tel: +44 1926 495 321, Email: simran.shergill@nhs.net\n2 2021\n21 12 2020\n21 12 2020\n5 2 ytaa50825 1 2020\n17 3 2020\n24 11 2020\n© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.\n2020\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com\n\nAbstract\n\nBackground\n\nMesalazine is a well-established 1st line treatment for inflammatory bowel disease (IBD). Cardiotoxicity following 5-aminosalicyclic-acid therapy remains a rare yet serious complication and can often be challenging to distinguish from myocarditis presenting as an extra-intestinal manifestation of IBD.\n\nCase summary\n\nWe present a case of a 22-year-old man with a background of ulcerative colitis commenced on a mesalazine preparation for disease progression. He presented to our hospital 12 days following drug initiation with acute chest pain, peak troponin-T of 242 ng/L, dynamic electrocardiogram changes, and severe left ventricular systolic dysfunction on transthoracic echocardiogram. The clinical diagnosis of myopericarditis was suspected and mesalazine was stopped shortly after. Outpatient cardiac magnetic resonance performed 2 weeks following mesalazine cessation demonstrated a recovery of cardiac function with associated symptom and biochemical resolution.\n\nDiscussion\n\nClinicians should be aware of this potentially fatal adverse effect of a commonly prescribed medication. Symptoms of myocarditis often occur within the early stages of mesalazine initiation, which aids the clinical diagnosis. The mainstay of treatment is to simply discontinue the drug with rapid resolution of symptoms seen without any permanent or long-term cardiac dysfunction. Close liaison with the gastroenterology team is key, as 2nd line IBD therapies are often required for the ongoing management of the patient’s colitis.\n\nMyocarditis\nMyopericarditis\n5-aminosalicyclic-acid (5-ASA)\nMesalazine\nCardiotoxicity\nInflammatory bowel disease\nCase report\n==== Body\nLearning points\n\nMesalazine can cause myocarditis early after initiation.\n\nClinicians should be aware of the non-infectious causes of myocarditis which would influence management.\n\nDiscontinuation of mesalazine remains the mainstay of treatment with cardiac dysfunction shown to return to baseline functioning.\n\nIntroduction\n\nMesalazine is an established 1st line therapy for inflammatory bowel disease (IBD) and is a common prescription due to a favourable safety profile with proven efficacy in active disease as well as maintaining remission and quiescence.1 Adverse side effects are rare but include agranulocytosis, pancreatitis, peripheral neuropathy, and cardiac inflammation.2 Cardiotoxicity following administration of mesalazine is a potentially fatal complication with a reported incidence up to 0.3%.3,4 Myocarditis may also present as an extra-intestinal manifestation of IBD which can often be challenging to differentiate from 5-aminosalicyclic-acid (5-ASA)-induced myocarditis. We present a case of a 22-year-old man with acute myopericarditis soon after mesalazine initiation.\n\nTimeline\n\nDate\tEvent\t\n2012\tDiagnosis of limited proctitis with minimal symptoms. A watchful wait approach taken.\t\nEarly-Mid 2019\tRelapse of acute colitis requiring oral steroids. Repeat flexible sigmoidoscopy (FOS) arranged to assess disease extent.\t\n12 days prior to admission\tFOS → active disease to the splenic flexure. Patient commenced on a mesalazine preparation alongside weaning prednisolone course.\t\nAdmission\n\nDay 0\n\n\tPresentation with acute chest pain, dyspnoea, and lethargy.\n\nElectrocardiogram (ECG) demonstrated concave ST-segment elevation laterally evolving into T-wave inversion. Blood profile showed a peak troponin-T of 242 ng/L.\n\n\t\nDay 1–3\tTransthoracic echocardiogram (TTE) demonstrated severe left ventricular (LV) systolic dysfunction.\n\nDiagnosis of myocarditis made and medical therapy for heart failure (HF) commenced.\n\nDischarged with planned outpatient cardiac magnetic resonance (CMR).\n\n\t\n2 weeks\tNurse-led HF clinic review; reported ongoing dyspnoea and chest pain.\n\nAngiotensin-converting enzyme inhibitors and beta blocker up-titrated.\n\n\t\n4 weeks\tLiaison with gastroenterology team and mesalazine stopped as suspected causative agent of myocarditis. Remained on weaning prednisolone course.\t\n5 weeks\tNurse-led HF clinic review; symptoms settling with improving exercise tolerance and fewer episodes of chest pain.\t\n6 weeks\tCMR → recovered cardiac function with no active inflammation or fibrosis.\t\n8 weeks\tCardiology clinic review; resolved symptoms, no further chest pain and return to baseline exercise tolerance.\n\nResolution of ECG T-wave inversion and repeat troponin-T measured at <5 ng/L.\n\n\t\n5 months\tSurveillance TTE demonstrated ongoing preserved LV systolic function.\t\n\nCase presentation\n\nA 22-year-old Caucasian non-smoker male presented to our hospital with sudden onset left-sided chest pain radiating to the shoulder tip. The pain was sharp in nature and exacerbated by deep inspiration and supine positioning. He also complained of preceding dyspnoea and general fatigue. There was no associated cough, fever, or coryzal prodrome. Past medical history included ulcerative colitis (UC) diagnosed at age 17. A watchful wait approach had been taken due to limited proctitis, however symptoms relapsed in the months prior to admission and he required multiple steroid courses. A repeat flexible sigmoidoscopy demonstrated active disease to the splenic flexure and a mesalazine preparation was commenced 12 days prior to presentation alongside a weaning course of steroids. Despite this, his colitis was still flaring on arrival to hospital with generalized abdominal pain, increased frequency, and bloody diarrhoea. Family history was strong for unprovoked deep vein thrombosis in his mother and maternal grandfather. Medication history on admission included mesalazine 1.6 g b.i.d. and prednisolone 40 mg.\n\nOn arrival, he was afebrile, normotensive with normal oxygen saturations. Cardio-respiratory examination was unremarkable. Chest X-ray demonstrated clear lung fields. Blood profile revealed an elevated white cell count of 19.46 × 109/L (normal: 4–11 × 109/L), D-dimer of 1.81 mg/L (normal: <0.50 mg/L), troponin-T of 209 ng/L (normal: <14ng/L), and normal serum electrolytes. Resting 12-lead electrocardiogram (ECG) (Figure 1) demonstrated sinus rhythm and concave ST-segment elevation in leads V4–V6 with associated biphasic T-waves. He suffered ongoing chest pain during the first 24 h of presentation and repeat ECG (Figure 2) demonstrated dynamic T-wave inversion in leads I, aVL, and V4–V6. Repeat troponin-T was recorded at 242 ng/L. He was initially treated as a suspected pulmonary embolus and transferred to the cardiology ward.\n\nFigure 1 Admission electrocardiogram demonstrating sinus rhythm with concave ST-elevation in V4–V6 with associated biphasic T-waves.\n\nFigure 2 Electrocardiogram 24 h after admission demonstrating sinus rhythm with dynamic T-wave inversion in leads I, aVL, and V4–V6.\n\nUpon review by the cardiology team, the working impression was a viral-induced myocarditis. Transthoracic echocardiogram (TTE) demonstrated a non-dilated but severely impaired left ventricular (LV) systolic and diastolic function with global hypokinesia; mitral annular plane systolic excursion was reduced at 4 mm (normal: ≥10 mm), mitral valve deceleration time was 121 ms with an average e′ of 7 cm/s and E/e′ of 13. Right ventricle was non-dilated with a preserved radial and longitudinal systolic function; tricuspid annular plane systolic excursion was 17 mm (normal: ≥16 mm) with a tricuspid annular systolic velocity of 12 cm/s. No pericardial effusion or significant valve defects were seen (Video 1).\n\nFollowing the TTE findings, our patient was commenced and titrated on standard heart failure (HF) treatment with an angiotensin-converting enzyme inhibitor (ramipril 1.25 mg) and a beta blocker (bisoprolol 2.5 mg). He was clinically euvolaemic and did not require any diuretic therapy during his admission. The patient stabilized and was discharged with a planned early outpatient cardiac magnetic resonance (CMR) at the local tertiary centre and close HF clinic surveillance. His prednisolone remained at 40 mg with a planned reduction of 5 mg weekly.\n\nTen days following discharge, he was reviewed in the nurse-led HF clinic where he reported ongoing episodes of chest pain with a reduced exercise tolerance. His HF medications were up-titrated and shortly after, his mesalazine was discontinued after liaison with the gastroenterology team as the suspected causative agent to his myopericarditis. A further follow-up was arranged 10 days following mesalazine cessation where he reported a markedly improved exercise tolerance with milder episodes of chest pain. At the time, he was on a weaning regime of prednisolone at a dose of 20 mg.\n\nCMR was conducted 2 weeks following cessation of mesalazine (6 weeks following admission) and demonstrated a normal biventricular systolic function with no myocardial scarring or fibrosis. No active myocardial inflammation was demonstrable with no abnormal elevation of T1 (980 ms at 1.5 T) or T2 values on T1 and T2 mapping (Figure 3). Upper limit of normal value for our 1.5 T Siemens Avanto magnetic resonance imaging scanner is 980 ms and 60 ms for T1 and T2 relaxation values respectively. A further consultation took place shortly after and the patient reported he was pain free, no longer breathless and exercise capacity had returned to baseline. Prednisolone dose had been further reduced and repeat ECG demonstrated sinus rhythm with upright T-waves (Figure 4) with troponin-T measuring <5 ng/L; signifying no ongoing myocardial inflammation. Surveillance echocardiogram 4 months later demonstrated an ongoing preserved and recovered LV systolic function (Video 2) and his IBD was now controlled on infliximab therapy.\n\nFigure 3 Cardiac magnetic resonance performed 2 weeks following discontinuation of mesalazine demonstrating no active myocarditis. T1 colour maps (A and B). (A) Basal SAX. (B) Mid SAX. (C) T2 colour map SAX. (D) 4Ch late gadolinium enhancement.\n\nFigure 4 Repeat electrocardiogram in the outpatients following cessation of mesalazine with recovered T-wave inversion.\n\nDiscussion\n\nCardiac extra-intestinal features of IBD are rare but may include dysrhythmias, pericardial disease, myocarditis, endocarditis, and conduction tissue disease.5 It is well documented that patients with IBD have a higher risk of developing myocarditis compared with the background population; a 16-year Danish Cohort study gave a risk of 4.6 per 100 000 years of risk for development of myocarditis in patients with chronic inflammatory colitis.6 The incidence rate ratio for developing myocarditis was 8.3 in Crohn’s disease and 2.6 in UC when compared with the general population.6\n\nEven though cardiotoxicity following mesalazine is rare with a reported incidence of up to 0.3%,3,4 it can prove fatal with data showing 30% of biopsy proven myocarditis progressing to a dilated cardiomyopathy, which carries a poor prognosis.7 Myocarditis as part of IBD can often be challenging to distinguish from 5-ASA mediated myocarditis. However, it is vital for clinicians to be aware of this adverse effect to allow prompt recognition and cessation of mesalazine prior to the development of any long-term dysfunction.\n\nIBD associated myocarditis involves an autoimmune response following autoantigen exposure,8 whereas the mechanism of mesalazine-induced cardiotoxicity is thought to be a cell-mediated hypersensitivity reaction; supported by eosinophilic infiltration on endomyocardial biopsy (EMB) specimens, rapid recovery of symptoms following drug discontinuation and freedom from permanent sequalae.9\n\nDiagnosis of 5-ASA-induced myocarditis is based on clinical grounds; with symptom onset typically occurring within the first 2–4 weeks of mesalazine initiation.10,11 Treatment is largely supportive with drug cessation being key with complete resolution of symptoms and cardiac dysfunction documented within the days following drug withdrawal.11,12 In addition, steroids are shown to aid and expedite myocardial recovery.13\n\nOur patient met the European Society of Cardiology Task Force criteria on the clinical diagnosis of myocarditis7 with an acute chest pain history, abnormal ECG, raised cardiac biomarkers, and LV systolic dysfunction on echocardiogram. However, he did not meet the Lake Louise Criteria (LLC) for myocarditis14 or demonstrate an abnormal elevation of T1 or T2 values on T1 and T2 mapping during CMR. We hypothesize that as the myocarditis driver was removed 2 weeks prior, this allowed resolution of the inflammation with a prompt return to baseline functioning as supported by the literature.9,11,12 This was possibly expedited by the concurrent steroid course he was prescribed for his colitis flare.13 Conversely, the time interval of 2 weeks following the acute myocarditis episode could also explain why LLC was negative.15\n\nIn our clinical case, the patient’s myocarditis symptomatology was secondary to mesalazine rather than active IBD; supported by the onset of symptoms within the first 2 weeks of drug commencement and rapid resolution of symptoms with recovery of cardiac function soon after discontinuing mesalazine. Despite this, EMB remains the gold standard practice for the diagnosis of myocarditis to confirm the underlying aetiology and characteristics of inflammation; which influences the treatment approach and prognosis.7 Despite being the gold standard practice, EMB remains largely underutilized in the real world.\n\nConclusion\n\nClinicians should be aware of the non-infectious causes of myocarditis that would influence management and lead to resolution like this case. This clinical report highlights the important and potentially life-threatening complication of 5-ASA therapy which should be considered as part of the differential diagnosis in patients who are on mesalazine presenting with chest pain or HF. Cessation of the drug should promptly follow, and other causes of myocarditis excluded. The mainstay of treatment remains to simply discontinue mesalazine, which leads to prompt and rapid recovery of symptoms and a return to baseline cardiac functioning. Close liaison with the gastroenterology team is required to ensure appropriate 2nd line therapy is initiated for the patient’s ongoing colitis management.\n\nLead author biography\n\nDr Simran Shergill graduated from the University of Birmingham in 2015. He completed his MRCP in 2018 and is currently working as a Cardiology Speciality Doctor at South Warwickshire NHS Foundation Trust.\n\nSupplementary material\n\nSupplementary material is available at European Heart Journal - Case Reports online.\n\nSlide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.\n\nConsent: The author confirms that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with the journal and COPE guidance.\n\nConflict of interest: none declared.\n\nFunding: none declared.\n\nSupplementary Material\n\nytaa508_Supplementary_Data Click here for additional data file.\n==== Refs\nReferences\n\n1 MowatC , ColeA , WindsorAL , AhmadT , ArnottI , DriscollR et al ; on behalf of the IBD Section of the British Society of Gastroenterology. Guidelines for the management of inflammatory bowel disease in adults. Gut 2011;60 :571–607.21464096\n2 BergmanR , ParkesM. Systematic review: the use of mesalazine in inflammatory bowel disease. Aliment Pharmacol Ther 2006;23 :841–855.16573787\n3 LoftusEVJr , KaneSV , BjorkmanD. Systematic review: short-term adverse effects of 5-aminosalicylic acid agents in the treatment of ulcerative colitis. Aliment Pharmacol Ther 2004;19 :179–189.14723609\n4 ZakkoSF , GordonGL , MurthyU , SedghiS , PruittR , BarrettAC et al Once-daily mesalamine granules for maintaining remission of ulcerative colitis: pooled analysis of efficacy, safety, and prognostic factors. Postgrad Med 2016;128 :273–281.26861051\n5 BrownSR , CovielloLC. Extraintestinal manifestations associated with inflammatory bowel disease. Surg Clin North Am 2015;95 :1245–1259.26596925\n6 SorensenHT , FonagerKM. Myocarditis and inflammatory bowel disease: a 16-year Danish nationwide cohort study. Dan Med Bull 1997;44 :442–444.9377906\n7 CaforioAL , PankuweitS , ArbustiniE , BassoC , Gimeno-BlanesJ , FelixSB et al Current state of knowledge on aetiology, diagnosis, management and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2013;34 :2636–2648.23824828\n8 BunuDM , TimofteCE , CiocoiuM , FloriaM , TarniceriuCC , BarboiOB et al Cardiovascular manifestations of inflammatory bowel disease: pathogenesis, diagnosis, and preventive strategies. Gastroenterol Res Pract 2019;2019 :1–14.\n9 HaqMI , AhmedS , PashaW , ZaidiSA. Mesalazine-induced cardiotoxicity. J Rare Disord Diagn Ther 2019;4 :24.\n10 MossAC , PeppercornMA. The risks and the benefits of mesalazine as a treatment for ulcerative colitis. Expert Opin Drug Saf 2007;6 :99–107.17367256\n11 BrownG. 5-Aminosalicyclic acid associated myocarditis and pericarditis: a narrative review. Can J Hosp Pharm 2016;69 :466–472.28123193\n12 LiuY , YeJ , ZhuJ , ChenW , SunY. Myocarditis due to mesalamine treatment in a patient with Crohn’s disease in China. Turk J Gastroenterol 2012;23 :304–306.22798127\n13 HinojarR , FooteL , SangleS , MarberM , MayrM , Carr-WhiteG et al Native T1 and T2 mapping by CMR in lupus myocarditis: disease recognition and response to treatment. Int J Cardiol 2016;222 :717–726.27521546\n14 FriedrichMG , SechtemU , Schulz-MengerJ , HolmvangG , AlakijaP , CooperLT et al Cardiovascular magnetic resonance in myocarditis: A JACC White Paper. J Am Coll Cardiol 2009;53 :1475–1487.19389557\n15 von Knobelsdorff-BrenkenhoffF , SchülerJ , DogangüzelS , DieringerMA , RudolphA , GreiserA et al Detection and monitoring of acute myocarditis applying quantitative cardiovascular magnetic resonance. Circ Cardiovasc Imaging 2017;10 :e005242.28213448\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2514-2119", "issue": "5(2)", "journal": "European heart journal. Case reports", "keywords": " Inflammatory bowel disease; 5-aminosalicyclic-acid (5-ASA); Cardiotoxicity; Case report; Mesalazine; Myocarditis; Myopericarditis", "medline_ta": "Eur Heart J Case Rep", "mesh_terms": null, "nlm_unique_id": "101730741", "other_id": null, "pages": "ytaa508", "pmc": null, "pmid": "33738396", "pubdate": "2021-02", "publication_types": "D002363:Case Reports", "references": "28123193;28213448;17367256;19389557;26596925;16573787;9377906;26861051;14723609;21464096;27521546;30733802;23824828;22798127", "title": "Mesalazine-induced myopericarditis: a case report.", "title_normalized": "mesalazine induced myopericarditis a case report" }

[ { "companynumb": "GB-TEVA-2021-GB-1968891", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "080354", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INITIAL DOSE UNKNOWN; LATER DOSE REDUCED TO 40MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Colitis ulcerative", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "080354", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MESALAMINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3.2 GRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "Colitis ulcerative", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": "2019", "drugstartdateformat": "602", "drugstructuredosagenumb": "1.6", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MESALAMINE" } ], "patientagegroup": "5", "patientonsetage": "22", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myocarditis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Rebound effect", "reactionmeddraversionpt": "24.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Colitis ulcerative", "reactionmeddraversionpt": "24.1", "reactionoutcome": "2" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20190101" } }, "primarysource": { "literaturereference": "Shergill S. Mesalazine-induced myopericarditis: a case report. Eur-Heart-J-Case-Rep 2020;5(2):ytaa508.", "literaturereference_normalized": "mesalazine induced myopericarditis a case report", "qualification": "1", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20211103", "receivedate": "20211028", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20009099, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20220303" } ]

{ "abstract": "Intrahepatic cholestasis of pregnancy is an incompletely understood disease that poses significant fetal risks, including stillbirth. Treatment of intrahepatic cholestasis of pregnancy is aimed at relieving maternal symptoms and improving fetal outcomes.\n\n\n\nA 21-year-old gravid woman, 3 para 0111, presented at 27 2/7 weeks of gestation with severe intrahepatic cholestasis of pregnancy. Her clinical course was refractory to first-line therapy with ursodiol, and she was started on rifampin with rapid improvement of symptoms and transaminitis. Despite maternal improvement, she was delivered at 31 weeks of gestation for persistent nonreassuring fetal status.\n\n\n\nRifampin may be an effective adjunctive therapy for intrahepatic cholestasis of pregnancy refractory to ursodiol alone. Additional research is needed to assess short-term and long-term maternal and newborn outcomes, because fetal deterioration still occurred in spite of maternal improvement.", "affiliations": "Department of Obstetrics & Gynecology, Beaumont Health System, Royal Oak, Michigan; the Center for Pregnancy and Newborn Research, Department of Obstetrics & Gynecology, University of Texas Health Sciences Center at San Antonio, and the Department of Obstetrics & Gynecology, University Health System, San Antonio, Texas.", "authors": "Liu|James|J|;Murray|Amanda M|AM|;Mankus|Erin B|EB|;Ireland|Kayla E|KE|;Acosta|Ometeotl M|OM|;Ramsey|Patrick S|PS|", "chemical_list": "D002756:Cholagogues and Choleretics; D019384:Nucleic Acid Synthesis Inhibitors; D014580:Ursodeoxycholic Acid; D012293:Rifampin", "country": "United States", "delete": false, "doi": "10.1097/AOG.0000000000002794", "fulltext": null, "fulltext_license": null, "issn_linking": "0029-7844", "issue": "132(3)", "journal": "Obstetrics and gynecology", "keywords": null, "medline_ta": "Obstet Gynecol", "mesh_terms": "D002756:Cholagogues and Choleretics; D002780:Cholestasis, Intrahepatic; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D019384:Nucleic Acid Synthesis Inhibitors; D011247:Pregnancy; D011248:Pregnancy Complications; D012293:Rifampin; D014580:Ursodeoxycholic Acid; D055815:Young Adult", "nlm_unique_id": "0401101", "other_id": null, "pages": "678-681", "pmc": null, "pmid": "30095766", "pubdate": "2018-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Adjuvant Use of Rifampin for Refractory Intrahepatic Cholestasis of Pregnancy.", "title_normalized": "adjuvant use of rifampin for refractory intrahepatic cholestasis of pregnancy" }

[ { "companynumb": "US-MYLANLABS-2018M1092150", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "URSODIOL" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "090530", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "300 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "URSODIOL CAPSULES" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BETAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHOLESTASIS OF PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BETAMETHASONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHOLESTASIS OF PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "URSODIOL" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "090530", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "300MG THREE TIMES DAILY; LATER IT WAS INCREASED TO 4 TIMES DAILY AFTER ONE WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHOLESTASIS OF PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "URSODIOL CAPSULES" } ], "patientagegroup": null, "patientonsetage": "21", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Normal newborn", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "LIU J, MURRAY AM, MANKUS EB, IRELAND KE, ACOSTA OM, RAMSEY PS. ADJUVANT USE OF RIFAMPIN FOR REFRACTORY INTRAHEPATIC CHOLESTASIS OF PREGNANCY. OBSTET-GYNECOL 2018?132(3):678-681.", "literaturereference_normalized": "adjuvant use of rifampin for refractory intrahepatic cholestasis of pregnancy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20181220", "receivedate": "20181220", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15746918, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "US-IMPAX LABORATORIES, LLC-2018-IPXL-03934", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "3", "activesubstance": { "activesubstancename": "URSODIOL" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "077895", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "300 MILLIGRAM, 4 /DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "4", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "URSODIOL." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "URSODIOL" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "077895", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "300 MILLIGRAM, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHOLESTASIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "URSODIOL." } ], "patientagegroup": null, "patientonsetage": "21", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Premature delivery", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood pressure increased", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LIU J, MURRAY AM, MANKUS EB, IRELAND KE, ACOSTA OM, RAMSEY PS.. ADJUVANT USE OF RIFAMPIN FOR REFRACTORY INTRAHEPATIC CHOLESTASIS OF PREGNANCY. OBSTET GYNECOL. 2018?132(3):678-681", "literaturereference_normalized": "adjuvant use of rifampin for refractory intrahepatic cholestasis of pregnancy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20181130", "receivedate": "20181130", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15677586, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "US-ALLERGAN-1840465US", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "3", "activesubstance": { "activesubstancename": "URSODIOL" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "020675", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG, QID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "4", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "URSODEOXYCHOLIC ACID UNK" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHOLESTASIS OF PREGNANCY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPIN." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "URSODIOL" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "020675", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHOLESTASIS OF PREGNANCY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "URSODEOXYCHOLIC ACID UNK" } ], "patientagegroup": null, "patientonsetage": "21", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Total bile acids increased", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Premature labour", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Aspartate aminotransferase increased", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Alanine aminotransferase increased", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pruritus generalised", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cholestasis of pregnancy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "LIU J, MURRAY AM, MANKUS EB, IRELAND KE, ACOSTA OM, RAMSEY PS. ADJUVANT USE OF RIFAMPIN FOR REFRACTORY INTRAHEPATIC CHOLESTASIS OF PREGNANCY. JOURNAL OF OPTHALMOLOGY. 2018?00(00):1?4", "literaturereference_normalized": "adjuvant use of rifampin for refractory intrahepatic cholestasis of pregnancy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180820", "receivedate": "20180820", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15297266, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" }, { "companynumb": "US-SA-2018SA321701", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "050420", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHOLESTASIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BETAMETHASONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRURITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BETAMETHASONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "URSODIOL" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHOLESTASIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "URSODEOXYCHOLIC ACID" } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": "1.54", "reaction": [ { "reactionmeddrapt": "Foetal distress syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LIU J, MURRAY AM, MANKUS EB, IRELAND KE, ACOSTA OM, RAMSEY PS.. ADJUVANT USE OF RIFAMPIN FOR REFRACTORY INTRAHEPATIC CHOLESTASIS OF PREGNANCY. OBSTET GYNECOL.. 2018?132(3):678-81.", "literaturereference_normalized": "adjuvant use of rifampin for refractory intrahepatic cholestasis of pregnancy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190102", "receivedate": "20181228", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15772759, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "US-ALLERGAN-1840468US", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "URSODIOL" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "020675", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "MATERNAL EXPOSURE TIMING UNSPECIFIED", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "URSODEOXYCHOLIC ACID UNK" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "URSODIOL" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "020675", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG, QID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "4", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "URSODEOXYCHOLIC ACID UNK" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": "3", "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "MATERNAL EXPOSURE TIMING UNSPECIFIED", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPIN." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": "1.54", "reaction": [ { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Premature baby", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Low birth weight baby", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LIU J, MURRAY AM, MANKUS EB, IRELAND KE, ACOSTA OM, RAMSEY PS. ADJUVANT USE OF RIFAMPIN FOR REFRACTORY INTRAHEPATIC CHOLESTASIS OF PREGNANCY. JOURNAL OF OPTHALMOLOGY. 2018?00(00):1?4", "literaturereference_normalized": "adjuvant use of rifampin for refractory intrahepatic cholestasis of pregnancy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180820", "receivedate": "20180820", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15298422, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" }, { "companynumb": "US-GLENMARK PHARMACEUTICALS-2018GMK037184", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "URSODIOL" }, "drugadditional": null, 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ADJUVANT USE OF RIFAMPIN FOR REFRACTORY INTRAHEPATIC CHOLESTASIS OF PREGNANCY.. OBSTETRICS + GYNECOLOGY. 2018", "literaturereference_normalized": "adjuvant use of rifampin for refractory intrahepatic cholestasis of pregnancy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20181026", "receivedate": "20180912", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15374910, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190204" }, { "companynumb": "PHHY2018US179334", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BETAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "FOETAL EXPOSURE DURING PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BETAMETHASONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "URSODIOL" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "FOETAL EXPOSURE DURING PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "URSODEOXYCHOLIC ACID" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "64150", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "FOETAL EXPOSURE DURING PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Low birth weight baby", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nonreassuring foetal heart rate pattern", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Premature baby", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LIU J, MURRAY AM, MANKUS EB, IRELAND KE, ACOSTA OM, RAMSEY PS. ADJUVANT USE OF RIFAMPIN FOR REFRACTORY INTRAHEPATIC CHOLESTASIS OF PREGNANCY. 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ADJUVANT USE OF RIFAMPIN FOR REFRACTORY INTRAHEPATIC CHOLESTASIS OF PREGNANCY. OBSTETRICS AND GYNECOLOGY. 2018?132(3):678-681.", "literaturereference_normalized": "adjuvant use of rifampin for refractory intrahepatic cholestasis of pregnancy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20181227", "receivedate": "20181227", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15767993, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "US-GLENMARK PHARMACEUTICALS-2018GMK037122", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BETAMETHASONE DIPROPIONATE" }, "drugadditional": "3", "drugadministrationroute": "064", "drugauthorizationnumb": "078930", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BETAMETHASONE DIPROPIONATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "URSODIOL" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "URSODEOXYCHOLIC ACID" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPIN." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nonreassuring foetal heart rate pattern", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LIU J, MURRAY AM, MANKUS EB, IRELAND KE, ACOSTA OM, RAMSEY PS.. ADJUVANT USE OF RIFAMPIN FOR REFRACTORY INTRAHEPATIC CHOLESTASIS OF PREGNANCY.. OBSTETRICS + GYNECOLOGY. 2018", "literaturereference_normalized": "adjuvant use of rifampin for refractory intrahepatic cholestasis of pregnancy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20181026", "receivedate": "20180824", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15315223, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190204" } ]

{ "abstract": "Vedolizumab is a humanized IgG1 monoclonal antibody that selectively blocks the lymphocyte integrin α4β7 and prevents its interaction with endothelial adhesion molecules and subsequent transmigration to the gastrointestinal tract. The drug was approved in 2014 for the induction and maintenance treatment of ulcerative colitis and moderate to severe Crohn's disease that is refractory or intolerant to conventional treatment with corticoids and immunosuppressants and/or anti-TNFα drugs. However, inflammatory bowel disease has a variable behavior following liver transplant. One third of patients with ulcerative colitis associated with primary sclerosing cholangitis are expected to deteriorate despite receiving immunosuppression to prevent rejection. There is limited experience with anti-TNFα agents in patients with inflammatory bowel disease in the setting of liver transplantation and the studies to date involve a limited number of cases. The efficacy and safety data of vedolizumab in this situation are unreliable and very preliminary. We present two cases with the aim to present the efficacy and safety of vedolizumab after one year of treatment in two patients who underwent a transplant due to primary sclerosing cholangitis. One case had de novo post-transplant ulcerative colitis refractory to two anti-TNFα drugs (golimumab and infliximab). The other patient had a colostomy due to fulminant colitis and developed severe ulcerative proctitis refractory to infliximab after reconstruction with an ileorectal anastomosis.", "affiliations": "Unidad Gestión Clínica Aparato Digestivo, Hospital Regional Universitario Málaga, España.;UGC Aparato Digestivo, Hospital Regional Universitario de Málaga, España.;UGC Aparato Digestivo, Hospital Regional Universitario de Málaga, España.;UGC Aparato Digestivo, Hospital Regional Universitario de Málaga, España.", "authors": "Olmedo Martín|Raúl Vicente|RV|;Amo Trillo|Víctor|V|;González Grande|Rocío|R|;Jiménez Pérez|Miguel|M|", "chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D005765:Gastrointestinal Agents; C543529:vedolizumab", "country": "Spain", "delete": false, "doi": "10.17235/reed.2017.5024/2017", "fulltext": null, "fulltext_license": null, "issn_linking": "1130-0108", "issue": "109(9)", "journal": "Revista espanola de enfermedades digestivas : organo oficial de la Sociedad Espanola de Patologia Digestiva", "keywords": null, "medline_ta": "Rev Esp Enferm Dig", "mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D015209:Cholangitis, Sclerosing; D003093:Colitis, Ulcerative; D005260:Female; D005765:Gastrointestinal Agents; D006801:Humans; D016031:Liver Transplantation; D016896:Treatment Outcome", "nlm_unique_id": "9007566", "other_id": null, "pages": "659-662", "pmc": null, "pmid": "28724302", "pubdate": "2017-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Efficacy and safety of vedolizumab as a treatment option for moderate to severe refractory ulcerative colitis in two patients after liver transplant due to primary sclerosing cholangitis.", "title_normalized": "efficacy and safety of vedolizumab as a treatment option for moderate to severe refractory ulcerative colitis in two patients after liver transplant due to primary sclerosing cholangitis" }

[ { "companynumb": "ES-ABBVIE-18P-144-2366834-00", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADALIMUMAB" }, "drugadditional": "1", "drugadministrationroute": "058", "drugauthorizationnumb": "125057", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": null, "drugenddate": "201209", "drugenddateformat": "610", "drugindication": "COLITIS ULCERATIVE", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "201205", "drugstartdateformat": "610", "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADALIMUMAB" } ], "patientagegroup": null, "patientonsetage": "37", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Therapy non-responder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Colitis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OLMEDO MARTIN R, AMO-TRILLO V, GONZALEZ-GRANDE R, JIMENEZ-PEREZ M. EFFICACY AND SAFETY OF VEDOLIZUMAB AS A TREATMENT OPTION FOR MODERATE TO SEVERE REFRACTORY ULCERATIVE COLITIS IN TWO PATIENTS AFTER LIVER TRANSPLANT DUE TO PRIMARY SCLEROSING CHOLANGITIS. SPANISH JOURNAL OF DIGESTIVE DISEASES. 2017?109(9):659-662.", "literaturereference_normalized": "efficacy and safety of vedolizumab as a treatment option for moderate to severe refractory ulcerative colitis in two patients after liver transplant due to primary sclerosing cholangitis", "qualification": "3", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "ES", "receiptdate": "20180530", "receivedate": "20180530", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14951493, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" } ]

{ "abstract": "PCDH19-related epilepsy is a genetic disorder that was first described in 1971, then referred to as \"epilepsy and mental retardation limited to females\". PCDH19 has recently been identified as the responsible gene, but a detailed characterization of the seizure manifestation based on video-EEG recording is still limited. The purpose of this study was to elucidate features of the seizure semiology in children with PCDH19-related epilepsy. To do this, ictal video-EEG recordings of 26 convulsive seizures in three girls with PCDH19-related epilepsy were analysed. All seizures occurred in clusters, mainly during sleep accompanied by fever. The motor manifestations consisted of six sequential phases: \"jerk\", \"reactive\", \"mild tonic\", \"fluttering\", \"mild clonic\", and \"postictal\". Some phases were brief or lacking in some seizures, whereas others were long or pronounced. In the reactive phase, the patients looked fearful or startled with sudden jerks and turned over reactively. The tonic and clonic components were less intense compared with those of typical tonic-clonic seizures in other types of epilepsy. The fluttering phase was characterised initially by asymmetric, less rhythmic, and less synchronous tremulous movement and was then followed by the subtle clonic phase. Subtle oral automatism was observed in the postictal phase. The reactive, mild tonic, fluttering and mild clonic phases were most characteristic of seizures of PCDH19-related epilepsy. Ictal EEG started bilaterally and was symmetric in some patients but asymmetric in others. It showed asymmetric rhythmic discharges in some seizures at later phases. The electroclinical pattern of the phasic evolution of convulsive seizure suggests a focal onset seizure with secondary generalisation. Based on our findings, we propose that the six unique sequential phases in convulsive seizures suggest the diagnosis of PCDH19-related epilepsy when occurring in clusters with or without high fever in girls. [Published with video sequences online].", "affiliations": "National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, NHO.;National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, NHO.;National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, NHO.;National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, NHO.;National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, NHO.;National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, NHO.;Department of Pediatrics, Jikei University School of Medicine, The Central Research Institute for the Molecular Pathomechanisms of Epilepsy of Fukuoka University.;The Central Research Institute for the Molecular Pathomechanisms of Epilepsy of Fukuoka University, Department of Pediatrics, Fukuoka University, School of Medicine, Japan.", "authors": "Ikeda|Hiroko|H|;Imai|Katsumi|K|;Ikeda|Hitoshi|H|;Shigematsu|Hideo|H|;Takahashi|Yukitoshi|Y|;Inoue|Yushi|Y|;Higurashi|Norimichi|N|;Hirose|Shinichi|S|", "chemical_list": "D015820:Cadherins; C438605:PCDH19 protein, human; D000091363:Protocadherins", "country": "France", "delete": false, "doi": "10.1684/epd.2016.0803", "fulltext": null, "fulltext_license": null, "issn_linking": "1294-9361", "issue": "18(1)", "journal": "Epileptic disorders : international epilepsy journal with videotape", "keywords": "EEG; PCDH19; PCDH19-related epilepsy; focal-onset convulsive seizures", "medline_ta": "Epileptic Disord", "mesh_terms": "D015820:Cadherins; D002648:Child; D002675:Child, Preschool; D004569:Electroencephalography; D004827:Epilepsy; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D000091363:Protocadherins; D012640:Seizures; D014741:Video Recording", "nlm_unique_id": "100891853", "other_id": null, "pages": "26-33", "pmc": null, "pmid": "26898795", "pubdate": "2016-03", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Characteristic phasic evolution of convulsive seizure in PCDH19-related epilepsy.", "title_normalized": "characteristic phasic evolution of convulsive seizure in pcdh19 related epilepsy" }

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null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZONISAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EPILEPSY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." } ], "patientagegroup": null, "patientonsetage": "6", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Epilepsy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "IMAI K, IKEDA H, SHIGEMATSU H, TAKAHASHI Y, INOUE Y, HIGURASHI N, ET AL. CHARACTERISTIC PHASIC EVOLUTION OF CONVULSIVE SEIZURE IN PCDH19-RELATED EPILEPSY. EPILEPTIC-DISORD. 2016;18(1):26-33", "literaturereference_normalized": "characteristic phasic evolution of convulsive seizure in pcdh19 related epilepsy", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20160603", "receivedate": "20160603", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12433154, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "JP-CONCORDIA PHARMACEUTICALS INC.-CO-ZO-JP-2016-053", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CARBAMAZEPINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBAMAZEPINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VALPROATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, 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"drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYSTAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ZONISAMIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "020789", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "EPILEPSY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZONEGRAN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." } ], "patientagegroup": null, "patientonsetage": "6", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "IKEDA H, IMAI K, SHIGEMATSU H, INOUE Y, HIGURASHI N. CHARACTERISTIC PHASIC EVOLUTION OF CONVULSIVE SEIZURE IN PCDH19-RELATED EPILEPSY. EPILEPTIC DISORD.. 2016 MAR;18(1):26-33.", "literaturereference_normalized": "characteristic phasic evolution of convulsive seizure in pcdh19 related epilepsy", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20160614", "receivedate": "20160427", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12310354, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "JP-MYLANLABS-2016M1020525", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "VALPROIC ACID" }, "drugadditional": null, 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"drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ZONISAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE CLUSTER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZONISAMIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CARBAMAZEPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE CLUSTER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBAMAZEPINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "IMAI K, IKEDA H, SHIGEMATSU H, TAKAHASHI Y, INOUE Y, HIGURASHI N, ET AL. CHARACTERISTIC PHASIC EVOLUTION OF CONVULSIVE SEIZURE IN PCDH19-RELATED EPILEPSY. EPILEPTIC-DISORD 2016;18(1):26-33.", "literaturereference_normalized": "characteristic phasic evolution of convulsive seizure in pcdh19 related epilepsy", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20160518", "receivedate": "20160518", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12379608, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" } ]

{ "abstract": "DIDS is a unique form of combined immune deficiency characterized by an unusual susceptibility to cutaneous viral infections, severe allergies with eosinophilia and elevated immunoglobulin E titers, autoimmunity, and cancer. HSCT is considered the standard of care for this deadly disease. We have retrospectively analyzed the outcome of allogeneic HSCT from unrelated donors in patients with DIDS. Data from four patients, with five transplants, are presented. All patients received transplants from unrelated donors' BM, except for one patient who received a cord blood transplant. The conditioning regimens were based on myeloablative protocols for BM derived transplants; a NM regimen was pursued for the patient who received a cord blood transplant, which resulted in graft rejection. Although recurrent pneumonia and skin infections resolved immediately after transplantation, all patients subsequently developed human herpesvirus infection, including cutaneous herpetic lesions, cytomegalovirus reactivation, and zona zoster, which could be attributed to the use of ATG. Despite the presence of serious morbidities prior to transplantation, all patients recovered successfully. DIDS can be successfully treated with allogeneic HSCT from unrelated donors following a myeloablative conditioning regimen, with a reasonable safety profile.", "affiliations": "Department of Pediatric Immunology, Antalya Training and Research Hospital, Antalya, Turkey.;Faculty of Medicine, Department of Pediatric Bone Marrow Transplantation Unit, MedicalPark Antalya Hospital, Bahçeşehir University, Antalya, Turkey.;Meram Medical Faculty, Division of Pediatric Immunology and Allergy, Necmettin Erbakan University, Konya, Turkey.;Meram Medical Faculty, Division of Pediatric Immunology and Allergy, Necmettin Erbakan University, Konya, Turkey.;Faculty of Medicine, Division of Pediatric Allergy and Immunology, Marmara University, İstanbul, Turkey.;Faculty of Medicine, Division of Pediatric Allergy and Immunology, Cukurova University, Adana, Turkey.;Meram Medical Faculty, Division of Pediatric Immunology and Allergy, Necmettin Erbakan University, Konya, Turkey.;Faculty of Medicine, Department of Pediatric Bone Marrow Transplantation Unit, MedicalPark Antalya Hospital, Bahçeşehir University, Antalya, Turkey.;Faculty of Medicine, Department of Pediatric Bone Marrow Transplantation Unit, MedicalPark Antalya Hospital, Bahçeşehir University, Antalya, Turkey.;Faculty of Medicine, Department of Pediatric Bone Marrow Transplantation Unit, MedicalPark Göztepe Hospital, Bahçeşehir University, İstanbul, Turkey.;Faculty of Medicine, Department of Pediatric Bone Marrow Transplantation Unit, MedicalPark Göztepe Hospital, Bahçeşehir University, İstanbul, Turkey.;Faculty of Medicine, Department of Pediatric Bone Marrow Transplantation Unit, MedicalPark Antalya Hospital, Bahçeşehir University, Antalya, Turkey.", "authors": "Uygun|Dilara Fatma K|DFK|;Uygun|Vedat|V|http://orcid.org/0000-0003-3257-7798;Reisli|İsmail|İ|;Keleş|Sevgi|S|;Özen|Ahmet|A|;Yılmaz|Mustafa|M|;Sayar|Esra H|EH|;Daloğlu|Hayriye|H|;Öztürkmen|Seda I|SI|;Çakı|Suar|S|;Karasu|Gülsün T|GT|;Yeşilipek|Akif|A|", "chemical_list": "C516591:DOCK8 protein, human; D020662:Guanine Nucleotide Exchange Factors", "country": "Denmark", "delete": false, "doi": "10.1111/petr.13015", "fulltext": null, "fulltext_license": null, "issn_linking": "1397-3142", "issue": "21(7)", "journal": "Pediatric transplantation", "keywords": "DOCK8 deficiency; HSCT; hyperimmunoglobulin E syndrome; unrelated donor", "medline_ta": "Pediatr Transplant", "mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D020662:Guanine Nucleotide Exchange Factors; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007589:Job Syndrome; D012189:Retrospective Studies; D016896:Treatment Outcome; D061349:Unrelated Donors", "nlm_unique_id": "9802574", "other_id": null, "pages": null, "pmc": null, "pmid": "28664550", "pubdate": "2017-11", "publication_types": "D016428:Journal Article", "references": null, "title": "Hematopoietic stem cell transplantation from unrelated donors in children with DOCK8 deficiency.", "title_normalized": "hematopoietic stem cell transplantation from unrelated donors in children with dock8 deficiency" }

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HEMATOPOIETIC STEM CELL TRANSPLANTATION FROM UNRELATED DONORS IN CHILDREN WITH DOCK8 DEFICIENCY. 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VERSUS HOST DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Transplant rejection", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "UYGUN DFK, UYGUN V, REISLI I, KELES S, OZEN A, YILMAZ M, ET AL. HEMATOPOIETIC STEM CELL TRANSPLANTATION FROM UNRELATED DONORS IN CHILDREN WITH DOCK8 DEFICIENCY. PEDIATR-TRANSPLANT 2017;21(7):E13015.", "literaturereference_normalized": "hematopoietic stem cell transplantation from unrelated donors in children with dock8 deficiency", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20171204", "receivedate": "20171128", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14230662, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" } ]

{ "abstract": "We herein report an autopsied case of a patient with adenocarcinoma of the lungs who developed nonbacterial thrombotic endocarditis (NBTE) that caused acute heart failure (AHF) due to acute aortic stenosis (AS). A 37-year-old man was admitted to our hospital due to chest pain and fever. He was diagnosed as having Stage IV lung cancer. Following the administration of chemotherapy, the patient presented with acute onset of dyspnea. He was diagnosed with having AHF based on his clinical course and physical findings, and ultimately he died without responding to treatment. The autopsy revealed that NBTE caused acute AS leading to AHF.", "affiliations": "Department of Respirology, Tokyo Saiseikai Central Hospital, Japan. daisuketaniyama@gmail.com", "authors": "Taniyama|Daisuke|D|;Yamamoto|Ryusuke|R|;Kawasaki|Maki|M|;Kamata|Hirofumi|H|;Miyamoto|Keisuke|K|;Mashimo|Shuko|S|;Sakamaki|Fumio|F|", "chemical_list": null, "country": "Japan", "delete": false, "doi": "10.2169/internalmedicine.52.0123", "fulltext": null, "fulltext_license": null, "issn_linking": "0918-2918", "issue": "52(14)", "journal": "Internal medicine (Tokyo, Japan)", "keywords": null, "medline_ta": "Intern Med", "mesh_terms": "D000208:Acute Disease; D000230:Adenocarcinoma; D000328:Adult; D001024:Aortic Valve Stenosis; D004696:Endocarditis; D006331:Heart Diseases; D006333:Heart Failure; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D013927:Thrombosis", "nlm_unique_id": "9204241", "other_id": null, "pages": "1617-20", "pmc": null, "pmid": "23857096", "pubdate": "2013", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Nonbacterial thrombotic endocarditis leading to acute heart failure due to aortic stenosis in a patient with lung cancer.", "title_normalized": "nonbacterial thrombotic endocarditis leading to acute heart failure due to aortic stenosis in a patient with lung cancer" }

[ { "companynumb": "PHHY2015JP011439", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG CARCINOMA CELL TYPE UNSPECIFIED STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "040196", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG CARCINOMA CELL TYPE UNSPECIFIED STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MORPHINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CARDIAC FAILURE ACUTE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MORPHINE" } ], "patientagegroup": null, "patientonsetage": "37", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Aortic stenosis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Haemorrhage subcutaneous", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "No therapeutic response", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac failure acute", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "TANIYAMA D, YAMAMOTO R, KAWASAKI M, KAMATA H, MIYAMOTO K, MASHIMO S, ET AL.. NONBACTERIAL THROMBOTIC ENDOCARDITIS LEADING TO ACUTE HEART FAILURE DUE TO AORTIC STENOSIS IN A PATIENT WITH LUNG CANCER.. INTERN-MED. 2013;52 (14):1617-1620", "literaturereference_normalized": "nonbacterial thrombotic endocarditis leading to acute heart failure due to aortic stenosis in a patient with lung cancer", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20150203", "receivedate": "20150203", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10756977, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" } ]

{ "abstract": "A proof-of-concept study was designed to evaluate the antiviral efficacy, safety and tolerability of a two-drug regimen with dolutegravir 50 mg once daily (QD) plus lamivudine 300 mg once daily as initial highly active antiretroviral therapy (HAART) among antiretroviral (ARV)-naive patients.\n\n\n\nPADDLE is a pilot study including 20 treatment-naive adults. To be selected, participants had no IAS-USA-defined resistance, HIV-1 RNA ≤100,000 copies/mL at screening and negative HBsAg. Plasma viral load (pVL) was measured at baseline; days 2, 4, 7, 10, 14, 21 and 28; weeks 6, 8 and 12; and thereafter every 12 weeks up to 96 weeks. Primary endpoint was the proportion of patients with HIV-1 RNA <50 copies/mL in an intention to treat (ITT)-exposed analysis at 48 weeks (the FDA snapshot algorithm).\n\n\n\nMedian HIV-1 RNA at entry was 24,128 copies/mL (interquartile range (IQR): 11,686-36,794). Albeit as per protocol, all patients had pVL ≤100,000 copies/mL at screening as required by inclusion criteria, four patients had ≥100,000 copies/mL at baseline. Median baseline CD4+ T-cell count was 507 per cubic millimetre (IQR: 296-517). A rapid decline in pVL was observed (median VL decay from baseline to week 12 was 2.74 logs). All patients were suppressed at week 8 onwards up to week 24. At week 48, 90% (18/20) reached the primary endpoint of a pVL <50 copies/mL. Median change in CD4 cell count between baseline and week 48 was 267 cells/mm3 (IQR: 180-462). No major tolerability/toxicity issues were observed. Nineteen patients completed 48 weeks of the study, and one patient (with undetectable VL at last visit) committed suicide. One patient presented a low-level protocol-defined confirmed virological failure at week 36, being the only observed failure. This patient had pVL <50 copies/mL at the end-of-study visit without having changed the two-drug regimen. Observed failure rate was 5%. This is the first report of integrase strand transfer inhibitor/lamivudine dual regimen in ARV-naive patients.\n\n\n\nThis novel dual regimen of dolutegravir and lamivudine warrants further clinical research and consideration as a potential therapeutic option for ARV-therapy-naive patients.\n\n\n\nNCT02211482.", "affiliations": "Clinical Research Department, Fundación Huésped, Buenos Aires, Argentina.;Clinical Research Department, Fundación Huésped, Buenos Aires, Argentina.;Clinical Research Department, Fundación Huésped, Buenos Aires, Argentina.;Laboratory, Clinical Research Department, Fundación Huésped, Buenos Aires, Argentina.;Clinical Research Department, Fundación Huésped, Buenos Aires, Argentina.;Clinical Research Department, Fundación Huésped, Buenos Aires, Argentina.", "authors": "Cahn|Pedro|P|;Rolón|María José|MJ|;Figueroa|María Inés|MI|;Gun|Ana|A|;Patterson|Patricia|P|;Sued|Omar|O|", "chemical_list": "D000998:Antiviral Agents; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D019259:Lamivudine; C562325:dolutegravir", "country": "Switzerland", "delete": false, "doi": "10.7448/IAS.20.01.21678", "fulltext": "\n==== Front\nJ Int AIDS SocJ Int AIDS SocZIASzias20Journal of the International AIDS Society1758-2652Taylor & Francis 132340210.7448/IAS.20.01.21678ArticleResearch ArticleDolutegravir–lamivudine as initial therapy in HIV-1 infected, ARV-naive patients, 48-week results of the PADDLE (Pilot Antiretroviral Design with Dolutegravir LamivudinE) study Cahn Pedro *aRolón María José aFigueroa María Inés aGun Ana bPatterson Patricia aSued Omar aa \nClinical Research Department, Fundación Huésped, Buenos Aires, Argentinab \nLaboratory, Clinical Research Department, Fundación Huésped, Buenos Aires, Argentina§ Corresponding author: Pedro Cahn, Fundación Huésped, Buenos AiresC1202ABBArgentina. (pedro.cahn@huesped.org.ar)2017 10 5 2017 20 1 2167817 11 2017 20 4 2017 © 2017 Cahn P et al; licensee International AIDS Society.2017The Author(s)This is an Open Access article distributed under the terms of the Creative Commons Attribution 3.0 Unported (CC BY 3.0) License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Abstract\nIntroduction: A proof-of-concept study was designed to evaluate the antiviral efficacy, safety and tolerability of a two-drug regimen with dolutegravir 50 mg once daily (QD) plus lamivudine 300 mg once daily as initial highly active antiretroviral therapy (HAART) among antiretroviral (ARV)-naive patients.\n\nMethods: PADDLE is a pilot study including 20 treatment-naive adults. To be selected, participants had no IAS-USA-defined resistance, HIV-1 RNA ≤100,000 copies/mL at screening and negative HBsAg. Plasma viral load (pVL) was measured at baseline; days 2, 4, 7, 10, 14, 21 and 28; weeks 6, 8 and 12; and thereafter every 12 weeks up to 96 weeks. Primary endpoint was the proportion of patients with HIV-1 RNA <50 copies/mL in an intention to treat (ITT)-exposed analysis at 48 weeks (the FDA snapshot algorithm).\n\nResults: Median HIV-1 RNA at entry was 24,128 copies/mL (interquartile range (IQR): 11,686–36,794). Albeit as per protocol, all patients had pVL ≤100,000 copies/mL at screening as required by inclusion criteria, four patients had ≥100,000 copies/mL at baseline. Median baseline CD4+ T-cell count was 507 per cubic millimetre (IQR: 296–517). A rapid decline in pVL was observed (median VL decay from baseline to week 12 was 2.74 logs). All patients were suppressed at week 8 onwards up to week 24. At week 48, 90% (18/20) reached the primary endpoint of a pVL <50 copies/mL. Median change in CD4 cell count between baseline and week 48 was 267 cells/mm3 (IQR: 180–462). No major tolerability/toxicity issues were observed. Nineteen patients completed 48 weeks of the study, and one patient (with undetectable VL at last visit) committed suicide. One patient presented a low-level protocol-defined confirmed virological failure at week 36, being the only observed failure. This patient had pVL <50 copies/mL at the end-of-study visit without having changed the two-drug regimen. Observed failure rate was 5%. This is the first report of integrase strand transfer inhibitor/lamivudine dual regimen in ARV-naive patients.\n\nConclusions: This novel dual regimen of dolutegravir and lamivudine warrants further clinical research and consideration as a potential therapeutic option for ARV-therapy-naive patients.\n\nClinicalTrials.gov Identifier: NCT02211482.\n\nKeywords\ndual therapydolutegravirlamivudinenaive patients\n==== Body\nIntroduction\nZidovudine (ZDV) monotherapy was the first attempt to control HIV replication. Soon after, two-drug combination became the preferred strategy, as ZDV effects lasted only for the short term, due to selection of resistance mutations. Unfortunately, the dual strategy also failed in achieving long-lasting virologic control. Combination antiretroviral therapy (ART) containing three active drugs from at least two different classes has been the standard of care for HIV treatment all over the world since 1996, based on the findings of two seminal studies [1,2].\n\nExpansion of access to antiretroviral (ARV) therapy has been the main driver of a striking 38% decline in HIV incidence and a 35% reduction in AIDS-associated mortality since 2000 [3]. Current HIV treatment guidelines recommend first-line ARV regimens consisting of two nucleoside/nucleotide analogue reverse-transcriptase inhibitors (NRTIs) as a “backbone” combined with a third agent from the non-nucleoside reverse-transcriptase inhibitor, the boosted protease inhibitor (PI), or the integrase strand transfer inhibitor (INSTI) classes. Over the past two decades, novel drugs for ART have improved the rates of long-term viral suppression, but even the most widely used regimens might result in treatment modification or interruption because of tolerability, toxicities or issues like challenging treatment schedules, drug interactions and food requirements [4].\n\nTo reduce toxicity, complexity, and costs, strategies that decrease the number of active drugs have been evaluated, both as initial therapy and as maintenance therapy for patients who achieved virologic suppression. Most efforts have yielded unacceptable high rates of treatment failure [5]. A two-drug regimen with a boosted PI plus lamivudine (3TC) has demonstrated favourable results in treatment-naive patients. The GARDEL study was the first to show non-inferiority of a dual combination of ritonavir-boosted lopinavir (LPV/r) plus 3TC, even in patients with baseline viral load (VL) above 100,000 copies/mL [6]. Other three studies showed non-inferior virologic efficacy of the same dual regimen or the combination of ritonavir-boosted atazanavir plus 3TC, all performed in virologically suppressed patients as a switch strategy [7–9].\n\nDolutegravir (DTG) is a potent INSTI, exhibiting rapid reduction in VL and a high barrier to resistance. DTG is a QD drug, well tolerated, that can be taken with or without food [10], with a low potential for drug–drug interactions [11], and a high genetic barrier [12]. Comparison with other preferred first-line drugs showed non-inferiority of DTG to raltegravir and superiority to efavirenz (EFV) and darunavir (DRV) in the randomized clinical trials SPRING, SINGLE and FLAMINGO, respectively [13–15].\n\nLamivudine (3TC) is a potent cytidine nucleoside analogue without major side effects, and it has a well-proven safety profile. In monotherapy, it has shown VL reduction up to 1.19 log [16]. It has a low genetic barrier selecting, in case of failure, the M184V mutation, which has been linked to a reduction in viral fitness [17]. This NRTI is also a QD drug, it can also be administered with or without food and no clinically relevant drug–drug interactions have been reported with its use [18].\n\nThe purpose of this pilot study was to assess the antiviral efficacy, safety and tolerability of a two-drug regimen with DTG 50 mg QD plus 3TC 300 mg QD as initial HAART among ARV-naive patients.\n\nMethods\nPADDLE is an ongoing pilot study involving HIV-1-infected patients naive to ARV treatment. Participants were enrolled in Argentina between 24 September 2014 and 28 February 2015. The last participant completed 48 weeks of treatment on 24 February 2016.\n\nThis study was conducted in accordance with good clinical practice procedures, all applicable regulatory requirements and the guiding principles of the Declaration of Helsinki. The study protocol was reviewed and approved by the Institutional Review Board (Comité de Bioética, Fundación Huésped). All patients provided written informed consent before entering the study.\n\nStudy design and participants\nEligible participants were 18 years of age or older, had HIV-1 infection, were naive to ARV treatment (never exposed to ARV drugs), had a plasma HIV-1 RNA level at screening visit >5000 copies and ≤100,000 copies per millilitre and a CD4+ T-cell count >200 per cubic millimetre with no evidence of genotypic of viral resistance to lamivudine as per IAS-USA 2013 resistance panel [19].\n\nMain exclusion criteria were previous exposure to ARVs, VL >100,000 copies/mL, CD4 count below 200 cells/mL at screening, pregnancy or breastfeeding, severe hepatic impairment, grade 4 laboratory abnormalities or alanine aminotransferase (ALT) >5 times the upper limit of normal (ULN) or ALT ≥3 times the ULN and bilirubin ≥1.5 times the ULN (with >35% direct bilirubin) or creatinine clearance of <50 mL/min via Cockroft–Gault method.\n\nAll participants were assigned to receive DTG 50 mg once daily plus 3TC 300 mg once daily.\n\nIn order to ensure patient’s safety, a phase 2 implementation protocol was designed: In phase 1, 10 patients were included. If, at week 8, at least 8 out of 10 patients showed a VL decrease >1 log, the study would continue to phase 2 in which another 10 patients would be enrolled. If more than two patients showed a VL decrease <1 log, the study would be discontinued. In addition, all patients would have an intensive follow-up. Patients would continue on study unless any of the following stopping rules were met: Patients with VL ≥1000 copies/mL at week 12, patients with VL ≥400 copies/mL at week 24 or 36 or patients with a confirmed viral rebound (>200 c/mL) after VL <50 c/mL.\n\nProcedures\nStudy visits were scheduled at baseline; days 2, 4, 7 and 10; and weeks 2, 3, 4, 6, 8, 12, 24, 36 and 48. On completion of the week 48 visits, all the participants were offered the opportunity to continue in a study extension until week 96. The Abbott Real-Time HIV-1 assay was used to detect the HIV-1 RNA plasma level (lower limit of detection, 40 copies per millilitre). Adverse events (AEs), serious adverse events (SAEs) and laboratory measurements (including haematological measurements, fasting lipid profile and blood-chemistry profile) were assessed intermittently throughout the study, and their severity graded according to the criteria of the Division of AIDS (DAIDS) at the National Institute of Allergy and Infectious Diseases of the National Institutes of Health. Specifically, safety evaluations were completed as follows: AEs and concomitant medications on all visits and laboratory parameters and vital signs on screening, baseline and weeks 2, 4, 8, 12, 24, 36 and 48. Viral genotype was analysed (TRUGENE HIV-1 Genotyping Kit) at the screening visit and had to be obtained at time of protocol-defined virologic failure (PDVF) defined as VL ≥1000 copies/mL at week 12, VL ≥400 copies/mL at week 24 or 36 or a confirmed viral rebound (>200 c/mL) after VL <50 c/mL.\n\nParticipants were required to withdraw from the study if PDVF was confirmed. Baseline was assessed with the AIDS Clinical Trials Group (ACTG) Adherence/Baseline questionnaire at baseline visit and with ACTG/Follow-up Questionnaire at visits: 4, 8, 12, 24, 36 and 48.\n\nOutcomes\nThe primary efficacy endpoint was the proportion of subjects with plasma HIV-1 RNA below 50 copies per millilitre at week 48 using the FDA snapshot algorithm (Missing, Switch or Discontinuation = failure) for the intention-to-treat exposed population (described in the Statistical analysis section). Secondary safety and efficacy endpoints included the frequency, type and severity of AEs and laboratory abnormalities, the proportion of patients with HIV-1 RNA <1000 copies/mL at week 12, the proportion of patients with HIV-RNA <400 at week 24, the incidence of genotypic and phenotypic resistance in case of virologic failure, the change from baseline in the CD4+-cell count, the lipid profile changes between baseline and week 48 and the viral decay rate.\n\nStatistical analysis\nVirological efficacy is shown as intention-to-treat (exposed) and as per protocol. Final analysis includes 48-week results for the 20 patients. Descriptive statistics were used to evaluate the primary and secondary outcomes. The results are given as median and interquartile ranges (IQRs) or frequencies (%) as appropriate. Changes in CD4 were analysed similarly. All AEs were evaluated, summarized and described as the proportion of patients presenting events and the total number of events. In all samples with plasma HIV-RNA below limit of detection, absence of signal was tested.\n\nRole of the funding source\nThe study was sponsored by Fundación Huésped. Trial funding was provided by ViiV Healthcare. ViiV Healthcare contributed towards scientific review of the study design and this report. All operational aspects of the study, including study design, monitoring, data collection, data analysis and writing of the report, were managed by Fundación Huésped. All the authors had full access to all the data in the study and are responsible for the veracity and completeness of the data reported. The corresponding author has final responsibility for the decision to submit for publication.\n\nResults\nA total of 35 patients were screened, and 20 patients were included and treated (Figure 1).\nFigure 1. Trial profile.\n\n\n\nDemographic and baseline disease characteristics are referred to in Table 1. The median HIV-1 RNA level at baseline was 24,128 copies/mL (IQR: 11,686–36,794). Albeit, as per protocol, all patients had pVL <100,000 copies/mL, four patients had ≥100,000 copies/mL at baseline and entered the study (Table 1).\nTable 1. Demographic and baseline disease characteristics.\n\nDemographic and baseline characteristics\t\nGender (male: female)\t19:1\t\nAge, years, median (IQR)\t34 (31–43)\t\nMode of transmission (n)\nMSM\nHeterosexual\t15\n5\t\nHIV-RNA (copies/mL), median (IQR)\t24,128 (11,686–36,794)\t\nCD4 count, cells/mm3, median (IQR)\t507 (296–517)\t\nCDC stage (%) A/B/C\t90/10/0\t\nIQR: interquartile range.\n\nCDC: Centers for Disease Control and Prevention.\n\n\n\n\nAll but one patient, who committed suicide, completed 48 weeks in the study and were evaluated for the primary endpoint. Figure 1 shows the disposition of patients during the trial. Adherence (self-reported and controlled by pill counts at each visit) was 100%. Median CD4 cell count change from baseline was 267 cells/mm3 (IQR: 180–462).\n\nAt week 48, 18 out of 20 subjects (90%, 95% confidence interval (CI): 77–100), reached plasma HIV-1 RNA level of less than 50 copies per millilitre in ITT-exposed analyses (Figure 2).\nFigure 2. Proportion of patients with plasma HIV-1 RNA lower than 50 copies per mL, by visit (Snapshot analysis). Analysis included all participants who received at least one dose of study drug.\n\n\n\nIn the per-protocol analyses, 18 out of 19 subjects were responders (95%, 95% CI: 85–100). All subjects, including the four subjects that entered the study with baseline pVL above 100,000 copies/mL, achieved VL below 400 copies at week 3 and HIV-1 RNA level of <50 copies per millilitre at 8 weeks.\n\nA rapid antiviral response was observed (median VL decay from baseline to week 12 was 2.74 logs).\n\nThrough week 48, only one patient met the criteria for protocol-defined virologic failure. This patient entered the study with a pVL of 106,320 copies, achieved pVL below 400 copies/mL at day 10 and pVL below 50 copies/mL at week 4 and remained so until week 24. On the week 36 visit, his pVL was 99 copies/mL. After reviewing patient’s compliance with the protocol, and ruling out potential intercurrent infections or vaccinations, a retest was performed three weeks later, showing a pVL of 246 copies/mL. The patient was discontinued from the study, as mandated by the protocol, but was followed off-study until week 48. The latest pVL obtained at that time was below 50 copies/mL, without any change on his ARV regimen (Figure 3).\nFigure 3. Viral load evolution (copies/mL) at virological failure by visit.\n\n\n\nAlbeit initially the subject denied any sex behaviour that might have put him at risk for reinfection, later on he disclosed that he had unprotected sexual intercourse with another male partner, who is HIV positive and on treatment, but still with detectable pVL. A virus pattern comparison between baseline and rebound could not be performed. Genotypic testing was performed at confirmed virological failure, but only the transcriptase region could be successfully amplified due to the low viremia. No mutations were found. Phenotypic resistance testing was not performed. The baseline genotypic test for integrase region did not reveal any mutation. A DTG plasma concentration was also obtained at failure. The DTG concentration in a sample collected 12 h after drug intake was 2.70 µg/mL, which was consistent with the pharmacokinetics and half-life reported in SPRING-1 [20] and far above the in vitro protein adjusted IC90 of viral suppression (0.064 µg/mL) [21], providing further evidence that non-adherence is not the most likely explanation for this transient viral rebound. Drug levels of 3TC were not performed.\n\nThe study drugs were well tolerated. Eight drug-related AEs were reported in six patients: headache (3), somnolence (1), epigastric pain (1), diarrhoea (1) and nausea (2) (grade 1 to 2), with no AEs leading to discontinuation of the study drug. The most frequent drug-related AE was headache in three patients. Grade 2 to 3 laboratory abnormalities (three events in three patients) were proteinuria (grade 3, since baseline), creatinine phosphokinase (grade3, only at baseline) and haematuria (grade 3, at week 48). One patient reported grade 2 insomnia at entry, without changes during the study and was deemed as not related to the study drugs.\n\nOne patient died during the study. He committed suicide, in the context of severe stress and emotional trauma. A relative disclosed that he had previous psychiatric disturbances, including a failed suicide attempt, which was not disclosed by the patient during his clinical visits. His death was noticed when he failed to show up at the week 36 visit. He achieved pVL below 50 copies/mL since week 2 and remained so until his last visit on week 24. No other SAEs were reported.\n\nDiscussion\nThis pilot study was designed to test the concept that a two-drug regimen based on an INSTI and lamivudine could be considered as an option for treatment-naive, HIV-infected patients. Successful dual therapy may reduce toxicity, treatment cost and the amount of drug required to be co-formulated in single tablet treatment regimens.\n\nDual-therapy strategies have been studied with heterogeneous results that were summarized in two recent systematic reviews [5,22].\n\nOne of the first studies using an NRTI-sparing dual therapy was the ACTG 5142 study that compared three arms as initial ART: EFV + 2 NRTIs, ritonavir-boosted LPV/r + 2 NRTIs or EFV + LPV/r. As the dual therapy showed lower efficacy and higher risk of emergency or resistance than the others, EFV + 2 NRTIs arm became the standard of care until recent years [23]. The GARDEL study was the first one to demonstrate non-inferiority of a dual therapy compared to triple therapy at 48 and 96 weeks [24,25]. An INSTI dual regimen of DRV and raltegravir (RAL) showed non-inferiority compared to a DRV triple therapy, but failed to do so in critical populations, like patients with pVL above 100,000 copies/mL and CD4 counts below 200 cells/mL [26]. A potential explanation of these results could be the requirement of two separated doses of RAL, while DRV was dosed once daily, which could have impaired adherence. The results of the PADDLE study provide further evidence that the potency required to achieve viral suppression does not necessarily mean the use of a three-drug ARV combination. Regarding the primary endpoint, 90% of the study population had undetectable pVL at week 48. Of note, all patients, including those with baseline pVL above 100,000 copies/mL had a rapid viral suppression that matches the one seen in other studies combining DTG with two NRTIs. Compared to SINGLE and SPRING studies, VL decay did not reveal any differences between treatments [27].\n\nThe patient that presented the only SAE (suicide) achieved pVL below 50 copies/mL at week 2 and remained so until his last visit on week 24. HIV and/or HAART have been previously related to suicidality. A nationwide Swiss study showed that in 2008, suicide rates in HIV-infected individuals were more than three times higher than the rates of the general population [28]. In a voluntary testing and counselling centre in South Africa, the investigators found that a significantly elevated risk of suicidal ideation was found in 83.1% of the patients who tested seropositive [29].\n\nEFV relationship with suicidality has been studied with divergent conclusions, ranging from a twofold increased hazard of suicidality compared with a regimen without EFV to no increased risk at all [30–32]. With DTG, events of suicidal ideation, attempt or behaviour have been reported in less than 2% of ARV treatment-naive or ARV treatment-experienced patients in eight registrational clinical trials (SPRING-1, SPRING-2, SINGLE, FLAMINGO, SAILING, VIKING, VIKING-3 and VIKING-4). These events were observed primarily in patients with a pre-existing history of depression or other psychiatric illness. Suicidal ideation is quoted in RAL and elvitegravir package inserts among the less common adverse reactions observed in treatment-experienced studies [33]. The relationship of our patient’s suicide with DTG cannot be absolutely ruled out, albeit our patient had at least two stressful and traumatic life events, as we found out retrospectively, and this could be the explanation for his tragic decision.\n\nThrough week 48, one patient met the criteria for PDVF (confirmed viral rebound above 50 copies after being undetectable). Therefore, the primary analysis shows 90% of the patients with pVL <50 copies in the ITT-exposed, FDA snapshot analysis. Observed failure, as the patient who committed suicide had undetectable pVL at last visit, was 5%.\n\nThe clinical implications of low-level viremia are controversial. Department of Human Health Services (DHHS) ARV guidelines define virologic failure as the inability to achieve or maintain suppression of viral replication to an HIV-RNA level <200 copies/mL and state that viremia “blips” are not usually associated with subsequent virologic failure [34].\n\nOur study has some limitations. As a pilot proof-of-concept trial, it has a small sample size. Given that this dual regimen has been never tested before, we preferred a cautious design, treating first a cohort of 10 patients, and recruiting the second cohort when initial success was achieved, as pre-defined in the study protocol. Other limitations include being an open-label study, with a single arm and a low median VL at entry, albeit four of the volunteers had baseline pVL above 100,000 copies/mL.\n\nA limitation for using this dual regimen is that patients with active hepatitis B infection (HBV) would not be eligible, as HBV would be exposed to 3TC monotherapy, which is no longer the standard-of-care for that infection. Universal HBV vaccination is encouraged as a public health intervention, regardless of the ARV strategy selected. Special populations like pregnant women and patients with active tuberculosis were excluded, hence this strategy cannot be considered for those populations until specific studies are completed. Nevertheless, the PADDLE study strategy might potentially address several unmet needs. First, toxicities associated with NRTIs other than 3TC may compromise lifelong exposures to those compounds. Tenofovir disoproxil fumarate (TDF) lowers bone density more than other NRTIs and can be nephrotoxic [35,36]. Abacavir can induce a potentially life-threatening hypersensitivity syndrome, and only patients who are negative for the HLA-B*5701 allele can be treated with this drug. Also, it has been associated with an increased risk of cardiovascular disease, albeit other studies failed to confirm this association [37]. The new tenofovir alafenamide formulation (TAF) has shown similar efficacy to TDF [38], with a better safety profile, but long-term data are needed to confirm the TAF safety profile. TAF is already available in western countries, but it is uncertain when it will be available in the rest of the world, which carries the heaviest burden of the epidemic. ZDV (still used in some developing countries) causes myelosuppression, gastrointestinal symptoms, headaches and mitochondrial toxicity that can lead to lipoatrophy, hepatic steatosis and lactic acidosis. Second, 3TC is a potent and inexpensive drug that can be easily co-formulated with DTG, providing a single pill QD first-line option that might be easy to administer, with minimal side effects and few drug interactions. Third, the total amount of active pharmaceutical ingredients required is low, allowing to produce smaller pills. Fourth, given the production cost of the DTG and 3TC, this regimen might be the cheapest drug combination according to a recent WHO forecast that estimated the annual cost per patient at about UDS44 [39]. Even in the US, the use of this combination as initial therapy or switching could result in significant savings. Girouard et al. compared no ART to an initial dual regimen (DTG + 3TC); to an induction–maintenance strategy (48-week induction regimen of DTG + abacavir + 3TC) followed by DTG + 3TC maintenance if virologically suppressed; and to a standard-of-care three-drug regimen (DTG + abacavir + 3TC) [40]. Two-drug regimen was the most cost-effective strategy if DTG + 3TC 48-week virologic suppression rate could exceed 90%.\n\nConclusions\nThe results of this small, proof-of-concept, pilot study encourage further exploration of this strategy. Our results suggest that the combination of DTG and 3TC could be considered as an alternative option in first line, sparing exposure to other nucleosides and preserving other treatment options downstream, if needed. The low rate of side effects reported in the study is attributable to the avoidance of the second NRTI. Dual therapy with DTG + 3TC could be a highly effective, simple and, in some settings, cost-effective first-line option for HIV patients. If our findings are confirmed in the ongoing randomized trials GEMINI 1 (NCT02831673) and GEMINI 2 (NCT02831764), this strategy may challenge the value of adding a third nucleosid(t)ide to the outcomes of HAART. Until then, the decision of using this dual regimen outside clinical trials should be carefully considered.\n\nAcknowledgements\nLamivudine and Dolutegravir were provided by ViiV Healthcare. The 24-week data in this report were presented at the 15th European AIDS Conference (Barcelona, Spain, 21–24 October 2015; oral presentation LBPS4/1). The 48-week data were presented at the IAS Conference in Durban, South Africa; Oral presentation # FRAB0104LB. We thank the PADDLE study participants and their families and caregivers for participation in the study and all the team of the Fundación Huésped Clinical Research Department for their commitment. Horacio Salomon, at INBIRS (Buenos Aires), performed the resistance tests. Santiago Perez Lloret provided statistical support. Dr Alieu B. Amara from Liverpool Bioanalytical Facility Royal Liverpool University Hospital for performing drug monitoring and Mark Wainberg for providing virological advice.\n\nPC, OS, MJR and MIF designed the study with support and limited input from ViiV Healthcare. Fundación Huésped investigators enrolled patients in the study and were involved in acquisition of data. AG was in charge of laboratory analysis. PP and MIF were responsible for patient’s clinical care. PC, MJR, MIF and OS analysed data, clinically oversaw the study and participated in data interpretation. The report was drafted by PC, OS, MIF and MJR. All authors provided input to the report and approved the final version. All authors have read and approved the final version.\n\nCompeting interest\nPC is a member of the WHO Guidelines Panel and a former member of the IAS-USA Guidelines Panel. He has served on the advisory boards for GlaxoSmithKline (ViiV), Merck, Pfizer, Gilead Sciences and Tibotec (Janssen) Therapeutics. He has served as investigator for Abbott, Avexa, Boehringer Ingelheim, Gilead Sciences, GlaxoSmithKline, Merck, Pfizer, Pharmasset, Roche Laboratories and Tibotec Therapeutics, and his institution has received honoraria for his speaking or chairing engagements from Abbott Laboratories, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Pfizer, Tibotec and ViiV Healthcare.\n\nOS has received honoraria for his speaking from Abbott Laboratories and Merck. He has served as investigator for Investigator Initiated Research funded by ViiV.\n\nMIF, MJR, AG, PP and SPL declare that they have no competing interests.\n==== Refs\nReferences\n1. Gulick RM , Mellors JW , Havlir D , Eron JJ , Gonzalez C , McMahon D , et al \nTreatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy . 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Clin Infect Dis . 2016 ;62 :784 –91 .26658053\n\n", "fulltext_license": "CC BY", "issn_linking": "1758-2652", "issue": "20(1)", "journal": "Journal of the International AIDS Society", "keywords": "dolutegravir; dual therapy; lamivudine; naive patients", "medline_ta": "J Int AIDS Soc", "mesh_terms": "D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D000998:Antiviral Agents; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections; D015497:HIV-1; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D019259:Lamivudine; D008297:Male; D010078:Oxazines; D010865:Pilot Projects; D010879:Piperazines; D011728:Pyridones; D019562:Viral Load", "nlm_unique_id": "101478566", "other_id": null, "pages": "21678", "pmc": null, "pmid": "28537061", "pubdate": "2017-05-09", "publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article", "references": "23596273;27470027;26491561;26062881;27023283;22018760;25397552;25394021;19019971;25350958;20008942;15482179;21716073;11052597;26817882;26849060;7477218;26658053;18480202;18387667;23372058;26762990;9544767;26424673;24074642;24979445;26544574;26842728;9287228;9791141;26642452;24872136;25103176;24195548;24783988", "title": "Dolutegravir-lamivudine as initial therapy in HIV-1 infected, ARV-naive patients, 48-week results of the PADDLE (Pilot Antiretroviral Design with Dolutegravir LamivudinE) study.", "title_normalized": "dolutegravir lamivudine as initial therapy in hiv 1 infected arv naive patients 48 week results of the paddle pilot antiretroviral design with dolutegravir lamivudine study" }

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{ "abstract": "The aim of this paper was to report a case of orthognathic surgery successfully done in a patient with multiple sclerosis.\n\n\n\nMultiple sclerosis (MS) is a chronic, progressive inflammatory disorder of the central nervous system affecting young adults, characterized by lymphocytic infiltration of the brain and spinal cord leading to demyelination and focal axonal damage. Clinically, MS patients present with reversible neurological dysfunction in the early stages, which progresses to irreversible neurological disability and deficit. Oral manifestations of MS include facial numbness or pain, neuralgias, facial paralysis, dysarthria and dysphagia. While dental treatment is not contraindicated in MS patients, it is, however, limited to preventive and supportive dental care.\n\n\n\nA 23-year-old Saudi male patient with a diagnosis of MS since 2008 reported to the oral and maxillo-facial surgery (OMFS) department for correction of dentofacial deformity. The patient was under follow-up with the neurology department and was being treated with interferon beta-1a. Following consent from the neurologist and the patient, a Lefort 1 segmental osteotomy was done under general anesthesia. The patient was stable throughout the surgical procedure and during the postoperative period. The patient was discharged upon complete surgical recovery and no acute exacerbations of MS were reported during the perioperative period.\n\n\n\nBased on our observations, orthognathic and maxillofacial surgical procedures can be safely carried out in patients with MS, provided a strict perioperative prophylactic regimen for stress reduction and prevention of acute attacks of MS is adhered to.\n\n\n\nDue to the stressful nature of dental treatment and oral and maxillofacial surgical procedures, acute exacerbations of MS are very much likely. Hence, it is imperative that dental and oral surgical practitioners are aware of the manifestations of MS and are able to manage such patients with suitable treatment modifications.", "affiliations": "Assistant Professor, Department of Maxillofacial Surgery, College of Dentistry, King Saud University, Riyadh, 11545, Saudi Arabia, Phone: +96653 2092386, e-mail: saalbazieomfs@gmail.com.", "authors": "Al-Bazie|Saleh A|SA|", "chemical_list": null, "country": "India", "delete": false, "doi": "10.5005/jp-journals-10024-1713", "fulltext": null, "fulltext_license": null, "issn_linking": "1526-3711", "issue": "16(6)", "journal": "The journal of contemporary dental practice", "keywords": "Multiple sclerosis; Orthognathic surgery; Dentofacial deformity; Interferon beta-1a; Lefort 1 osteotomy.", "medline_ta": "J Contemp Dent Pract", "mesh_terms": "D063169:Dentofacial Deformities; D006801:Humans; D008297:Male; D009103:Multiple Sclerosis; D056948:Orthognathic Surgical Procedures; D019340:Osteotomy, Le Fort; D013515:Surgery, Oral; D055815:Young Adult", "nlm_unique_id": "101090552", "other_id": null, "pages": "507-11", "pmc": null, "pmid": "26323455", "pubdate": "2015-06-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Orthognathic Surgery in a Patient with Multiple Sclerosis.", "title_normalized": "orthognathic surgery in a patient with multiple sclerosis" }

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"VECURONIUM BROMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "7", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VECURONIUM BROMIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": 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"drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "XYLOCAINE WITH EPINEPHRINE (EPINEPHRINE BITARTRATE\\LIDOCAINE HYDROCHLORIDE)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SEVOFLURANE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "030", "drugtreatmentduration": null, 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"drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIDAZOLAM" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "INTERFERON BETA-1A" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": "103628", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RELAPSING-REMITTING MULTIPLE SCLEROSIS", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2008", "drugstartdateformat": "602", "drugstructuredosagenumb": "30", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AVONEX" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CEFAZOLIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, 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ORTHOGNATHIC SURGERY IN A PATIENT WITH MULTIPLE SCLEROSIS. J CONTEMP DENT PRACT. JUN 2015?16(6):507-511.", "literaturereference_normalized": "orthognathic surgery in a patient with multiple sclerosis", "qualification": "1", "reportercountry": "SA" }, "primarysourcecountry": "SA", "receiptdate": "20151026", "receivedate": "20150914", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11500306, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160304" } ]

{ "abstract": "A 60-year-old woman with history of vaginal malignant melanoma and inguinal nodal metastases underwent F-FDG PET/CT for restaging following ipilimumab (Yervoy) immunotherapy, a Food and Drug Administration-approved human monoclonal antibody targeting cytotoxic T-lymphocyte-associated antigen 4. PET/CT demonstrated mildly FDG-avid multifocal enlarging bilateral lung opacities. Within each lung lesion, there was circumferential uptake localizing to a high-attenuation rim with a photopenic ground-glass center on CT, consistent with \"reversed halo sign.\" Patient was asymptomatic at the time of imaging. Ipilimumab was discontinued, and 3-month follow-up PET/CT revealed spontaneous complete resolution of the lung lesions, supporting the diagnosis of ipilimumab-induced organizing pneumonia.", "affiliations": "From the *Division of Nuclear Medicine, Department of Radiology, and †Division of Oncology, Department of Medicine, New York University School of Medicine, New York, NY.", "authors": "Raad|Roy A|RA|;Kannan|Rajni|R|;Madden|Kathleen|K|;Pavlick|Anna|A|", "chemical_list": "D000074324:Ipilimumab; D019788:Fluorodeoxyglucose F18", "country": "United States", "delete": false, "doi": "10.1097/RLU.0000000000001673", "fulltext": null, "fulltext_license": null, "issn_linking": "0363-9762", "issue": "42(7)", "journal": "Clinical nuclear medicine", "keywords": null, "medline_ta": "Clin Nucl Med", "mesh_terms": "D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D000074324:Ipilimumab; D008545:Melanoma; D008875:Middle Aged; D011014:Pneumonia; D000072078:Positron Emission Tomography Computed Tomography", "nlm_unique_id": "7611109", "other_id": null, "pages": "e345-e346", "pmc": null, "pmid": "28481788", "pubdate": "2017-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Ipilimumab-Induced Organizing Pneumonia on 18F-FDG PET/CT in a Patient With Malignant Melanoma.", "title_normalized": "ipilimumab induced organizing pneumonia on 18f fdg pet ct in a patient with malignant melanoma" }

[ { "companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2017-041671", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "IPILIMUMAB" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "125377", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Unknown", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Malignant melanoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IPILIMUMAB" } ], "patientagegroup": "5", "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Organising pneumonia", "reactionmeddraversionpt": "25.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Raad RA, Kannan R, Madden K, Pavlick A. Ipilimumab-induced organizing pneumonia on 18F-FDG PET/CT in a patient with malignant melanoma. Clinical Nuclear Medicine. 2017; 42(7): e345-6. 10.1097/RLU.0000000000001673", "literaturereference_normalized": "ipilimumab induced organizing pneumonia on 18f fdg pet ct in a patient with malignant melanoma", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220530", "receivedate": "20170519", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13565248, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220721" } ]

{ "abstract": "The neuropharmacology of marijuana, including its effects on selective serotonin reuptake inhibitor (SSRI)/antidepressant metabolism and the subsequent response and tolerability in youth, has received limited attention. We sought to (1) review clinically relevant pharmacokinetic (PK) and pharmacodynamic (PD) interactions between cannabinoids and selected SSRIs, (2) use PK models to examine the impact of cannabinoids on SSRI exposure (area under curve (AUC)) and maximum concentration (CMAX) in adolescents, and (3) examine the frequency of adverse events reported when SSRIs and cannabinoids are used concomitantly. Cannabinoid metabolism, interactions with SSRIs, impact on relevant PK/PD pathways and known drug-drug interactions were reviewed. Then, the impact of tetrahydrocannabinol (THC) and cannabidiol (CBD) on exposure (AUC24) and CMAX for escitalopram and sertraline was modeled using pediatric PK data. Using data from the Food and Drug Administration Adverse Events Reporting System (FAERS), the relationship between CBD and CYP2C19-metabolized SSRIs and side effects was examined. Cannabis and CBD inhibit cytochrome activity, alter serotonergic transmission, and modulate SSRI response. In PK models, CBD and/or THC increases sertraline and es/citalopram concentrations in adolescents, and coadministration of CBD and CYP2C19-metabolized SSRIs increases the risk of cough, diarrhea, dizziness, and fatigue. Given the significant SSRI-cannabinoid interactions, clinicians should discuss THC and CBD use in youth prescribed SSRIs and be aware of the impact of initiating, stopping, or decreasing cannabinoid use as this may significantly affect es/citalopram and sertraline exposure.", "affiliations": "Division of Child and Adolescent Psychiatry, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA.;Division of Child and Adolescent Psychiatry, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA.;Division of Biomedical Informatics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA.;Division of Biomedical Informatics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA.;Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA.", "authors": "Vaughn|Samuel E|SE|;Strawn|Jeffrey R|JR|;Poweleit|Ethan A|EA|;Sarangdhar|Mayur|M|;Ramsey|Laura B|LB|0000-0001-6417-3961", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.3390/jpm11070615", "fulltext": "\n==== Front\nJ Pers Med\nJ Pers Med\njpm\nJournal of Personalized Medicine\n2075-4426\nMDPI\n\n34209709\n10.3390/jpm11070615\njpm-11-00615\nPerspective\nThe Impact of Marijuana on Antidepressant Treatment in Adolescents: Clinical and Pharmacologic Considerations\nVaughn Samuel E. 1*\nStrawn Jeffrey R. 123\nPoweleit Ethan A. 45\nSarangdhar Mayur 467\nhttps://orcid.org/0000-0001-6417-3961\nRamsey Laura B. 35\nLee Moon-Soo Academic Editor\n1 Division of Child and Adolescent Psychiatry, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA; strawnjr@mail.uc.edu\n2 Department of Psychiatry and Behavioral Neuroscience, College of Medicine, University of Cincinnati, Cincinnati, OH 45219, USA\n3 Division of Clinical Pharmacology, Cincinnati Children’s Hospital Medical Center, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA; laura.ramsey@cchmc.org\n4 Division of Biomedical Informatics, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA; poweleen@mail.uc.edu (E.A.P.); mayur.Sarangdhar@cchmc.org (M.S.)\n5 Division of Research in Patient Services, Cincinnati Children’s Hospital Medical Center, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA\n6 Department of Biomedical Informatics, College of Medicine, University of Cincinnati, Cincinnati, OH 45219, USA\n7 Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA\n* Correspondence: Samuel.Vaughn@cchmc.org; Tel.: +1-513-636-4788\n29 6 2021\n7 2021\n11 7 61504 6 2021\n24 6 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nThe neuropharmacology of marijuana, including its effects on selective serotonin reuptake inhibitor (SSRI)/antidepressant metabolism and the subsequent response and tolerability in youth, has received limited attention. We sought to (1) review clinically relevant pharmacokinetic (PK) and pharmacodynamic (PD) interactions between cannabinoids and selected SSRIs, (2) use PK models to examine the impact of cannabinoids on SSRI exposure (area under curve (AUC)) and maximum concentration (CMAX) in adolescents, and (3) examine the frequency of adverse events reported when SSRIs and cannabinoids are used concomitantly. Cannabinoid metabolism, interactions with SSRIs, impact on relevant PK/PD pathways and known drug–drug interactions were reviewed. Then, the impact of tetrahydrocannabinol (THC) and cannabidiol (CBD) on exposure (AUC24) and CMAX for escitalopram and sertraline was modeled using pediatric PK data. Using data from the Food and Drug Administration Adverse Events Reporting System (FAERS), the relationship between CBD and CYP2C19-metabolized SSRIs and side effects was examined. Cannabis and CBD inhibit cytochrome activity, alter serotonergic transmission, and modulate SSRI response. In PK models, CBD and/or THC increases sertraline and es/citalopram concentrations in adolescents, and coadministration of CBD and CYP2C19-metabolized SSRIs increases the risk of cough, diarrhea, dizziness, and fatigue. Given the significant SSRI–cannabinoid interactions, clinicians should discuss THC and CBD use in youth prescribed SSRIs and be aware of the impact of initiating, stopping, or decreasing cannabinoid use as this may significantly affect es/citalopram and sertraline exposure.\n\nselective serotonin reuptake inhibitors\nmarijuana\nCYP2C19\ndrug–drug interaction\nadverse reactions\n==== Body\n1. Introduction\n\nAnxiety and depressive disorders, the most common mental health conditions in children and adolescents [1], are frequently treated with selective serotonin reuptake inhibitors (SSRIs) [2,3,4]. However, treatment response varies considerably [5,6,7,8] and is often difficult to predict [9]. The considerable variation in SSRI response in adolescents with depressive and anxiety disorders is complex and is related to multiple factors, including comorbidity, pharmacogenetics, and substance use [10,11,12].\n\nYouth with depression are twice as likely to report cannabis use and use amongst depressed teens has increased more rapidly over the past 15 years compared to their peers [13]. Further, an estimated one in three twelfth graders (17–18 years old) used marijuana in the past year and 6% of these adolescents used marijuana on a daily basis. Similarly, among eighth and tenth graders, daily use increased since 2018, with 1.3% of eighth graders (an 85.7% increase in 13–14-year-olds) and 4.8% of tenth graders (a 41.2% increase in 15–16-year-olds) reporting daily use (NIDA, NIH, NHHS).\n\nCannabinoids and several SSRIs are hepatically metabolized by CYP2C19 and CYP2D6. CYP2D6, and CYP2C19 metabolize many neuropsychiatric medications. CYP2D6 has over 100 known allelic variants and over 20 of these polymorphisms impact function. Broadly, these alleles are classified as normal function, decreased function, and no function [14]. As each individual patient inherits two alleles, phenotypes depend on the combination of inherited alleles. Four metabolic phenotypes have been predicted for CYP2D6: ultrarapid metabolizers inheriting duplications of functional alleles (1–20% of patients), normal (extensive) metabolizers inheriting at least one normal function allele (19–63%), intermediate metabolizers inheriting at least one decreased function or no function allele (14–72%), and poor metabolizers (0–6%) inheriting only no function alleles. Fluoxetine, fluvoxamine, and paroxetine are metabolized by CYP2D6 [15].\n\nCYP2C19 is highly polymorphic, with over 30 identified allelic variants. These can be grouped in broad functional groups. There are five predicted phenotypes for CYP2C19: ultrarapid metabolizers carrying two increased function alleles (0–5% of patients), rapid metabolizers carrying an increased function allele paired with a normal function allele (1–27% of patients), normal (extensive) metabolizers carrying two normal function alleles (9–47%), intermediate metabolizers carrying one normal or increased function allele together with one decreased or no function allele (24–47%), and poor metabolizers carrying two decreased or no function alleles (2–46%). Citalopram, escitalopram, and sertraline are metabolized primarily by CYP2C19 [14,15,16] (Figure 1).\n\nThe predicted phenotypes are the focus of functional studies, which evaluate the impact of allelic variation on SSRI pharmacokinetics and clinical outcomes, including efficacy and tolerability. For example, we previously demonstrated that CYP2C19 metabolizer status impacts the outcomes with escitalopram/citalopram in youth with anxiety and depressive disorders [17,18]. Slower metabolizers were more likely to discontinue treatment compared to normal metabolizers, and were more likely to experience significant side effects, including weight gain and activation.\n\nFor citalopram and escitalopram, the Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends that clinicians treating CYP2C19 rapid and ultrarapid metabolizers consider alternative medications that are not significantly metabolized by CYP2C19 [15]. For sertraline, the difference in CYP2C19 ultrarapid metabolizers appears to be less pronounced, so no dose adjustment is recommended [15]. In CYP2C19 poor metabolizers, CPIC recommends a dose reduction of 50% for citalopram, escitalopram, and sertraline because elevated medication concentrations have been observed (e.g., citalopram/escitalopram) or more side effects have been reported (e.g., sertraline). These recommendations are based on data from adults, but pediatric data are increasingly reported [17,19,20,21] and will be assessed in the update of the CPIC SSRI guideline, expected to be published in late 2021 or early 2022.\n\nVariation in SSRI response may also relate to differences in SSRI exposure (e.g., blood concentration) among adolescents [12,22]. Importantly, marijuana use may also influence the pharmacology of SSRIs, including their pharmacokinetic profile. The pharmacology of cannabinoids may accentuate this variation in response in adolescents with these disorders. However, the neuropharmacology of marijuana use; interactions between marijuana and serotonergic transmission; and the effects of marijuana on an SSRI metabolism, response, and tolerability have received limited attention in the current literature. With this in mind, we sought to (1) describe the impact of marijuana on SSRI treatment in children and adolescents, (2) characterize and examine the effect of marijuana on enzymes that metabolize SSRIs with regard to variation in SSRI response in adolescents, and (3) examine the frequency of adverse events reported when SSRIs and cannabinoids are used concomitantly. Hereafter, we focus primarily on es/citalopram and sertraline as (1) these SSRIs are primarily metabolized by CYP2C19, (2) CPIC has issued genotype-specific dosing guidelines for these medications, and (3) CBD appears to have a greater interaction with CYP2C19 than CYP2D6.\n\n2. Pharmacokinetic Interactions\n\n2.1. Cannabis and Cannabidiol Impact Cytochrome Activity\n\nAlthough cannabis contains hundreds of individual chemicals, we focus on cannabinoids in this review. The most abundant phytocannabinoids in cannabis are Δ9-tetrahydrocannabinol (THC) [23] and CBD [24,25]. Cannabinoids are metabolized in the liver predominantly by CYP2C9 and CYP3A4 [26], although CYP2D6 and CYP2C19 are also involved [27]. In addition to being metabolized by these enzymes, THC and CBD inhibit CYP2D6 [28] (Food and Drug Administration (FDA) Epidiolex, FDA news alert) and CYP2C19 [29] (FDA Epidiolex, FDA news alert, Sativex regulatory) in vitro (Table 1), as summarized in Zendulka, Dovrtelova [30]. Based on in vitro experiments and the estimated plasma drug levels, CBD was predicted to induce strong drug interactions with CYP2C19 and moderate interactions with CYP2D6 [31]. However, THC, taken orally or inhaled, was not predicted to induce drug interactions with CYP2C19 or CYP2D6 [31]. CBD also inhibits CYP2C19 in vivo [32,33,34]. Taken together, these data suggest that medications with a CYP2C19-dependent metabolism are likely to be susceptible to drug–drug interactions with cannabinoids [35].\n\n2.2. Cannabis and Cannabidiol Potentially Interact with SSRIs\n\nTo date, no studies have examined the impact of marijuana use on SSRI efficacy or tolerability in adolescents. However, extrapolating from in vivo studies of the impact of cannabidiols on medications metabolized in a manner similar to SSRIs can provide guidance. Clobazam, which is metabolized primarily by CYP3A4 and CYP2C19, is slowly metabolized in CYP2C19 poor metabolizers, leading to accumulation of the active metabolite n-clobazam and increased side effects [36]. Coadministering clobazam and CBD increases plasma clobazam concentrations by about 60% and increases n-clobazam concentrations five-fold [37]. Similarly, CBD also increases the concentrations of stiripentol, another antiepileptic medication metabolized by CYP2C19 [38].\n\n2.3. Pharmacokinetics of Cannabinoids\n\nOne significant challenge to studying the drug–drug interaction between marijuana and SSRIs is the difficulty in estimating marijuana exposure. As marijuana is composed of numerous cannabinoids, which vary in their concentration, including cannabis strain differences, isolation of specific cannabinoids, such as those found in over-the-counter products such as CBD oil [39], to medicinal preparations of synthetic cannabinoids, such as dronabinol. Of relevance to pharmacokinetic effects of cannabinoids and SSRIs, the method of preparation and the administration route significantly impact cannabinoid pharmacokinetics, as do frequency and the amount of use (summarized in Grotenhermen [40]). For example, oral THC bioavailability ranges from 5–20% and its absorption is delayed by 1–3 h as it is slowly absorbed by the gastrointestinal tract. Further, oral THC absorption is also influenced by sex, weight, and the presence of food [41]. By contrast, the pharmacokinetics of inhaled THC are more variable, with up to 50% of inhaled smoke exhaled and some localized pulmonary metabolism. This results in a bioavailability of 10–25%, faster absorption (generally within minutes) [42], and inhaled THC exhibits first-order kinetics [43].\n\n2.4. Preliminary Models Of SSRI–Cannabinoid Pharmacokinetic Interactions\n\nWe determined that the total body clearance of SSRIs may be reduced based on a recently reported pharmacokinetic interaction risk between oral THC or low-dose CBD and cytochrome enzymes [31]. Therefore, using previously estimated pharmacokinetic parameters and standard dosing regimens for an adolescent CYP2C19 normal metabolizer [12], we estimated the influence of concurrent THC or low-dose CBD (5–15 mg/day) use with escitalopram or sertraline (Figure 2).\n\nIn the pharmacokinetic model, the half-life of escitalopram with concurrent THC or low-dose over-the-counter CBD increased from 21.3 to 28.3 h. For escitalopram-treated adolescents receiving 20 mg/day, concurrent THC or low-dose over-the-counter CBD use increased the AUC and CMAX by 35% (34.1 vs. 46.1 days ng/mL) and 25% (45.3 vs. 56.9 ng/mL), respectively (Table 2). Similarly, in the pharmacokinetic model for sertraline, concurrent THC or low-dose over-the-counter CBD increased the half-life of sertraline from 22.1 to 29.5 h. For sertraline-treated adolescents receiving 150 mg/day, concurrent THC or low-dose over-the-counter CBD use increased the AUC and CMAX by 33% (54.2 vs. 72.1 days ng/mL) and 26% (66.0 vs. 83.2 ng/mL), respectively (Table 3). For both models, concurrent THC or low-dose CBD increased the time required for a patient to achieve a steady state.\n\nWe estimated the effects of concurrent THC or low-dose CBD use with sertraline or escitalopram using MwPharm (version 3.82, Mediware, Czech Republic [44]). MwPharm is a pharmacokinetic modeling program that enables users to approximate a patient’s clearance, volume of distribution, exposure, and concentration of individual medications (e.g., sertraline and escitalopram) based on previously published parameters. Model parameters of a medication are entered into the program, in addition to patient characteristics, including age, body size, sex, and medication/dosing history. Considering patient and medication information, the program simulates a time course of medication plasma concentrations for a patient, in addition to their estimated effects. For the escitalopram model, total body clearance was 25 L/h/70 kg, V1 was 12 L/kg lean body mass, and Ka was 0.8 h−1. For the sertraline model, total body clearance was 152 L/h/70 kg, V1 was 76 L/kg lean body mass, and Ka was 0.8 h−1. The effect of THC or low-dose CBD use was estimated based on recent clinical data [31] suggesting a reduction in escitalopram or sertraline clearance by 25% (to 18.75 and 114 L/h/70 kg, respectively). The area under the concentration–time curve (AUC) and the maximal concentration (CMAX) [45] were estimated from the final dose of each titration during steady state. Additional details of the pharmacokinetic modeling approach and specific pharmacokinetic parameters have been described (Strawn, Poweleit [12]).\n\n2.5. Case Illustration of SSRI-Cannabinoid Pharmacokinetic Interactions\n\nTo illustrate the potential clinical impact of concurrent SSRI and cannabinoid use, we present the following.\n\nA 15-year-old adolescent who met the DSM-5 criteria for generalized anxiety disorder with panic attacks and recurrent, moderate major depressive disorder was treated with escitalopram 5 mg beginning from the age of 15 years 8 months. She had no relevant past medical history, no history of trauma, and was not treated with any other CYP2C19-metabolized medications. Her depressive and anxiety symptoms were in remission while treated with escitalopram 10 mg each morning for 3 months, and titrated up to 15 mg/day when anxiety worsened, including increasing panic attacks. Unbeknownst to her clinician or parents, she began consuming CBD/THC in edible form. As CBD/THC use continued, her anxiety symptoms worsened, her panic attacks became more intense and more frequent, and her depressive symptoms intensified. Escitalopram was titrated to 20 mg each morning, with some initial improvement, but her anxiety symptoms recrudesced. Following disclosure of the CBD/THC use to her parents and clinician, CBD/THC use stopped. Nausea, abdominal pain, and headaches were also reported at this time. A time course of the patient’s treatment, clinical outcome scores, and simulated escitalopram levels is illustrated in Figure 3. Using the same escitalopram plasma drug level simulation strategy as described above and shown in Figure 2, we simulated the change in escitalopram plasma concentrations in this patient with concurrent CBD/THC use. The side effects reported at the first visit following disclosure of CBD/THC use may relate to the modeled elevation in escitalopram exposure.\n\n2.6. Real-World Cannabinoid and SSRI Interactions\n\nThe increased use of cannabinoids both recreationally and in clinical practice leads to a greater chance for coadministration with SSRIs and possible adverse events. Foster et al. [47] examined the U.S. Food and Drug Administration (FDA)’s Adverse Event Reporting System (FAERS) and found a significant number of adverse event reports involving marijuana or a derivative thereof, suggesting that there is a risk of marijuana–drug interaction. Reports have increased over time compared to other drug–supplement interactions, possibly correlating with the increased availability of marijuana-derived products, including both prescription and OTC THC- and CBD-derived medical and recreational products. Data on direct clinical interactions are slowly emerging as evidenced by a recent case report of a cannabis hyperemesis syndrome that may have occurred at least in part due to concurrent SSRI use [48].\n\n2.7. Data Mining of Large-Scale Clinical Effects and Hypothesis Generation Using U.S. Food and Drug Administration’s Adverse Event Reporting System (FAERS) Data\n\nAdverse events data reported to FAERS and normalized within AERSMine [49] were used to identify differential rates of side effects typically associated with antidepressants. We analyzed ~15 million patient reports from the FDA for use of CYPC219-metabolized medications (sertraline, escitalopram, and citalopram, n = 427,932), cannabinoids (tetrahydrocannabinol, cannabidiol, and cannabinoids, n = 7008), and their combination (n = 421). The three mutually exclusive cohorts were analyzed for their frequencies of side effects. Side-effect frequencies in the CYP2C19 medication cohort were used as a baseline for comparison to the cannabinoid and combination cohorts. Drug label data were extracted from Lexicomp [50] and 23 side effects with >5% frequency on the sertraline or escitalopram label were used for benchmarking our comparative analysis. Standard pharmacovigilance metrics, relative risks, and safety signals [51,52], were used to identify drug and drug combination side effect associations. The Benjamini, Hochberg, and Yekutieli test [53] was used for false discovery rate (FDR) correction using a significance threshold of 0.05.\n\n2.8. Combination Of CYP2C19-Metabolized Medications and Cannabinoids Presents Elevated Risk of Antidepressant-Related Side Effects\n\nTo understand the relative safety profile of sertraline and es/citalopram in combination with cannabinoids, we analyzed 23 side effects with >5% frequency on sertraline or es/citalopram labels. Comparative analysis of these 23 side effects in the FAERS data revealed that patients on a combination of CYP2C19-metabolized medications and cannabinoids showed a disproportionately higher risk of certain side effects. Compared to patients taking sertraline or es/citalopram alone, patients in the combination group presented a 4.97-fold increase in cough, 3.33-fold higher rate of diarrhea, 3.29-fold higher rate of fatigue, 2.87-fold increase in dizziness, and 2.54-fold increase in influenza (FDR correction at 0.05, Figure 4). Conversely, weight gain was not common in patients in the combination group, 0.24% vs. 2.53% in the sertraline or es/citalopram group (p < 0.005, Figure 4, See Supplementary Table S1 for side effect frequencies in the FAERS data).\n\n3. Pharmacodynamic Interactions\n\nIn addition to the potential impact of cannabinoids on SSRI pharmacokinetics, studies also examined the impact of cannabinoids on serotonin pharmacodynamics. In preclinical studies, mice administered a CB1 antagonist together with an SSRI showed improved performance on a behavioral test compared to either agent alone, and at lower doses [54]. In another pre-clinical study, administration of citalopram together with a CB1 antagonist increased 5-HT release in both the prefrontal cortex and locus cereulus of awake rats [55]. However, neither study examined the impact of concurrent medications on cytochrome metabolism, so it is unclear if these results are due to direct action at CB1 or changes in medication exposure due to hepatic drug–drug interactions.\n\nThere is also a direct link between 5-HT signaling and the endocannabinoid system (Figure 5). Long-term cannabinoid administration alters the 5-HT receptor signaling, upregulating 5-HT2A activity and down-regulating 5-HT1A activity [56]. In addition, CB agonists upregulate the 5-HT2A receptor signaling [57]. This interaction appears to be bidirectional; serotonin-mediated 5-HT2 receptor activation increases endocannabinoid release and CB1 receptor activation [58]. Regarding exogenous cannabinoids, THC is an agonist at CB1 receptors, which may result in increased appetite, decreased working memory, and the euphoria associated with intoxication, whereas THC also agonizes CB2 [59] and 5-HT3, potentially conferring antiemetic properties (summarized in Pertwee [60]).\n\n4. Discussion\n\nMarijuana use is common in adolescents and its recreational and medicinal use has increased contemporaneously. The FDA has approved one cannabis-derived drug and three FDA-approved synthetic cannabis-related drugs. Further, OTC CBD products are increasingly marketed as treatments for anxiety and depression. As SSRIs are frequently prescribed in adolescents [61], we must better understand potential SSRI–cannabinoid interactions. Although there are limited studies of direct SSRI–cannabinoid interactions, accumulating data suggest the potential for PK and PD interactions.\n\nAs THC and CBD inhibit CYP2C19, and to a lesser degree CYP2D6, SSRIs metabolized by CYP2C19, including sertraline and es/citalopram, have a high likelihood of drug–drug interactions. This would be most likely observed in individuals with a poor metabolizer phenotype, who would already be likely to have increased drug concentrations (compared to normal metabolizers).\n\nWith the utility of cannabinoids as antiepileptic drugs, including recent FDA approval of the first cannabinoid-derived drug, Epidiolex® (cannabidiol), drug–drug interactions between cannabinoids and other antiepileptic drugs metabolized by cytochrome enzymes have been described. Drug–drug interactions between cannabinoids and two substrates of CYP2C19, stiripentol and clobazam, have been described, supporting the possibility that cannabinoids affect other CYP2C19 substrates, including sertraline and es/citalopram [62]. Herein, we focused on SSRIs metabolized primarily by CYP2C19. Thus, our conclusions may not generalize across SSRIs. The increased side effects from concurrent cannabinoid and SSRIs we identified were all amongst the most common identified in the FDA package insert, and may relate to SSRI dose or plasma concentrations [63].\n\nOur model predicts a clinically significant increase in plasma drug concentration variation with concurrent use of marijuana or low-dose CBD and SSRIs. This increase in plasma concentration would be magnified if high-dose CBD and SSRIs were concomitantly prescribed. As increased SSRI plasma concentration is associated with increased activation [64], the implications include a decrease in tolerability secondary to activation. Because medication-related side effects and clinical symptoms of disease can overlap and monitoring SSRI plasma drug levels is uncommon in clinical practice, the correlation between drug levels and side effects is poorly understood. Multiple trials found that common SSRI side effects increase as the SSRI dose is increased [63]. However, as the psychological effects of cannabinoids include euphoria and relaxation [65], activation may be masked with active concurrent use. Interestingly, given the prolonged half-life of cannabinoids, cannabis cessation, especially in the short term, may lead to worsened symptoms, potentially unmasking any underlying activation as cannabis-induced pharmacokinetic changes are likely to linger compared to the immediate psychological effects, which will return to baseline relatively quickly. Alternatively, as SSRI plasma concentration decreases following cannabis cessation, efficacy would also likely decrease. Considering the delayed release of 5-HT following CB1 stimulation, serotonergic pharmacodynamics are likely to be disrupted, decreasing drug efficacy.\n\nAlthough the existing literature suggests a direct interaction between cannabinoids and SSRIs, direct studies are lacking. Studies examining SSRIs coadministered with cannabinoids (either CBD or recreational marijuana) and tolerability/efficacy are needed. In addition, it will be vital to measure SSRI plasma concentrations to better characterize the potential drug–drug interactions.\n\n5. Conclusions\n\nAccumulating data suggest that CBD and THC affect concentrations of CYP2C19-metabolized SSRIs, including es/citalopram and sertraline. Using cannabidiol and or THC likely increases sertraline and es/citalopram concentrations in adolescents and may increase the risk of concentration-related SSRI side effects. Clinicians should consider inquiring as to the frequency and amount of THC and CBD use. Further, in sertraline- or es/citalopram-treated patients, stopping or decreasing marijuana or CBD use may decrease concentrations of sertraline or es/citalopram in stably treated patients.\n\nAcknowledgments\n\nFigures were created with Biorender.com.\n\nSupplementary Materials\n\nThe following are available online at https://www.mdpi.com/article/10.3390/jpm11070615/s1, Table S1: Side effect frequencies in FAERS data.\n\nClick here for additional data file.\n\nAuthor Contributions\n\nConceptualization, L.B.R., J.R.S., S.E.V. and E.A.P.; methodology, L.B.R., M.S., J.R.S., S.E.V. and E.A.P.; validation, L.B.R., M.S. and E.A.P.; formal analysis, L.B.R., M.S., J.R.S., S.E.V. and E.A.P.; resources, L.B.R. and J.R.S.; data curation, E.A.P., S.E.V. and M.S.; writing—original draft preparation, S.E.V., L.B.R. and J.R.S.; writing—review and editing, L.B.R., M.S., J.R.S., S.E.V. and E.A.P.; visualization, E.A.P. and M.S.; supervision, L.B.R. and J.R.S.; project administration, L.B.R. and J.R.S.; funding acquisition, L.B.R. and J.R.S. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research was funded by Eunice Kennedy Shriver National Institute of Child Health and Human Development, grant numbers R01HD099775 (J.R.S. and L.B.R.) and R01HD098757 (J.R.S.)\n\nInstitutional Review Board Statement\n\nNot applicable.\n\nInformed Consent Statement\n\nNot applicable.\n\nData Availability Statement\n\nAdverse event data were obtained from the FDA Adverse Event Reporting System (https://fis.fda.gov/sense/app/d10be6bb-494e-4cd2-82e4-0135608ddc13/sheet/7a47a261-d58b-4203-a8aa-6d3021737452/state/analysis accessed on 14 March 2021).\n\nConflicts of Interest\n\nStrawn has received research support from NIH (National Institute of Mental Health/National Institute of Environmental Health Sciences/NICHD), Allergan, Otsuka, and Neuronetics. He has received material support from and provided consultation to Myriad Genetics and has received royalties from the publication of two texts (Springer). He has served as an author for UpToDate, an Associate Editor for Current Psychiatry, and has received honoraria from CMEology and Neuroscience Educational Institute. He has provided consultation to the Food and Drug Administration. Ramsey has received research support from NIH (NICHD). She has received an educational grant and provided consultation to BTG Specialty Pharmaceuticals. The remaining authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.\n\nFigure 1 SSRI metabolism and the effects of cannabidiol (CBD) and tetrahydrocannabinol (THC) on CYP2C19 and CYP2D6 activity. Both CBD and THC inhibit CYP2C19, decreasing the metabolism of CYP2C19 substrates, including sertraline and es/citalopram, delaying production of active metabolites. THC and CBD have a reduced effect on CYP2D6, indicated by the thickness of the lines showing inhibition.\n\nFigure 2 Simulated time course of (A) escitalopram and (B) sertraline plasma concentrations in adolescent CYP2C19 normal metabolizers consuming THC or low-dose CBD versus not consuming. For escitalopram, treatment was initiated at 10 mg daily and increased to 20 mg daily at week 4. For sertraline, treatment was initiated at 50 mg daily and increased by 50 mg each subsequent week until reaching 200 mg daily. Concurrent THC or low-dose CBD (5–15 mg/day) use with escitalopram or sertraline was simulated with the total body clearance reduced by 25%. Abbreviations: THC, tetrahydrocannabinol; CBD, cannabidiol.\n\nFigure 3 Time course with simulation of escitalopram plasma concentrations in adolescent CYP2C19 normal metabolizer taking low-dose over-the-counter CBD. This patient was being treated with escitalopram, treatment was well-controlled at 10 mg daily and increased to 15 mg daily at month 10 with worsening anxiety. The dose was increased to 20 mg daily at 18.5 months when anxiety again worsened. The green line indicates the simulated escitalopram plasma concentration plotted on the left y-axis. The black line indicates the CGI-S score, plotted on the right y-axis. The gray boxes indicate the escitalopram daily dose. The hashed gray box indicates when the patient was using the THC/CBD. The dashed lines indicate the upper and lower therapeutic reference range (15–80 ng/mL) in adults [46]. Abbreviations: CBD, cannabidiol; OTC, over-the-counter, CGI-S, Clinical Global Impression Scale-Severity of Illness, THC, tetrahydrocannabinol.\n\nFigure 4 FAERS analysis of side effects in patients on antidepressants. The heatmap shows differential rates of side effects in patients on CYP2C19-metabolized medications (sertraline, es/citalopram), cannabinoids (CBD and THC) and the patients taking both as reported to FAERS. Rates of 23 side effects that are on the sertraline or es/citalopram label at >5% frequency were compared across three patient groups. Side effects with higher frequencies in the combination compared to the baseline (CYP2C19 medications without cannabinoids) and passing the FDR correction are highlighted using asterisks (* p < 0.05, *** p < 0.005). Frequencies of the side effects in the FAERS data are color coded as gray (0%), blue (5%), and red (10% or greater). Number of patients in each group: CYP2C19 (427,932), CBD (7008), CBD + CYP2C19 (421). Groups were mutually exclusive. Bejamini, Hochberg, and Yekutieli test used for FDR correction, significance threshold 0.05. FDR: false discovery rate.\n\nFigure 5 Cannabinoid-mediated impact on monoamine signaling in the brain. Cannabinoid-mediated stimulation of CB1 receptors on monoaminergic neurons leads to delayed transport of monoamines to the synapse, decreasing monoamines in the synapse. Abbreviations: GABA, gamma aminobutyric acid; Glu, glutamate; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA, N-methyl-D-aspartate; CB1, cannabinoid-1 receptor.\n\njpm-11-00615-t001_Table 1 Table 1 Impact following tetrahydrocannabinol/cannabidiol administration on in vitro CYP enzyme activity [30].\n\n\tIC50µ (µM) 1\t\n\tCBD\tTHC\t\nCYP2C19\t0.30 ± 0.03\t0.57 ± 0.22\t\nCYP2D6\t0.95 ± 0.50\t1.28 ± 0.25\t\nCYP3A4\t0.38 ± 0.11\t1.30 ± 0.34\t\n1 CBD, cannabidiol; THC, tetrahydrocannabinol; IC50µ, binding-corrected 50% inhibitory concentration.\n\njpm-11-00615-t002_Table 2 Table 2 Pharmacokinetic parameters at steady state for a model escitalopram normal metabolizer with concurrent cannabinoid use assuming a 25% reduction in clearance based on Bansal et al. [31].\n\n\tTHC or Low-Dose CBD 1\t\n\t−\t+\t\nt1/2 (h)\t21.3\t28.3\t\nAUC24, 10 mg q.d. (days ng/mL)\t17.1\t23.1\t\nCmax, 10 mg q.d. (ng/mL)\t22.7\t28.4\t\nAUC24, 20 mg q.d. (days ng/mL)\t34.1\t46.1\t\nCmax, 20 mg q.d. (ng/mL)\t45.4\t56.9\t\n1 Abbreviations: t1/2, half-life; AUC24, area under the curve (24-h); q.d., quaque die (once daily); THC, tetrahydrocannabinol; CBD, cannabidiol.\n\njpm-11-00615-t003_Table 3 Table 3 Pharmacokinetic parameters at steady state for a model sertraline normal metabolizer with concurrent cannabinoid use assuming a 25% reduction in clearance.\n\n\tTHC or Low-Dose CBD\t\n\t−\t+\t\nt1/2 (h)\t22.1\t29.5\t\nAUC24, 50 mg q.d. (days ng/mL)\t18.0\t23.7\t\nCmax, 50 mg q.d. (ng/mL)\t21.9\t27.4\t\nAUC24, 100 mg q.d. (days ng/mL)\t36.1\t47.9\t\nCmax, 100 mg q.d. (ng/mL)\t44.0\t55.3\t\nAUC24, 150 mg q.d. (days ng/mL)\t54.2\t72.1\t\nCmax, 150 mg q.d. (ng/mL)\t66.0\t83.2\t\nAUC24, 200mg q.d. (days ng/mL)\t72.3\t98.45\t\nCmax, 200 mg q.d. (ng/mL)\t88.0\t111.7\t\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Merikangas K.R. He J.-P. 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Hernandez A.V. Keurentjes J.C. Lang S. Misso K. Ryder S. Cannabinoids for Medical Use: A Systematic Review and Meta-Analysis JAMA J. Am. Med. Assoc. 2015 313 2456 2473 10.1001/jama.2015.6358 26103030\n\n", "fulltext_license": "CC BY", "issn_linking": "2075-4426", "issue": "11(7)", "journal": "Journal of personalized medicine", "keywords": "CYP2C19; adverse reactions; drug–drug interaction; marijuana; selective serotonin reuptake inhibitors", "medline_ta": "J Pers Med", "mesh_terms": null, "nlm_unique_id": "101602269", "other_id": null, "pages": null, "pmc": null, "pmid": "34209709", "pubdate": "2021-06-29", "publication_types": "D016428:Journal Article", "references": "31152723;32579280;24874020;23151877;18314433;15483195;28910830;30817183;18466100;24667219;32126453;30837874;12451290;31066578;27441996;31433338;19723786;17135988;17828291;20436762;18583433;31071346;18571641;23562616;12432948;3012605;26651971;15533655;12648025;27404875;32857933;28120229;25980507;20118579;25974703;21705438;18344185;26114620;32918835;17303175;30791225;20855043;26103030;29800213;31747464;15967059;29588049;32500537;1617949;28861892;22237437;33234666;31112844;18562622;18974308;23318708;17362921;32587099;21704641;21192150;26552940;29358037", "title": "The Impact of Marijuana on Antidepressant Treatment in Adolescents: Clinical and Pharmacologic Considerations.", "title_normalized": "the impact of marijuana on antidepressant treatment in adolescents clinical and pharmacologic considerations" }

[ { "companynumb": "US-CIPLA LTD.-2021US05153", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "3", "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078604", "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "Generalised anxiety disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078604", "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM, QD (EACH MORNING)", "drugenddate": null, "drugenddateformat": null, "drugindication": "Panic attack", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": "3", "drugtreatmentdurationunit": "802", "medicinalproduct": "ESCITALOPRAM" }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078604", "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "TITRATED UP TO 15 MG/DAY AT 10 MONTH", "drugenddate": null, "drugenddateformat": null, "drugindication": "Major depression", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078604", "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "TITRATED TO 20 MG EACH MORNING AT 18.5 MONTHS", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anxiety", "reactionmeddraversionpt": "24.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Depressive symptom", "reactionmeddraversionpt": "24.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Panic attack", "reactionmeddraversionpt": "24.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Headache", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abdominal pain", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Vaughn SE, Strawn JR, Poweleit EA, Sarangdhar M, Ramsey LB. The impact of marijuana on antidepressant treatment in adolescents: Clinical and pharmacologic considerations. Journal of Personalized Medicine. 2021;11, 615:1 to 14", "literaturereference_normalized": "the impact of marijuana on antidepressant treatment in adolescents clinical and pharmacologic considerations", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211108", "receivedate": "20210727", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19612634, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220304" } ]

{ "abstract": "Osteoporosis-related fractures create a heavy economic and healthcare burden. Although diphosphonate medications have been successful at decreasing the risk of osteoporotic fragility fractures and have become staples in the treatment of osteoporosis, concerns have been raised about the association of diphosphonate therapy with spontaneous nonvertebral fractures. Diphosphonate fractures are characteristically transverse or slightly oblique in nature and occur in the lateral cortex, or tension side, of the subtrochanteric region of the femur where diffuse cortical thickening and fracture can be observed on radiographs. A multidisciplinary approach incorporating both medical and surgical teams should be used in the case of diphosphonate-associated fractures. Future medical and surgical developments that augment fracture fixation and counteract diphosphonate-associated osteoclast apoptosis may play a role in therapy. Although diphosphonate use has decreased the rate of osteoporosis-related fractures, increased awareness and association with atypical subtrochanteric fractures is an important concern for clinicians to keep in mind.", "affiliations": null, "authors": "Balach|Tessa|T|;Baldwin|Paul C|PC|;Intravia|Jessica|J|", "chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates", "country": "United States", "delete": false, "doi": "10.5435/JAAOS-D-14-00024", "fulltext": null, "fulltext_license": null, "issn_linking": "1067-151X", "issue": "23(9)", "journal": "The Journal of the American Academy of Orthopaedic Surgeons", "keywords": "alendronate; atypical femur fracture; diphosphonate; diphosphonate-related fractures; ibandronate; osteoporosis; risedronate; subtrochanteric femur fracture; zoledronic acid", "medline_ta": "J Am Acad Orthop Surg", "mesh_terms": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D005264:Femoral Fractures; D005592:Fracture Fixation; D006801:Humans; D010024:Osteoporosis; D010348:Patient Care Team", "nlm_unique_id": "9417468", "other_id": null, "pages": "550-7", "pmc": null, "pmid": "26195566", "pubdate": "2015-09", "publication_types": "D016428:Journal Article; D016454:Review", "references": null, "title": "Atypical Femur Fractures Associated With Diphosphonate Use.", "title_normalized": "atypical femur fractures associated with diphosphonate use" }

[ { "companynumb": "US-CIPLA LTD.-2015US07770", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ALENDRONATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "076768", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "70 MG, WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "70", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALENDRONATE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ALENDRONATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "076768", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALENDRONATE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Gait disturbance", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lumbar spinal stenosis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Femur fracture", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fractured sacrum", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Humerus fracture", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Muscular weakness", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pain in extremity", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 200804" } }, "primarysource": { "literaturereference": "BALACH T, BALDWIN P AND INTRAVIA J. ATYPICAL FEMUR FRACTURES ASSOCIATED WITH DIPHOSPHONATE USE. JOURNAL OF THE AMERICAN ACADEMY OF ORTHOPAEDIC SURGEONS. 2015?23:550-557", "literaturereference_normalized": "atypical femur fractures associated with diphosphonate use", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151008", "receivedate": "20151008", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11611147, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" } ]

{ "abstract": "Loperamide abuse has been increasing in the United States as a potential alternative to manage opioid withdrawal symptoms or to achieve euphoric effects of opioid use. In June 2016, the Food and Drug Administration warned health care providers and the general public about potential serious adverse outcomes, including cardiac dysrhythmias and death. The purpose of this study is to determine recent trends in intentional loperamide abuse and misuse, reported clinical effects and management, and medical outcomes as reported to poison centers across the United States.\n\n\n\nLoperamide exposures reported to the National Poison Data System indicating intentional misuse, abuse, and suspected suicide between January 1, 2010, and December 31, 2015, were assessed. Demographic and temporal trends, as well as reported clinical effects, medical management, and health outcomes, were analyzed.\n\n\n\nThere was a 91% increase in reported exposures from 2010 to 2015, of which half were single-agent loperamide use only. Loperamide exposures reported to the National Poison Data System increased at approximately 38 cases per year (95% confidence interval [CI] 32.5 to 42.9; P<0.0001). Fifteen deaths were reported during this time frame, of which 8 involved single-agent loperamide abuse.\n\n\n\nLoperamide abuse and misuse are projected to increase in the absence of any methods to reduce exposure or curb abuse. Health care providers should consider the potential for loperamide toxicity when managing patients with opioidlike toxicity.", "affiliations": "Division of Medical Toxicology, Department of Emergency Medicine, University of Virginia School of Medicine, Charlottesville, VA.;Division of Medical Toxicology, Department of Emergency Medicine, University of Virginia School of Medicine, Charlottesville, VA.;Division of Medical Toxicology, Department of Emergency Medicine, University of Virginia School of Medicine, Charlottesville, VA. Electronic address: ch2xf@virginia.edu.", "authors": "Vakkalanka|J Priyanka|JP|;Charlton|Nathan P|NP|;Holstege|Christopher P|CP|", "chemical_list": "D008139:Loperamide", "country": "United States", "delete": false, "doi": "10.1016/j.annemergmed.2016.08.444", "fulltext": null, "fulltext_license": null, "issn_linking": "0196-0644", "issue": "69(1)", "journal": "Annals of emergency medicine", "keywords": null, "medline_ta": "Ann Emerg Med", "mesh_terms": "D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D062787:Drug Overdose; D005260:Female; D006801:Humans; D008139:Loperamide; D008297:Male; D008875:Middle Aged; D019966:Substance-Related Disorders; D014481:United States; D055815:Young Adult", "nlm_unique_id": "8002646", "other_id": null, "pages": "73-78", "pmc": null, "pmid": "27823872", "pubdate": "2017-01", "publication_types": "D016428:Journal Article", "references": null, "title": "Epidemiologic Trends in Loperamide Abuse and Misuse.", "title_normalized": "epidemiologic trends in loperamide abuse and misuse" }

[ { "companynumb": "US-MYLANLABS-2016M1057160", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "072741", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUICIDE ATTEMPT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMPHETAMINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMFETAMINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Suicide attempt", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANN-EMERG-MED 2016;:.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20161222", "receivedate": "20161222", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13055464, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-JNJFOC-20161225122", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "019860", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "019860", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANNALS OF EMERGENCY MEDICINE;69 (1):73-78.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20161230", "receivedate": "20161230", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13077314, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-TEVA-725372USA", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "73122", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUICIDE ATTEMPT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMPHETAMINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMFETAMINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Suicide attempt", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANN-EMERG-MED 2016;:.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20171110", "receivedate": "20171110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14180094, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20180321" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2016US-125326", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "PHENOTHIAZINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENOTHIAZINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DIPHENHYDRAMINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, 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EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. 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EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. 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EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. 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EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. 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EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. 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EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANNALS OF EMERGENCY MEDICINE. 2017;69(1):73-8", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170426", "receivedate": "20170426", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13486768, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170830" }, { "companynumb": "US-MYLANLABS-2016M1057194", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "072741", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUICIDE ATTEMPT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Suicide attempt", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANN-EMERG-MED 2016;:.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20161222", "receivedate": "20161222", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13055468, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-BION-006468", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHYLPHENIDATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": 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EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. 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EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANN EMERG MED. 2017 JAN;69(1):73-78.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170718", "receivedate": "20170718", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13762918, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20171127" }, { "companynumb": "US-BION-006471", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021855", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE UNKNOWN PRODUCT" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Completed suicide", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. 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EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. 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"VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANN-EMERG-MED 2016;:.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20161222", "receivedate": "20161222", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13055466, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-JNJFOC-20161225117", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "019860", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "019860", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Completed suicide", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANNALS OF EMERGENCY MEDICINE;69 (1):73-78.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20161230", "receivedate": "20161230", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13077316, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "US-MYLANLABS-2016M1057188", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "072741", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. 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EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANNALS OF EMERGENCY MEDICINE;69 (1):73-78.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20161230", "receivedate": "20161230", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13075806, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-BION-006470", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXTROMETHORPHAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXTROMETHORPHAN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021855", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE UNKNOWN PRODUCT" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANN EMERG MED. 2017 JAN;69(1):73-78.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170718", "receivedate": "20170718", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13762876, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20171127" }, { "companynumb": "US-BION-006475", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021855", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE HYDROCHLORIDE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANN EMERG MED. 2017 JAN;69(1):73-78.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170718", "receivedate": "20170718", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13762906, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20171127" }, { "companynumb": "US-BION-006479", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021855", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE HYDROCHLORIDE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANN EMERG MED. 2017 JAN;69(1):73-78.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170718", "receivedate": "20170718", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13762926, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20171127" }, { "companynumb": "US-MYLANLABS-2016M1057201", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "072741", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANN-EMERG-MED 2016;:.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20161222", "receivedate": "20161222", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13055469, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-JNJFOC-20161225118", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "019860", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DIPHENHYDRAMINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIPHENHYDRAMINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "019860", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANNALS OF EMERGENCY MEDICINE;69 (1):73-78.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20161230", "receivedate": "20161230", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13077319, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "US-BION-006477", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021855", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE UNKNOWN PRODUCT" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANN EMERG MED. 2017 JAN;69(1):73-78.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170718", "receivedate": "20170718", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13762912, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20171127" }, { "companynumb": "US-JNJFOC-20161225116", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXTROMETHORPHAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXTROMETHORPHAN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "019860", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "019860", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANNALS OF EMERGENCY MEDICINE;69 (1):73-78.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20161230", "receivedate": "20161230", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13077312, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-JNJFOC-20161225115", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "019872", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETAMINOPHEN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "019860", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "000000", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "019872", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, 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null, "medicinalproduct": "PHENOTHIAZINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "NAPROXEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NAPROXEN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXTROMETHORPHAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXTROMETHORPHAN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "019860", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DIPHENHYDRAMINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIPHENHYDRAMINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHYLPHENIDATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021121", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SUSTAINED RELEASE TABLETS", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPHENIDATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Intentional product misuse", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANNALS OF EMERGENCY MEDICINE;69 (1):73-78.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20161230", "receivedate": "20161230", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13076412, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-BION-006481", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021855", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE UNKNOWN PRODUCT" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANN EMERG MED. 2017 JAN;69(1):73-78.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170718", "receivedate": "20170718", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13762942, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20171127" }, { "companynumb": "US-MYLANLABS-2016M1057215", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "072741", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXTROMETHORPHAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXTROMETHORPHAN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANN-EMERG-MED 2016;:.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20161222", "receivedate": "20161222", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13055472, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-JNJFOC-20161225126", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "019860", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "019860", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANNALS OF EMERGENCY MEDICINE;69 (1):73-78.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20161230", "receivedate": "20161230", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13077322, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-MYLANLABS-2016M1057223", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "072741", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Suicide attempt", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANN-EMERG-MED 2016;:.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20161222", "receivedate": "20161222", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13055482, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-BION-006472", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021855", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE UNKNOWN PRODUCT" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DIPHENHYDRAMINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIPHENHYDRAMINE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANN EMERG MED. 2017 JAN;69(1):73-78.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170718", "receivedate": "20170718", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13762882, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20171127" }, { "companynumb": "US-BION-006476", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021855", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE UNKNOWN PRODUCT" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Completed suicide", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANN EMERG MED. 2017 JAN;69(1):73-78.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170718", "receivedate": "20170718", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13762902, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20171127" }, { "companynumb": "US-MYLANLABS-2016M1057161", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "072741", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG ABUSE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANN-EMERG-MED 2016;:.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20161222", "receivedate": "20161222", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13055480, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-JNJFOC-20161225114", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "019860", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "019860", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Completed suicide", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANNALS OF EMERGENCY MEDICINE;69 (1):73-78.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20161230", "receivedate": "20161230", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13077310, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "US-BION-006469", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021855", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Completed suicide", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANN EMERG MED. 2017 JAN;69(1):73-78.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170718", "receivedate": "20170718", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13762870, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20171127" }, { "companynumb": "US-MYLANLABS-2016M1057178", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "072741", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANN-EMERG-MED 2016;:.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20161222", "receivedate": "20161222", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13055450, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-TEVA-725370USA", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "73122", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUICIDE ATTEMPT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Suicide attempt", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANN-EMERG-MED 2016;:.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20171110", "receivedate": "20171110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14180095, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20180321" }, { "companynumb": "US-JNJFOC-20161224180", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "019487", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "019487", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Completed suicide", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Intentional product misuse", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANNALS OF EMERGENCY MEDICINE;69 (1):73-78.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20161230", "receivedate": "20161230", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13075805, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "US-BION-006482", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021855", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE UNKNOWN PRODUCT" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANN EMERG MED. 2017 JAN;69(1):73-78.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170718", "receivedate": "20170718", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13762965, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20171127" }, { "companynumb": "US-MYLANLABS-2016M1057191", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DIPHENHYDRAMINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIPHENHYDRAMINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "072741", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANN-EMERG-MED 2016;:.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20161222", "receivedate": "20161222", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13055455, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-MYLANLABS-2016M1057200", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "072741", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANN-EMERG-MED 2016;:.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20161222", "receivedate": "20161222", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13055465, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-MYLANLABS-2016M1057163", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "072741", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG ABUSE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANN-EMERG-MED 2016;:.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20161222", "receivedate": "20161222", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13055485, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-BION-006480", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021855", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE HYDROCHLORIDE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE?ABUSE AND MISUSE. ANN EMERG MED. 2017 JAN;69(1):73-78.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170718", "receivedate": "20170718", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13762935, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20171127" }, { "companynumb": "US-JNJFOC-20161225123", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "019860", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "019860", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. 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EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANNALS OF EMERGENCY MEDICINE;69 (1):73-78.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20161230", "receivedate": "20161230", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13077321, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "US-BION-006474", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021855", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE HYDROCHLORIDE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANN EMERG MED. 2017 JAN;69(1):73-78.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170718", "receivedate": "20170718", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13762891, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20171127" }, { "companynumb": "US-MYLANLABS-2016M1057162", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "072741", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG ABUSE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANN-EMERG-MED 2016;:.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20161222", "receivedate": "20161222", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13055471, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-MYLANLABS-2016M1057175", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "072741", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUICIDE ATTEMPT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Suicide attempt", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. 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EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. 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EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANNALS OF EMERGENCY MEDICINE;69 (1):73-78.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20161230", "receivedate": "20161230", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13077323, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "US-TEVA-725375USA", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPERAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "73122", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUICIDE ATTEMPT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOPERAMIDE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Suicide attempt", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAKKALANKA JP, CHARLTON NP, HOLSTEGE CP. EPIDEMIOLOGIC TRENDS IN LOPERAMIDE ABUSE AND MISUSE. ANN-EMERG-MED 2016;:.", "literaturereference_normalized": "epidemiologic trends in loperamide abuse and misuse", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20171110", "receivedate": "20171110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14180103, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20180321" } ]

{ "abstract": "The increase in infections caused by drug-resistant ESBL-producing Enterobacteriaceae (ESBL-ENT) is a global concern. The characteristics and outcomes of patients infected with ESBL-ENT were examined in a pooled analysis of Phase 3 clinical trials of ceftolozane/tazobactam in patients with complicated urinary tract infections (ASPECT-cUTI) and complicated intra-abdominal infections (ASPECT-cIAI).\n\n\n\nTrials were randomized and double blind. The ASPECT-cUTI regimen was 7 days of either intravenous ceftolozane/tazobactam (1.5 g) every 8 h or levofloxacin (750 mg) once daily. The ASPECT-cIAI regimen was 4-14 days of either intravenous ceftolozane/tazobactam (1.5 g) plus metronidazole (500 mg) or meropenem (1 g) every 8 h. Baseline cultures were obtained in both indications. Enterobacteriaceae were selected for ESBL characterization based on predefined criteria and were verified genotypically. Outcomes were assessed at the test-of-cure visit 5-9 days post-therapy in ASPECT-cUTI and 24-32 days post-randomization in ASPECT-cIAI among microbiologically evaluable (ME) patients.\n\n\n\nOf 2076 patients randomized, 1346 were included in the pooled ME population and 150 of 1346 (11.1%) had ESBL-ENT at baseline. At US FDA/EUCAST breakpoints of ≤2/≤1 mg/L, 81.8%/72.3% of ESBL-ENT (ESBL-Escherichia coli, 95%/88.1%; ESBL-Klebsiella pneumoniae, 56.7%/36.7%) were susceptible to ceftolozane/tazobactam versus 25.3%/24.1% susceptible to levofloxacin and 98.3%/98.3% susceptible to meropenem at CLSI/EUCAST breakpoints. Clinical cure rates for ME patients with ESBL-ENT were 97.4% (76/78) for ceftolozane/tazobactam [ESBL-E. coli, 98.0% (49 of 50); ESBL-K. pneumoniae, 94.4% (17 of 18)], 82.6% (38 of 46) for levofloxacin and 88.5% (23 of 26) for meropenem.\n\n\n\nRandomized trial data demonstrated high clinical cure rates with ceftolozane/tazobactam treatment of cIAI and cUTI caused by ESBL-ENT.", "affiliations": "Merck & Co., Inc., Kenilworth, NJ, USA myra.popejoy@merck.com.;Center for Clinical Research, University of Queensland, Brisbane, Australia.;Merck & Co., Inc., Kenilworth, NJ, USA.;Merck & Co., Inc., Kenilworth, NJ, USA.;Merck & Co., Inc., Kenilworth, NJ, USA.;Merck & Co., Inc., Kenilworth, NJ, USA.;Merck & Co., Inc., Kenilworth, NJ, USA.;Merck & Co., Inc., Kenilworth, NJ, USA.;Merck & Co., Inc., Kenilworth, NJ, USA.;Detroit Medical Center and Department of Medicine, Wayne State University, Detroit, MI, USA.", "authors": "Popejoy|Myra W|MW|;Paterson|David L|DL|;Cloutier|Daniel|D|;Huntington|Jennifer A|JA|;Miller|Benjamin|B|;Bliss|Caleb A|CA|;Steenbergen|Judith N|JN|;Hershberger|Ellie|E|;Umeh|Obiamiwe|O|;Kaye|Keith S|KS|", "chemical_list": "D000892:Anti-Infective Agents, Urinary; D002511:Cephalosporins; D013845:Thienamycins; D065093:beta-Lactamase Inhibitors; C000594038:ceftolozane, tazobactam drug combination; D008795:Metronidazole; D064704:Levofloxacin; D010397:Penicillanic Acid; D001618:beta-Lactamases; D000077731:Meropenem; D000078142:Tazobactam", "country": "England", "delete": false, "doi": "10.1093/jac/dkw374", "fulltext": null, "fulltext_license": null, "issn_linking": "0305-7453", "issue": "72(1)", "journal": "The Journal of antimicrobial chemotherapy", "keywords": null, "medline_ta": "J Antimicrob Chemother", "mesh_terms": "D061605:Administration, Intravenous; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000892:Anti-Infective Agents, Urinary; D002511:Cephalosporins; D004311:Double-Blind Method; D004926:Escherichia coli; D004927:Escherichia coli Infections; D005260:Female; D005838:Genotype; D006801:Humans; D059413:Intraabdominal Infections; D007710:Klebsiella Infections; D007711:Klebsiella pneumoniae; D064704:Levofloxacin; D008297:Male; D000077731:Meropenem; D008795:Metronidazole; D008875:Middle Aged; D010397:Penicillanic Acid; D000078142:Tazobactam; D013845:Thienamycins; D016896:Treatment Outcome; D014552:Urinary Tract Infections; D055815:Young Adult; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases", "nlm_unique_id": "7513617", "other_id": null, "pages": "268-272", "pmc": null, "pmid": "27707990", "pubdate": "2017-01", "publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016449:Randomized Controlled Trial", "references": null, "title": "Efficacy of ceftolozane/tazobactam against urinary tract and intra-abdominal infections caused by ESBL-producing Escherichia coli and Klebsiella pneumoniae: a pooled analysis of Phase 3 clinical trials.", "title_normalized": "efficacy of ceftolozane tazobactam against urinary tract and intra abdominal infections caused by esbl producing escherichia coli and klebsiella pneumoniae a pooled analysis of phase 3 clinical trials" }

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EFFICACY OF CEFTOLOZANE/TAZOBACTAM AGAINST URINARY TRACT AND INTRA-ABDOMINAL INFECTIONS CAUSED BY ESBL-PRODUCING ESCHERICHIA COLI AND KLEBSIELLA PNEUMONIAE: A POOLED ANALYSIS OF PHASE 3 CLINICAL TRIALS. JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY ADVANCE. 2016", "literaturereference_normalized": "efficacy of ceftolozane tazobactam against urinary tract and intra abdominal infections caused by esbl producing escherichia coli and klebsiella pneumoniae a pooled analysis of phase 3 clinical trials", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20161025", "receivedate": "20161025", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12879548, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "US-CIPLA LTD.-2016US19872", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOFLOXACIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "750 MG, ONCE DAILY FOR 7 DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "URINARY TRACT INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "750", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOFLOXACIN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "POPEJOY MW, PATERSON DL, CLOUTIER D, HUNTINGTON JA, MILLER B ET AL.. EFFICACY OF CEFTOLOZANE/TAZOBACTAM AGAINST URINARY TRACT AND INTRA-ABDOMINAL INFECTIONS CAUSED BY ESBL-PRODUCING ESCHERICHIA COLI AND KLEBSIELLA PNEUMONIAE: A POOLED ANALYSIS OF PHASE 3 CLINICAL TRIALS. 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EFFICACY OF CEFTOLOZANE/TAZOBACTAM AGAINST URINARY TRACT AND INTRA-ABDOMINAL INFECTIONS CAUSED BY ESBL-PRODUCING ESCHERICHIA COLI AND KLEBSIELLA PNEUMONIAE: A POOLED ANALYSIS OF PHASE 3 CLINICAL TRIALS. 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EFFICACY OF CEFTOLOZANE/TAZOBACTAM AGAINST URINARY TRACT AND INTRA-ABDOMINAL INFECTIONS CAUSED BY ESBL-PRODUCING ESCHERICHIA COLI AND KLEBSIELLA PNEUMONIAE: A POOLED ANALYSIS OF PHASE 3 CLINICAL TRIALS. 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{ "abstract": "Delayed gastric emptying (DGE) commonly limits the use of enteral nutrition (EN) and may increase ventilator-associated pneumonia. Nasointestinal feeding has not been tested against dual prokinetic treatment (Metoclopramide and Erythromycin) in DGE refractory to metoclopramide. This trial tests the feasibility of recruiting this 'treatment-failed' population and the proof of concept that nasointestinal (NI) feeding can increase the amount of feed tolerated (% goal) when compared to nasogastric (NG) feeding plus metoclopramide and erythromycin treatment.\n\n\n\nEligible patients were those who were mechanically ventilated and over 20 years old, with delayed gastric emptying (DGE), defined as a gastric residual volume ≥250 ml or vomiting, and who failed to respond to first-line prokinetic treatment of 3 doses of 10 mg IV metoclopramide over 24 h. When assent was obtained, patients were randomised to receive immediate nasointestinal tube placement and feeding or nasogastric feeding plus metoclopramide and erythromycin (prokinetic) treatment.\n\n\n\nOf 208 patients with DGE, 77 were eligible, 2 refused assent, 25 had contraindications to intervention, almost exclusively prokinetic treatment, and it was feasible to recruit 50. Compared to patients receiving prokinetics (n = 25) those randomised to nasointestinal feeding (n = 25) tolerated more of their feed goal over 5 days (87-95% vs 50-89%) and had a greater area under the curve (median [IQR] 432 [253-464]% vs 350 [213-381]%, p = 0.026) demonstrating proof of concept. However, nasointestinally fed patients also had a larger gastric loss (not feed) associated with the NI route but not with the fluid volume or energy delivered.\n\n\n\nThis is first study showing that in DGE refractory to metoclopramide NI feeding can increase the feed goal tolerated when compared to dual prokinetic treatment. Future studies should investigate the effect on clinical outcomes.\n\n\n\nEudraCT number: 2012-001374-29.", "affiliations": "Department of Nutrition and Dietetics, Level 6, Gate 10, Brunel Building, Southmead Hospital, Bristol, BS105 NB, UK. Electronic address: stephen.taylor@nbt.nhs.uk.;Department of Nutrition and Dietetics, Level 6, Gate 10, Brunel Building, Southmead Hospital, Bristol, BS105 NB, UK. Electronic address: kaylee.allan@nbt.nhs.uk.;Department of Nutrition and Dietetics, Level 6, Gate 10, Brunel Building, Southmead Hospital, Bristol, BS105 NB, UK. Electronic address: Helen.McWilliam@nuth.nhs.uk.;Department of Anaesthetics, Level 3 Gate 38, Brunel Building, Southmead Hospital, Bristol, BS10 5NB, UK. Electronic address: alex.manara@nbt.nhs.uk.;Department of Anaesthetics, Level 3 Gate 38, Brunel Building, Southmead Hospital, Bristol, BS10 5NB, UK. Electronic address: jules.brown@nbt.nhs.uk.;Research Design Service - South West, University Hospitals Bristol NHS Foundation Trust, Level 3 Education Centre, Upper Maudlin Street, Bristol, BS2 8AE, UK. Electronic address: rosemary.greenwood@UHBristol.nhs.uk.;Department of Engineering Design and Mathematics, University of the West of England, Frenchay Campus, Bristol, BS16 1QY, UK. Electronic address: Deirdre.toher@uwe.ac.uk.", "authors": "Taylor|Stephen J|SJ|;Allan|Kaylee|K|;McWilliam|Helen|H|;Manara|Alex|A|;Brown|Jules|J|;Greenwood|Rosemary|R|;Toher|Deirdre|D|", "chemical_list": "D005765:Gastrointestinal Agents; D004917:Erythromycin; D008787:Metoclopramide", "country": "England", "delete": false, "doi": "10.1016/j.clnesp.2016.04.020", "fulltext": null, "fulltext_license": null, "issn_linking": "2405-4577", "issue": "14()", "journal": "Clinical nutrition ESPEN", "keywords": "Delayed gastric emptying; Nasogastric; Nasointestinal; Prokinetic", "medline_ta": "Clin Nutr ESPEN", "mesh_terms": "D000328:Adult; D016638:Critical Illness; D004750:Enteral Nutrition; D004917:Erythromycin; D005260:Female; D005746:Gastric Emptying; D005765:Gastrointestinal Agents; D006040:Goals; D006801:Humans; D007421:Intestine, Small; D007441:Intubation, Gastrointestinal; D008297:Male; D008787:Metoclopramide; D008875:Middle Aged; D009752:Nutritional Status; D017211:Treatment Failure; D016896:Treatment Outcome; D014839:Vomiting", "nlm_unique_id": "101654592", "other_id": null, "pages": "1-8", "pmc": null, "pmid": "28531392", "pubdate": "2016-08", "publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "A randomised controlled feasibility and proof-of-concept trial in delayed gastric emptying when metoclopramide fails: We should revisit nasointestinal feeding versus dual prokinetic treatment: Achieving goal nutrition in critical illness and delayed gastric emptying: Trial of nasointestinal feeding versus nasogastric feeding plus prokinetics.", "title_normalized": "a randomised controlled feasibility and proof of concept trial in delayed gastric emptying when metoclopramide fails we should revisit nasointestinal feeding versus dual prokinetic treatment achieving goal nutrition in critical illness and delayed gastric emptying trial of nasointestinal feeding versus nasogastric feeding plus prokinetics" }

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{ "abstract": "A 62-year-old previously healthy male who was a welder/smoker/drinker was admitted to Kani Tono Hospital for severe hypoxemia (Day 0). Initial physical and radiological examinations suggested an acute exacerbation of chronic obstructive pulmonary disease. However, respiratory failure developed rapidly, and he died on Day + 4. Aspergillus fumigatus was identified after his death, and he was diagnosed with invasive pulmonary aspergillosis. The clinical and pathological features are precisely described with pathogenetic considerations.", "affiliations": "Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.;Department of Hematology, JCHO Kani Tono Hospital, 1221-5 Dota, Kani 509-0206, Japan.;Department of Pathology and Laboratory Medicine, Kariya Toyota General Hospital, 5-15 Sumiyoshi-cho, Kariya 448-0852, Japan.;Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.;Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.", "authors": "Ohara|Yuuki|Y|;Ito|Takahiko|T|;Ito|Makoto|M|;Yamashita|Kyoko|K|;Toyokuni|Shinya|S|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.mmcr.2018.02.002", "fulltext": "\n==== Front\nMed Mycol Case RepMed Mycol Case RepMedical Mycology Case Reports2211-7539Elsevier S2211-7539(18)30014-910.1016/j.mmcr.2018.02.002Case ReportAcute fulminant invasive pulmonary aspergillosis in an immunocompetent host: An autopsy case report Ohara Yuuki yuuki.oohara.1196@gmail.coma⁎Ito Takahiko bIto Makoto cYamashita Kyoko aToyokuni Shinya aa Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japanb Department of Hematology, JCHO Kani Tono Hospital, 1221-5 Dota, Kani 509-0206, Japanc Department of Pathology and Laboratory Medicine, Kariya Toyota General Hospital, 5-15 Sumiyoshi-cho, Kariya 448-0852, Japan⁎ Corresponding author. yuuki.oohara.1196@gmail.com09 2 2018 6 2018 09 2 2018 20 39 42 31 12 2017 8 2 2018 8 2 2018 © 2018 The Authors2018This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).A 62-year-old previously healthy male who was a welder/smoker/drinker was admitted to Kani Tono Hospital for severe hypoxemia (Day 0). Initial physical and radiological examinations suggested an acute exacerbation of chronic obstructive pulmonary disease. However, respiratory failure developed rapidly, and he died on Day + 4. Aspergillus fumigatus was identified after his death, and he was diagnosed with invasive pulmonary aspergillosis. The clinical and pathological features are precisely described with pathogenetic considerations.\n\nKeywords\nInvasive pulmonary aspergillosisAspergillus fumigatusImmunocompetent hostSmokerWelderAlcoholism\n==== Body\n1 Introduction\nInvasive pulmonary aspergillosis (IPA) is generally seen in immunocompromised hosts. Risk factors include malignant tumors, organ transplant, HIV infection, chemotherapy, diabetes mellitus, and corticosteroid therapy [1], [2]. Although the Aspergillus-specific galactomannan test and a timely radiographic screening can effectively diagnose IPA, overall mortality rates remain high despite antifungal treatments [1]. In addition to opportunistic infections, acute community-acquired IPA should be recognized as an uncommon form of invasive aspergillosis. Several local and systemic risk factors are mutually involved, including malnourishment, chronic obstructive pulmonary disease (COPD), and alcoholism [1], [2], [3], [4]. Certain viral respiratory infections, such as the influenza virus, may also predispose patients to this invasive fungal infection [1], [4], [5], [6].\n\nHerein, we report an autopsy case of fulminant IPA in a previously healthy male. Although IPA is rarely encountered in healthy individuals, our case exacerbated rapidly. Of note, acute community-acquired necrotizing pneumonia is triggered by potentially virulent fungal pathogens, especially Aspergillus species, on rare occasions.\n\n2 Case\nA 62-year-old male was referred to the outpatient clinic of Kani Tono Hospital for a fever lasting seven days and suspected pneumonia. He had no medical, medication, or family history. The patient was a current cigarette smoker (40 cigarettes per day) and a habitual drinker consuming 42–84 g of ethanol per day. His occupation was a welder, presumably exposed to metallic dust. His vital signs at admission were as follows: body temperature, 37.8 °C; pulse rate, 120 bpm; blood pressure, 138/81 mmHg; and SpO2, 83% in room air. Physical examination showed a dry cough, dyspnea, tachypnea, and no pretibial edema. Bilateral wheezing was auscultated. Laboratory data showed a white blood cell count of 10,600 cells/μL (neutrophils, 86%; lymphocytes, 5%; monocytes, 10%; eosinophils, 0%; basophils, 0%); hemoglobin (Hb), 15.0 g/dL; HbA1c, 5.5%; platelets, 154,000/μL; and C-reactive protein, 22.39 mg/dL. Hepatic and renal functions were within normal limits. Tests were negative for human immunodeficiency virus, hepatitis B virus, and hepatitis C virus. Arterial blood gases were pH, 7.459; pO2, 53.4 mmHg; pCO2, 40.6 mmHg; HCO3-, 28.4 mEq/L; base excess, 4.6 mEq/L; lactate, 18.0 mg/dL; and blood glucose, 147 mg/dL. Chest radiography showed a slight infiltrative shadow (Fig. 1A). Thoracic computed tomography (CT) showed non-specific findings, such as thickened bronchial walls (Fig. 1B), slightly increased bronchial density, and mild emphysematous changes. The patient was immediately hospitalized (Day 0), suspected of an acute COPD exacerbation. Treatment started with the following drugs: 6-methylprednisolone, 40 mg ×2; ceftriaxone, 2 g; garenoxacin, 400 mg; and salmeterol xinafoate/fluticasone propionate.Fig. 1 Radiological images and macroscopic findings. (A) Chest radiograph upon admission (Day 0, standing position). (B) Thoracic CT (Day 0) showing a slight thickening of the bronchial walls. (C) Chest radiograph (Day + 4, decubitus position) showing an infiltrative shadow. (D) Macroscopic findings of the lung at autopsy (Day + 4). Most bronchi are surrounded by ocher membranous lesions (arrows). Scale bar, 10 mm.\n\nFig. 1\n\nOn Day + 2, his respiratory status became severely dyspneic, and his arterial blood gases were pH, 7.25; pO2, 82.5 mmHg; pCO2, 78.0 mmHg; and HCO3-, 33.0 mEq/L. Noninvasive positive-pressure ventilation was performed, alternatively with an oxygen mask.\n\nInvasive positive-pressure ventilation with tracheal intubation was started on Day + 3 due to exacerbated respiratory failure. However, effective oxygenation was not achieved because decreased pulmonary compliance and increased airway resistance made efficient ventilation difficult. Arterial blood gases were pH, 7.08; pO2, 70.9 mmHg; pCO2, 116 mmHg; and HCO3-, 32.7 mEq/L. The patient also developed heart and renal failure (BNP, 1543.5 pg/mL; BUN, 53.7 mg/dL; and creatinine, 2.92 mg/dL).\n\nOn Day + 4, a chest radiograph showed a clear infiltrative shadow (Fig. 1C). His platelet count was reduced to 88,000/μL, with D-dimer concentrations being elevated to 77.9 μg/mL. The overall data represented systemic inflammatory response syndrome with coagulative disorder. A filamentous fungus was isolated from the sputum collected on Day + 2. His serum (1,3)-β-D-glucan level was elevated to 530.7 pg/mL. Preemptive antifungal treatment was initiated at 70 mg of caspofungin acetate intravenously. However, therapeutic interventions did not improve the multiple organ failure, and the patient died on Day + 4. Three days later (Day + 7), the isolated fungus was identified as Aspergillus fumigatus based on colony morphology.\n\nAn autopsy was performed three hours after the patient's death (Day + 4). The body height was 160 cm, and the weight was 50 kg. The most remarkable findings were confined to the lungs. Grossly, both lungs were swollen and profusely consolidated. From the main bronchus to the peripheral branches, most bronchi were surrounded and occluded by necrotic ocher membranous lesions (Fig. 1D). A diffuse pulmonary hemorrhage was also observed. Histologically, the lung specimens revealed abundant Aspergillus proliferation in the bronchi, with severe necrosis and exudative inflammation (Fig. 2A). The microscopic bronchial lesions corresponded to the macroscopic ocher membranous lesions (Fig. 1D). Aspergillus also invaded the alveolar areas. These areas were severely damaged, showing neutrophil infiltration, hemorrhaging, and edema (Fig. 2B). Grocott's methenamine silver staining clearly showed invasive mycelial fungal growth (Fig. 2C) as well as conidial heads (Fig. 2D). Angioinvasion was also demonstrated, with the affected vessels being obliterated by thrombi (Fig. 2E). Based on the sputum culture and these histological findings, IPA was diagnosed. Apart from invasive aspergillosis, alveolar emphysematous changes were focal and mild (Fig. 2F). Iron deposition inside the alveolar macrophages (hemosiderin-laden macrophages) was remarkable (Fig. 2G), a finding likely associated with the patient's job as a welder. Systemic examination showed no disseminated infection elsewhere. Notably, no predisposing cavity was found that would provoke a fungal colonization. No hepatic or pancreatic lesions from alcohol consumption were observed. Passive congestion and hyperemia were observed in several organs, including the liver, kidneys, and alimentary tract.Fig. 2 Histological findings. (A) Exudative inflammation around the bronchus, corresponding to the ocher membranous lesions in Fig. 1D. Aspergillus (arrows) proliferation in a bronchus. (B) Severe alveolar damage. The alveoli show necrosis, with neutrophil infiltration, hemorrhaging, and edema. (C) Aspergillus mycelia stained with Grocott's methenamine silver. (D). Conidial heads of Aspergillus. (E) Thrombosis. A thrombus (arrows) is seen in the blood vessel (arrow heads). (F) Low power magnification of the lung tissue. Emphysematous changes in alveoli (arrow heads) are not severe. (G) Iron deposition in the lung. Macrophages phagocytizing iron shown by positive Berlin blue staining.\n\n(A), (B), (D)-(F) H&E staining, (C) Grocott's methenamine silver staining, (G) Berlin blue staining. Scale bar, 1 mm in (A), (E) and (F); 200 µm in (B) and (G); 50 µm in (C) and (D).\n\nFig. 2\n\n3 Discussion\nIPA usually occurs in immunocompromised patients. In rare instances, however, it may affect immunocompetent hosts [1], [2], [3], [4] even with no predisposing non-invasive aspergillosis, such as simple aspergilloma or chronic cavity pulmonary aspergillosis. The present case was unique in that acute IPA developed into rapidly progressive respiratory failure. No clinical or radiographic evidence indicated a precedent fungal colonization. At the initial stage, it was difficult to consider a community-acquired pulmonary fungal infection.\n\nAutopsy revealed angioinvasive aspergillosis extensively involving the entire lungs associated with necrotizing pneumonia and bronchitis. Anatomically, the patient's severe ventilation failure may have been related to the damaged bronchial structure collapsing along with massive intraalveolar exudate. The severe pneumonia could have led to decreased pulmonary compliance and increased pulmonary shunt. The membranous bronchitis is thought to have increased airway resistance. Thrombosis in pulmonary vessels and hemorrhaging would have caused ventilation/perfusion mismatch and pulmonary hypertension. These pathogenic events would result in ventilatory insufficiency (hypercapnic respiratory failure) progressing in the short term, despite using a mechanical ventilator, ultimately leading to multiple organ failure and death. In addition, the hypoxic state may have potentiated the invasive Aspergillus fumigatus growth. Recent studies have shown that Aspergillus fumigatus virulence depends highly on adaptability to a hypoxic microenvironment in the infective site [7]. In a severely hypoxic state, Aspergillus fumigatus can survive and facilitate mycelial growth to vigorously invade the lung tissue as demonstrated in this case.\n\nSeveral pulmonary conditions should be considered potential risk factors for certain invasive bacterial or fungal pathogens. IPA cases in immunocompetent patients with COPD have been reported [1]. According to the Japanese Guideline for Management of Deep-seated Mycoses 2014 [2], COPD and pulmonary fibrosis are listed as predisposing factors for IPA. The present patient was a longstanding cigarette smoker and a welder believed to be constantly exposed to metallic dust. Cigarette smoke and/or a deficiency of surfactant proteins in COPD can cause dysfunction in immune response against pathogens, including fungi [8], [9], [10]. Welder's siderosis (arc welder's pneumoconiosis) is caused by iron oxide accumulating inside alveolar macrophages [11]. Although welder's siderosis does not cause pulmonary fibrosis and typically produces no symptoms, silicosiderosis can occur and pulmonary fibrosis may develop when a substantial quantity of silica mixes with the inhaled iron [11]. In addition, iron overload has also been linked to an increased risk of bacterial [12] and fungal infections independently of IPA in immunocompromised patients [13], [14]. Iron overload catalyzes the Fenton reaction, generating hydroxyl radicals, which damage the body and play important roles in various lesions, including fibrosis [15] and tumors [16], [17]. In the present case, no severe COPD or pulmonary fibrosis was observed. However, the iron deposition and locally damaged airway condition with the impaired mucociliary clearance by cigarette smoke may have contributed to the fungal infection. Because Aspergillus was localized in the lungs (without disseminated infection), iron overload was suspected to be involved with the Aspergillus infection in the present case.\n\nBased on CT (Fig. 1B) and autopsy (Fig. 1D) findings, the patient may have been suffering from Aspergillus tracheobronchitis (ATB) at admission, which had progressed to IPA when he died. ATB is a rare, confined form of IPA [18] and could be an early stage of IPA [19]. Non-specific radiographic findings make it difficult to diagnose. In COPD patients, ATB symptoms would likely be regarded as COPD exacerbations [20].\n\nCertain respiratory viral infections are said to involve risks for developing IPA [1], [4], [5], [6]. Unfortunately, no data relevant to an influenza infection was available in the present case.\n\nIn the case reported here, the patient was a smoker, a heavy alcohol drinker, and a welder. The combination of these risk factors would promote Aspergillus infection and rapid IPA development.\n\nAcknowledgements\nWe thank Mr. Nobuaki Misawa (Nagoya University Graduate School of Medicine) and Mr. Naoki Kawai (Kani Tono Hospital) for technical assistance. Yuuki Ohara was a recipient of Takeda Science Foundation Fellowship (April 2014-March 2018).\n\nAuthorship statement\nAll authors meet the ICMJE authorship criteria.\n\nAll authors made substantial contributions to all of the following: (1) the conception and design of the study, or acquisition of data, or analysis and interpretation of data, (2) drafting the article or revising it critically for important intellectual content, (3) final approval of the version to be submitted. Yuuki Ohara wrote the initial draft and Makoto Ito assisted in the preparation of the manuscript.\n\nConflict of interest\nThere are none.\n\nFunding\nThere are none.\n==== Refs\nReferences\n1 Kousha M. Tadi R. Soubani A.O. Pulmonary aspergillosis: a clinical review Eur. Respir. Rev. 20 2011 156 174 21881144 \n2 Kohno S. Tamura K. Niki Y. Izumikawa K. Oka S. Ogawa K. Executive summary of japanese domestic guidelines for management of deep-seated mycosis 2014 Med Mycol. J. 57 2016 (E117-e63) \n3 Bulpa P. Dive A. Sibille Y. Invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease Eur. Respir. J. 30 2007 782 800 17906086 \n4 Clancy C.J. Nguyen M.H. Acute community-acquired pneumonia due to Aspergillus in presumably immunocompetent hosts: clues for recognition of a rare but fatal disease Chest 114 1998 629 634 9726758 \n5 Nulens E.F. Bourgeois M.J. Reynders M.B. Post-influenza aspergillosis, do not underestimate influenza B Infect. 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Powell L.W. Value of hepatic iron measurements in early hemochromatosis and determination of the critical iron level associated with fibrosis Hepatology 6 1986 24 29 3943787 \n16 Toyokuni S. Role of iron in carcinogenesis: cancer as a ferrotoxic disease Cancer Sci. 100 2009 9 16 19018762 \n17 Ohara Y. Chew S.H. Shibata T. Okazaki Y. Yamashita K. Toyokuni S. Phlebotomy as a preventive measure for crocidolite-induced mesothelioma in male rats Cancer Sci. 109 2018 330 339 29193587 \n18 Karnak D. Avery R.K. Gildea T.R. Sahoo D. Mehta A.C. Endobronchial fungal disease: an under-recognized entity Respiration 74 2007 88 104 16864987 \n19 Wu N. Huang Y. Li Q. Bai C. Huang H.D. Yao X.P. Isolated invasive Aspergillus tracheobronchitis: a clinical study of 19 cases Clin. Microbiol. Infect. 16 2010 689 695 19689467 \n20 Barberan J. Sanchez-Haya E. del Castillo D. Sanz F. Alcazar B. Malmierca E. Report of 38 cases of tracheobronchitis in non-immunocompromised patients with dual isolation of Aspergillus in lower respiratory tract samples Rev. Esp. Quimioter. 27 2014 110 114 24940892\n\n", "fulltext_license": "CC BY", "issn_linking": "2211-7539", "issue": "20()", "journal": "Medical mycology case reports", "keywords": "Alcoholism; Aspergillus fumigatus; Immunocompetent host; Invasive pulmonary aspergillosis; Smoker; Welder", "medline_ta": "Med Mycol Case Rep", "mesh_terms": null, "nlm_unique_id": "101598259", "other_id": null, "pages": "39-42", "pmc": null, "pmid": "29552460", "pubdate": "2018-06", "publication_types": "D016428:Journal Article", "references": "16532017;15286693;27904053;16418244;11251302;17906086;21811407;16864987;11181646;19409098;17614303;9726758;19689467;21881144;3943787;29193587;28260935;19018762;24940892;20507748", "title": "Acute fulminant invasive pulmonary aspergillosis in an immunocompetent host: An autopsy case report.", "title_normalized": "acute fulminant invasive pulmonary aspergillosis in an immunocompetent host an autopsy case report" }

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{ "abstract": "We report a case of Scedosporium apiospermum mold causing ear infection, central skull base osteomyelitis and finally, occlusion of carotid artery in a 48-year-old diabetic man. The exact diagnosis was established and the severity of the disease understood several months after the onset of symptoms. Despite of appropriate antifungal therapy, and repeated surgical and otological procedures, the infection progressed to fatal cerebral infarction.", "affiliations": "Department of Infectious Diseases, Division of Medicine, Turku University Hospital, Turku, Finland; Faculty of Medicine, Turku University, Turku, Finland.;Department of Emergency Radiology, Medical Imaging Center of Southwest Finland, Turku University Hospital, Turku, Finland.;Department of Pathology, Turku University Hospital, Turku, Finland; Faculty of Medicine, Turku University, Turku, Finland.;Department of Clinical Microbiology, Turku University Hospital, Turku, Finland.;Department of Infectious Diseases, Division of Medicine, Turku University Hospital, Turku, Finland; Faculty of Medicine, Turku University, Turku, Finland.;Department of Infectious Diseases, Division of Medicine, Turku University Hospital, Turku, Finland; Faculty of Medicine, Turku University, Turku, Finland.", "authors": "Jalava-Karvinen|Päivi|P|;Nyman|Mikko|M|;Gardberg|Maria|M|;Harju|Inka|I|;Hohenthal|Ulla|U|;Oksi|Jarmo|J|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.mmcr.2016.04.002", "fulltext": "\n==== Front\nMed Mycol Case RepMed Mycol Case RepMedical Mycology Case Reports2211-7539Elsevier S2211-7539(16)30025-210.1016/j.mmcr.2016.04.002Case ReportScedosporium apiospermum as a rare cause of central skull base osteomyelitis Jalava-Karvinen Päivi ae⁎Nyman Mikko bGardberg Maria ceHarju Inka dHohenthal Ulla aeOksi Jarmo aea Department of Infectious Diseases, Division of Medicine, Turku University Hospital, Turku, Finlandb Department of Emergency Radiology, Medical Imaging Center of Southwest Finland, Turku University Hospital, Turku, Finlandc Department of Pathology, Turku University Hospital, Turku, Finlandd Department of Clinical Microbiology, Turku University Hospital, Turku, Finlande Faculty of Medicine, Turku University, Turku, Finland⁎ Corresponding author at: Department of Infectious Diseases, Division of Medicine, Turku University Hospital, Turku, Finland.Department of Infectious Diseases, Division of Medicine, Turku University HospitalTurkuFinland07 4 2016 3 2016 07 4 2016 11 28 30 13 3 2016 31 3 2016 6 4 2016 © 2016 The Authors2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).We report a case of Scedosporium apiospermum mold causing ear infection, central skull base osteomyelitis and finally, occlusion of carotid artery in a 48-year-old diabetic man. The exact diagnosis was established and the severity of the disease understood several months after the onset of symptoms. Despite of appropriate antifungal therapy, and repeated surgical and otological procedures, the infection progressed to fatal cerebral infarction.\n\nKeywords\nScedosporium apiospermumCentral skull base osteomyelitisMold infection\n==== Body\n1 Introduction\nScedosporium apiospermum (teleomorph state Pseudallescheria boydii) is a mold commonly found in the environment. It is capable of causing invasive infections in both immunocompromised and competent individuals [1], [2], [3]. In patients with normal immune system, S. apiospermum typically causes local infections such as skin ulcers or arthritis [3] but as a result of immunosuppression, the pathogen can invade to vessel walls and blood circulation and cause disseminated infection [4], [5]. S. apiospermum has a predilection to the central nervous system (CNS) and patients with brain abscesses have been reported [5], [6]. Neutropenia, use of corticosteroids, and diabetes are risk factors for opportunistic Scedosporium infections [1], [3], [4], [5]. Treatment is challenging and requires immune system reconstruction, aggressive surgical treatment and prolonged antifungal treatment. Guidelines rely on the experience gathered from single case reports. Voriconazole (VCZ) is suggested as the first line therapy of infections caused by these multidrug resistant molds [7].\n\nCentral skull base osteomyelitis (SBO) is a rare life-threatening condition originating from external auditory canal or less frequently from sinonasal infections [8], [9], [10]. It is defined as an osteitis of the temporal bone and skull base, including the bony labyrinth, the medial part of the petrosa, the sphenoidal and occipital bones and the clivus, even reaching the infratemporal fossa [11]. The infection may spread through the skull base forming granulomas and abscesses in the brain tissue and also lower cranial nerves can get affected [12], [13]. In the diagnosis of SBO and its complications magnetic resonance imaging (MRI) is the most important method [14]. The most frequent etiology of SBO is bacterial but 20% to 50% are fungal [8]. Fungal SBO is most often caused by Aspergillus spp. [15].\n\nWe report a patient with S. apiospermum ear infection, central SBO, and finally, mycotic occlusion of the internal carotid artery (ICA) leading to death.\n\n2 Case\nA 48-year old man had suffered from type I diabetes for 35 years. His blood glucose had been poor for years. He had several diabetic complications including retinopathy and nephropathy. Hemodialysis had been started in September, 2013. He was using oral prednisolone 20 mg daily for painful chronic calcification wounds on his legs.\n\nIn December, 2013 (day 0), the patient complained of pain in his right ear. On the examination, there was an occluding mass inside the ear canal. Pathological anatomical diagnosis (PAD) showed an ulcer with granulation tissue. Bacterial cultures remained negative but no fungal tests were performed. Computed tomographic scanning (day 20) showed large soft tissue mass inside the mastoid sinus, middle ear and bony ear canal with bone erosions in the right jaw joint. Although the PAD suggested an abscess with fungal hyphae inside, no systemic antimicrobial treatment was commenced. Because of the worsening headache, drainage of the right ear, and temporal impairment of the left upper limb function, he visited the emergency, in February 2014 (day 80).\n\nHe had no signs of an acute infection, but complained of double images. Right-sided abducens nerve paresis was observed. C-reactive protein was 33 mg/l (normal<10 mg/l), and white blood cell count 8.0×109/l (normal 3.4–8.2×109/l). MRI showed a cerebral lesion that was interpreted as ischemic or infective. There was a suspicion of vessel wall inflammation in the right ICA at the level of skull base (Fig. 1). The cerebrospinal fluid (CSF) contained no leukocytes but protein was elevated at 800 mg/l (normal 150–450 mg/l). Fungal polymerase chain reaction (PCR) showed weak positivity for Aspergillus nidulans considered as a contamination by the laboratory. Fungal and bacterial cultures remained negative.\n\nEmpirical treatment with intravenous (iv) ceftriaxone, iv vancomycin, oral rifampicin, and iv fluconazole (FCZ) 400 mg daily was started. Neurological symptoms were suspected to be due to partial seizures resulting from a cerebral infarction. He needed opiates because of severe headache.\n\nOn day 97, MRI revealed progression of infective areas in the skull base. Inflammation of the right ICA wall was stronger with occlusion and aneurysmatic enlargement which was suspected to be mycotic. On the right frontal and parietal lobes, multiple small focal abscesses were detected (Fig. 1). Due to the worsening situation and the PCR finding of A. nidulans FCZ was switched to oral VCZ (200 mg bid). Ceftriaxone was switched to meropenem. On day 101, an operation involving right sphenoidal and ethmoidal sinuses as well as right medial and superior conchae, was performed. PAD showed no fungal hyphae but a possibility of a healing fungal infection.\n\nA mold was isolated from a sample taken from the sphenoidal sinus and was identified as S. apiospermum on the basis of typical colony morphology and shape of the conidiophores. The identification was confirmed by matrix-assisted laser-desorption-ionization time-of flight (MALDI-TOF) mass spectrometry, using Microflex LT instrument, MALDI Biotyper software version 3.1 and Filamentous Fungi Library database version 1.0 (supplied by Bruker Daltonics, Bremen, Germany). Specimen preparation was carried out as described by Schulthess et al. [16]. Antifungal resistance testing was performed at the Mycological Unit of the Clinical Microbiology Laboratory of Helsinki University Hospital (HUSLAB). The isolate showed minimum inhibitory concentrations of 0.38 for VCZ, 4 for posaconazole (PCZ), 32 for itraconazole and 12 for amphotericine B. The serum concentration of VCZ with both oral and iv (200 mg bid) administrations remained markedly below the suggested therapeutic concentration 2–5.5 mg/l. On day 121, VCZ dosing was switched back to oral 300 mg bid. VCZ concentration reached the level of 1.7 mg/l and patient's markedly improved condition made us to believe in the ongoing therapy. On day 135, MRI showed disappearing of the cortical lesions but the skull base involvement remained unchangeable. The non-enhancing mass occluding the ICA was larger (Fig. 1). The patient was discharged to an outpatient hospital on day 149 with oral VCZ and meropenem. He had no pain or problems with his ear and was scheduled for regular visits to the departments of infectious diseases and otolaryngology.\n\nOn day 162, patient's liver function tests (LFTs) appeared to be elevated: gamma-glutamyl transpeptidase 3722 U/l (normal 15–115 U/l), alkaline phosphatase 1291 U/l (normal 35 – 105 U/l), alanine aminotransferase 88 U/l (normal 10–70 U/l), and bilirubin 41 µmol/l (normal<21 µmol/l). Meropenem was discontinued with no improvement on LFTs. On day 174, VCZ was switched to oral PCZ (400 mg bid) with no improvement on LFTs. The serum PCZ concentration of 0.4 mg/l (0.1–5 ml/l) was reached. Finally, antifungal treatment was discontinued because of the concern for patient's liver. An attempt was made to acquire isavuconazole (ICZ), a new azole-group antifungal at phase III clinical trials, probably with equal effectiveness but fewer side effects than the older azoles. MRI showed that cortical abscesses had almost disappeared and infective changes in the skull base were improving. However, the right ICA occlusion was still present and the non-enhancing mass in the vessel lumen was now almost at the level of middle cerebral artery (MCA) bifurcation.\n\nOn day 207, the patient contacted the emergency because of headache and dizziness. On examination, he still had abducens nerve palsy. CSF analysis revealed 2021×106/l leukocytes, indicating meningitis. Bacterial and fungal cultures and PCRs remained negative. Next day, the patient's condition collapsed, he was unconscious, rejecting pain with extension. MRI revealed an occlusion of the ICA at the level of MCA bifurcation. There was a suspected rupture of proximal right MCA with intracerebral hematoma and a large brain infarct of the corresponding MCA area. ICZ (received for compassionate use) was instituted but continued only two days before the patient died on day 212. Postmortem findings were consistent with previous investigations: skull base and vessel wall of the ICA were affected by fungal infection as seen also on histological sections (Fig. 2). S. apiospermum was cultured from both structures but not from the brain tissue. Massive cerebral infarction had led to brain herniation and to the death of the patient.\n\n3 Discussion\nFungal central SBO is a rare condition and most often caused by Aspergillus spp. [15]. The fungal hyphae of Aspergillus and Scedosporium cannot be differentiated in microscopical examination and culture remains the gold standard for the diagnosis. S. apiospermum is extremely rare as a cause of central SBO, and has been rarely reported. Our patient did not have severe immunosuppression but suffered from diabetes and terminal uremia and was using oral prednisolone. Previously, patients with underlying HIV infection and central SBO caused by S. apiospermum have been reported [17], [18]. One of these was successfully treated with itraconazole and the other died without effective treatment [17], [18]. As in other mold infections, the severity of the underlying condition and degree of immunosuppression markedly influence on the outcome of the patient. Vasoo et al. treated their 51-year-old diabetic patient with right-sided otorrhea, cranial nerve palsies and SBO caused by S. apiospermum with VCZ for six months. Despite of extensive bony erosions, their patient remained in remission without further antifungal medication [19]. The possibility of this rare fungal infection should be recalled, because the treatment of severe fungal infections with amphotericine B will not be effective.\n\nIn the present case, the diagnosis was made very late mainly because the possibility of such a rare condition had not occurred to anybody's mind. Samples for fungal culture should have been taken in December, 2013. FCZ was started as a part of an empiric treatment because fungi were considered to be partly involved. FCZ is not effective against filamentous fungi why the treatment choice was not optimal. If amphotericine B had been started, it would have not worked either. Infectious disease specialist was engaged in the treatment in the middle of February, 2014. VCZ concentration did not reach optimal level either with iv or oral administration possibly due to the patient being a fast metabolizer. We do not know how PCZ would have worked if the patient had received it earlier. So far, there is much less experience on the use of PCZ against S. apiospermum infections but successful reports exist [6], [7] and at least, therapeutic concentration was reached in our case. ICZ came too late to be able to influence on the disease progression.\n\nThe patient had elevated LFTs which finally lead to the cessation of the antifungal treatment, and presumably to the exacerbation of the infection. As seen also in one comparable previous case report, molds tend to evade vessels [2]. Due to the diffuse spread of the infection through bone, vessel, and brain tissues, radical surgery was not possible either in the present or the previously published case [2].\n\nThe outer ear infection initially detected and treated was only the tip of the iceberg. During treatment, the mold infection was irresistibly spreading inside the right ICA leading to the fatal rupture of the proximal MCA. Retrospectively, we can see how the process progressed despite of the apparently effective treatment with VCZ (Fig. 1). Hyperbaric oxygen might be an option as an adjunctive therapy but it was not used in our case. The prognosis of disseminated S. apiospermum infection is dismal with the mortality rate of CNS infection being 74% according to case reports [5]. Although our case represents rather local spread than wider dissemination, this patient case with an unhappy ending highlights the insidious nature of Scedosporium infection.\n\nConflict of interest\nThere is none.\n\nAcknowledgements\nWe thank Turku University Hospital EVO Grant 13900 for support when writing this paper.\n\nFig. 1 MRI showing the evolution of the right ICA (arrow) infiltration at the level of cavernous sinus. On day 80 there is no visible infiltration and vessel walls are normal. On day 97, vessel walls are thick and the flow in the ICA seems to be slower. On day 135, the whole right ICA is occluded by non-enhancing material which was later proven to be of fungal origin.\n\nFig. 1.Fig. 2 Photomicrograph of the ICA, PAS staining. Fungal hyphae (arrow) are seen among arterial wall smooth muscle cells and necrotic debris.\n\nFig. 2.\n==== Refs\nReferences\n1 Campa-Thompson M.M. West J.A. Guileyardo J.M. Spak C.W. Sloan L.M. Beal S.G. Clinical and morphologic findings in disseminated Scedosporium apiospermun infections in immunocompromised patients Bayl. Univ. Med. Cent. Proc. 27 2014 253 256 \n2 Watson J.C. Myseros J.S. Bullock M.R. True fungal mycotic aneurysm of the basilar artery: a clinical and surgical dilemma Cerebrovasc. Dis. 9 1999 50 53 9873163 \n3 Koehler P. Tacke D. Cornely O.A. Bone and joint infections by Mucorales , Scedosporium , Fusarium and even rarer fungi Crit. Rev. Microbiol. 9 2014 1 14 \n4 Munoz P. Marin M. Tornero P. Martin Rabadan P. Rodriquez-Creixems M. Bouza E. Successful outcome of Scedosporium apiospermum disseminated infection treated with voriconazole in a patient receiving corticosteroid therapy Clin. Infect. Dis. 31 2000 1499 1501 11096022 \n5 Kantarciougly A.S. Guarro J. de Hoog G.S. Central nervous system infections by members of the Pseudallescheria boydii species complex in healthy and immunocompromised hosts: epidemiology, clinical characteristics and outcome Mycoses 51 2008 275 290 18331448 \n6 Mellinghoff I.K. Winston D.J. Mukwaya G. Schiller G.J. Treatment of Scedosporium apiospermun Brain Abscesses with Posaconazole Clin. Infect. Dis. 34 2002 1648 1650 12032903 \n7 Tortorano A.M. Richardson M. Roilides E. van Diepeningen A. Caira M. Munoz P. ESCMID and ECMM joint guidelines on diagnosis and management of hyalohyphomycosis: Fusarium spp., Scedosporium spp. and others Clin. Microbiol. Infect. 20 Suppl. 3 2014 S27 S46 \n8 Blyth C.C. Gomes L. Sorrell T.C. da Cruz M. Sud A. Chen S. Skull base osteomyelitis: fungal vs. bacterial infection Clin. Microbiol. Infect. 17 2011 306 311 20384699 \n9 Johnson A.K. Batra P.S. Central skull base osteomyelitis: an emerging clinical entity Laryngoscope 124 2014 1084 1088 \n10 Rubin J. Barnsletter B.F. Yu V.L. 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Osteomyelitis of the base of the skull secondary to Aspergillus Am. J. Otolaryngol. 18 1997 19 22 9006672 \n16 Schulthess B. Ledermann R. Mouttet F. Zbinden A. Bloemberg G.V. Bötter E.C. Use of the MALDI Biotyper for identification of molds in the clinical mycology laboratory J. Clin. Microbiol. 52 2014 2797 2803 24850347 \n17 Eckburg P.B. Zolopa A.R. Montoya J.G. Invasive fungal sinusitis due to Scedosporium apiospermum in a patient with Aids. Clin. Infect. Dis. 29 1999 212 213 10433595 \n18 Slack C.L. Watson D.W. Abzug M.J. Shaw C. Chan K.H. Fungal mastoiditis in immunocompromised children Arch. Otolaryngol. Head Neck Surg. 125 1999 73 75 9932592 \n19 Vasoo S. Yeo S.B. Lim P.L. Anq B.S. Lye D.C. Efficacy of voriconazole for Scedosporium apiospermum skull base osteomyelitis: case report and literature review Int. J. Antimicrob. Agents 31 2008 184 185 18083011\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2211-7539", "issue": "11()", "journal": "Medical mycology case reports", "keywords": "Central skull base osteomyelitis; Mold infection; Scedosporium apiospermum", "medline_ta": "Med Mycol Case Rep", "mesh_terms": null, "nlm_unique_id": "101598259", "other_id": null, "pages": "28-30", "pmc": null, "pmid": "27134821", "pubdate": "2016-03", "publication_types": "D016428:Journal Article", "references": "10433595;11096022;12032903;12917118;14720566;18083011;18331448;19466617;20015773;20384699;24115113;24548001;24809926;24850347;24982580;25381580;9006672;9873163;9932592", "title": "Scedosporium apiospermum as a rare cause of central skull base osteomyelitis.", "title_normalized": "scedosporium apiospermum as a rare cause of central skull base osteomyelitis" }

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{ "abstract": "Secondary thrombocytosis, often referred to as a reactive thrombocytosis, is more common than primary thrombocytosis and has many potential etiologies including anemia, infection, inflammation, medications, and post-splenectomy. When considering the critically ill patient in the ICU setting potential medication-related etiologies of thrombocytosis should be included in the differential diagnosis. We present a 15-year-old adolescent with a traumatic brain injury who developed thrombocytosis that was temporally related to the administration of enoxaparin. There was a prompt return of the platelet count to normal following the discontinuation of enoxaparin therapy which led to the probable diagnosis of enoxaparin-induced thrombocytosis.", "affiliations": "Department of Pediatrics, Division of Pediatric Critical Care Medicine, Nationwide Children's Hospital, Columbus, OH, USA.;Department of Pediatrics, Division of Pediatric Critical Care Medicine, Nationwide Children's Hospital, Columbus, OH, USA.", "authors": "Murray|Robert|R|0000-0003-0477-3791;Tobias|Joseph T|JT|0000-0003-0550-6951", "chemical_list": null, "country": "New Zealand", "delete": false, "doi": "10.2147/CPAA.S327541", "fulltext": "\n==== Front\nClin Pharmacol\nClin Pharmacol\ncpaa\nClinical Pharmacology : Advances and Applications\n1179-1438\nDove\n\n327541\n10.2147/CPAA.S327541\nCase Report\nA Case of Thrombocytosis Associated with Enoxaparin Therapy in an Adolescent\nMurray and Tobias\nMurray and Tobias\nhttp://orcid.org/0000-0003-0477-3791\nMurray Robert 1\nhttp://orcid.org/0000-0003-0550-6951\nTobias Joseph T 1 2 3\n1 Department of Pediatrics, Division of Pediatric Critical Care Medicine, Nationwide Children’s Hospital, Columbus, OH, USA\n2 Department of Anesthesiology & Pain Medicine, Nationwide Children’s Hospital, Columbus, OH, USA\n3 Department of Anesthesiology & Pain Medicine, The Ohio State University College of Medicine, Columbus, OH, USA\nCorrespondence: Robert Murray Department of Pediatrics, Division of Pediatric Critical Care Medicine, Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH, 43205, USA Tel +1 614 722-4200 Fax +1 614 722-4203 Email Robert.Murray@Nationwidechildrens.org\n18 10 2021\n2021\n13 203207\n02 7 2021\n23 9 2021\n© 2021 Murray and Tobias.\n2021\nMurray and Tobias.\nhttps://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).\nAbstract\n\nSecondary thrombocytosis, often referred to as a reactive thrombocytosis, is more common than primary thrombocytosis and has many potential etiologies including anemia, infection, inflammation, medications, and post-splenectomy. When considering the critically ill patient in the ICU setting potential medication-related etiologies of thrombocytosis should be included in the differential diagnosis. We present a 15-year-old adolescent with a traumatic brain injury who developed thrombocytosis that was temporally related to the administration of enoxaparin. There was a prompt return of the platelet count to normal following the discontinuation of enoxaparin therapy which led to the probable diagnosis of enoxaparin-induced thrombocytosis.\n\nKeywords\n\nenoxaparin\nthrombocytosis\nplatelet count\nheparin\nanticoagulation\n==== Body\npmcIntroduction\n\nThrombocytosis is generally defined as a platelet count greater than 450,000/mm3 (normal range 150–450/mm3). Thrombocytosis can be further classified as either primary or secondary.1–3 Primary thrombocytosis is caused by an intrinsic mechanism within the megakaryocyte or its precursor cells. Primary thrombocytosis, which is far less common than secondary thrombocytosis, can be caused by acquired or inherited defects in the genes which regulate thrombopoiesis. These can include malignancies such as chronic myeloid leukemia or acute myeloid leukemia, polycythemia vera, and myelodysplastic syndromes. Features suggestive of a primary rather than secondary cause include: unexplained vasomotor symptoms (flushing or pruritis), constitutional symptoms (night sweats, fever or weight loss), splenomegaly, thrombosis in unusual sites, an abnormal peripheral blood smear or a family history suggestive of thrombosis. In such scenarios, referral to a hematologist for further work-up is warranted.\n\nSecondary thrombocytosis, often referred to as a reactive thrombocytosis, is more common than primary thrombocytosis and has many potential etiologies including anemia, infection, inflammation, medications, and post-splenectomy.2,3 The presence of thrombocytosis is often found incidentally on a complete blood count (CBC). The initial work-up should include a repeat CBC with differential, a review of the peripheral blood smear, and a thorough history and physical examination, including a review of the recent medical history and medications. We present a 15-year-old adolescent with a traumatic brain injury (TBI) who developed thrombocytosis that was noted to be temporally related to the administration of enoxaparin. An approach to identify the etiology of thrombocytosis is presented, previous reports regarding the association of thrombocytosis with enoxaparin are reviewed, and the potential pathophysiology is discussed.\n\nCase Report\n\nReview of this case and presentation in this format was approved by the Institutional Review Board of Nationwide Children’s Hospital. Informed consent for publication was obtained from the patient’s mother and the patient was unable to assent given the residual effects of his TBI. The patient was a 15-year-old male who was admitted to the Pediatric Intensive Care Unit (PICU) with a severe TBI following a motor vehicle collision. He was a previously healthy teenager with a medical history significant only for attention deficit hyperactive disorder. His other injuries at the time of admission included bilateral pelvic fractures and a left internal carotid artery dissection. Following admission, a right femoral central venous catheter was placed for access during the management of his increased intracranial pressure (ICP). Due to the internal carotid artery dissection, a heparin infusion was started at 20 units/kg/hour with a low anti-Xa goal of 0.3–0.5 IU/mL. Full anticoagulation with a higher anti-Xa was deemed contraindicated due to the cerebral contusions associated with his TBI and concerns for intracranial bleeding. His hospital course was unremarkable and there was gradual resolution of the increased ICP related to his TBI. Due to clinical concern for thrombus formation, an ultrasound of the right leg was performed, revealing a non-occlusive catheter associated thrombosis in the right femoral vein. In consultation with neurosurgery, it was determined that anticoagulation was appropriate and therapeutic enoxaparin (40 mg twice a day) was started and the heparin infusion was discontinued. An anti-Xa level was obtained following the initiation of enoxaparin with a peak level of 0.55 IU/mL, within the desired therapeutic goal for our patient (0.35–0.7 IU/mL). Platelet count trends before, during and after enoxaparin therapy are presented in Figure 1. Following the initiation of enoxaparin, on day 13 of hospitalization, there was an increase in platelet count and hematology consultation was obtained. The increasing platelet count continued from hospital day 13 to 20. As other possible causes for the thrombocytosis were ruled out including anemia, infection and inflammation, medication causes were considered. It was at this time, day 19, that enoxaparin was discontinued. After the discontinuation of enoxaparin his platelet count continued to rise for one subsequent day followed by a gradual return of the platelet count to normal values. Due to a continued need to provide some level of anticoagulation for this patient’s internal carotid artery dissection aspirin (81 mg daily) was started on hospital day 19 following the discontinuation of enoxaparin. As his acute medical concerns began to resolve the patient was transferred to an inpatient rehabilitation facility to continue working on mobility, self-care, cognition, and oral intake. He was able to be discharged home from inpatient rehabilitation approximately 2 months after his initial TBI.Figure 1 Platelet count over time. Enoxaparin therapy was started on hospital day 13 and discontinued on hospital day 19.\n\nDiscussion\n\nEnoxaparin is a low molecular weight heparin compound commonly used for both the prevention and treatment of thrombotic diseases. Clinical uses include the prophylaxis of deep vein thrombosis (DVT), as well as therapeutic anticoagulation for various thrombotic conditions including pulmonary embolism. Clinical advantages over unfractionated heparin include therapeutic anticoagulation with subcutaneous administration, a longer plasma half-life, a linear dose-response relationship, feasibility for administration in the outpatient setting and a limited need to monitor its anticoagulant effect.4 The most common adverse effects of enoxaparin include anemia, hemorrhage, and thrombocytopenia.4 Peripheral edema, ecchymoses, nausea, hematuria, alterations in liver function tests, confusion, and fever have also been reported.\n\nIn our patient, there was a temporal association between the initiation of enoxaparin therapy and the development of thrombocytosis. During the work-up for thrombocytosis in conjunction with pediatric hematology specialists, other potential etiologies were ruled out. At the time that our patient developed thrombocytosis, they were approximately 2 weeks removed from the initial traumatic injury, their clinical condition was improving, they were not anemic, and there was no evidence of an ongoing infectious or inflammatory process. Other possible pharmacologic causes were reviewed and ruled out. Therefore, the conclusion was that the reactive thrombocytosis was most likely secondary to enoxaparin. Most importantly, there was a prompt decline in the platelet count following discontinuation of the enoxaparin. This conclusion is support by our calculated Naranjo score of 7, presented in Figure 2, suggesting a probable adverse drug reaction linking enoxaparin to thrombocytosis in our patient.Figure 2 Selections for each criterion in the Naranjo Score are bolded. A score of 7 suggests a probable adverse drug reaction. 1While no conclusive evidence exists to support this reaction, it has been previously seen in other populations and has been reported in the literature previously. 2While there are alternative causes for secondary thrombocytosis, we were able to exclude them in our case leaving enoxaparin as the most likely cause.\n\nThrombocytosis associated with enoxaparin has been anecdotally reported in various clinical scenarios previously in both adult and pediatric patients.5–8 A multicenter study evaluating the safety of enoxaparin for the prevention of postoperative thromboembolism unexpectedly noted thrombocytosis in the study cohort of 290 adult patients.9 The patients received either 20 or 40 mg of subcutaneous enoxaparin once daily with platelet counts evaluated prior to surgery and on the 5th, 7th, 11th, and 15th postoperative day. Although no thrombocytopenia or thrombosis were noted, there was an increase in postoperative platelet counts in most patients. Postoperative thrombocytosis was greater in patients with neoplasms as well as those with excessive perioperative blood loss and transfusion requirements. No thrombotic complications related to the thrombocytosis were noted. The authors concluded that as changes in the platelet counts were not the main topic of their study, the data should be regarded only as preliminary and further investigations are needed to resolve the cause of the observed phenomenon of thrombocytosis with enoxaparin.\n\nThe mechanism by which enoxaparin leads to thrombocytosis has not been fully elucidated. In a murine experiment, an increase in platelet count, immature megakaryocytes, and colony-forming unit megakaryocytes in the bone marrow occurred after the intraperitoneal administration of a low molecular weight heparin compound, fraxiparin, for 4 days.10 The authors hypothesized that fraxiparin interacts with heparin cofactor II and antithrombin III to promote megakaryocyte colony formation. It has also been demonstrated that heparin can potentiate the megakaryocyte-poietic activity of the C-Mpl ligand and interleukin-6 as well as neutralize the inhibitory actions of platelet factor 4 and transforming growth factor β1 on megakaryocyte colony growth.11 These factors would result in the stimulation of hematopoiesis in the bone marrow leading to an increase in platelet formation.\n\nConclusion\n\nAlthough physicians are generally aware of the association of heparin with thrombocytopenia (heparin-induced thrombocytopenia), thrombocytosis has been only anecdotally reported. We suggest that enoxaparin should be considered in the differential diagnosis of thrombocytosis, supported by a Naranjo Score of 7 in our case, suggesting a probable adverse drug reaction. Cessation of heparin therapy is suggested if feasible based on the risk-benefit ratio of the individual patient. It is generally postulated that reactive thrombocytosis does not represent a significant thrombotic risk however, no conclusion has been reached regarding this potential association. Currently, there is limited evidence-based medicine on which to guide decisions regarding the need for anti-platelet therapy such as aspirin in patients with thrombocytosis.12,13 Although we chose not to initiate additional therapy in our patient other than transition to once daily aspirin (81 mg) for their internal carotid artery dissection, clinicians should evaluate the thrombotic and bleeding risks on a case-by-case basis to develop the most appropriate management plan for each patient.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n==== Refs\nReferences\n\n1. Skoda RC. Thrombocytosis. Hematology. 2009;2009 :159–167. doi:10.1182/asheducation-2009.1.159\n2. Harrison CN, Bareford D, Butt N, et al. Guideline for investigation and management of adults and children presenting with a thrombocytosis. Br J Haemat. 2010;149 :352–375. doi:10.1111/j.1365-2141.2010.08122.x 20331456\n3. Yohannan MD, Higgy KE, Al-Mashhadani SA, Santhosh-Kumar CR. Thrombocytosis. Clin Pediatr. 1994;33 :340–343. doi:10.1177/000992289403300605\n4. Hofmann T. Clinical application of enoxaparin. Expert Rev Cardiovasc Ther. 2004;2 :321–337. doi:10.1586/14779072.2.3.321 15151480\n5. Ranze O, Ranze P, Magnani HN, et al. Heparin-induced thrombocytopenia in paediatric patients: a review of the literature and a new case treated with danaparoid sodium. Eur J Pediatr. 1999;158 (suppl 3 ):S130–3. doi:10.1007/PL00014338 10650852\n6. Tonbul A, Uras N, Tayman C, Halici T, Polat A, Mansur Tatli M. Thrombocytosis associated with enoxaparin: a very rare cause in newborns. Platelets. 2010;21 :300–302. doi:10.3109/09537101003649807 20367573\n7. Xiang T, Cheng M. Enoxaparin-induced reactive thrombocytosis: a case report. Thromb J. 2021;19 :34. doi:10.1186/s12959-021-00290-x 34039362\n8. Hummel MC, Morse BC, Hayes LE. Reactive thrombocytosis associated with enoxaparin. Pharmacotherapy. 2006;26 :1667–1670. doi:10.1592/phco.26.11.1667 17064215\n9. Ziaja K, Simka M, Krupowies A, Dugaj M, Ludyga T. Thrombocytosis after prophylactic administration of enoxaparin: unexpected findings in a Polish prospective multicenter trial on the efficacy and safety of enoxaparin in the prevention of postoperative thromboembolism. Int Angiol. 1999;18 :65–69.10392483\n10. Shen ZX, Basara N, Xi XD, et al. Fraxiparin, a low-molecular-weight heparin, stimulates megakaryocytopoiesis in vitro and in vivo in mice. Br J Haematol. 1994;88 :608–612. doi:10.1111/j.1365-2141.1994.tb05080.x 7819073\n11. Han ZC, Bellucci S, Shen ZX, et al. Glycosaminoglycans enhance megakaryocytopoiesis by modifying the activities of hematopoietic growth regulators. J Cell Physiol. 1996;168 :97–104. doi:10.1002/(SICI)1097-4652(199607)168:1<97::AID-JCP12>3.0.CO;2-M 8647928\n12. Buss DH, Stuart JJ, Lipscomb GE. The incidence of thrombotic and hemorrhagic disorders in association with extreme thrombocytosis: an analysis of 129 cases. Am J Hematol. 1985;20 :365–372. doi:10.1002/ajh.2830200408 3865532\n13. Randi ML, Stocco F, Rossi C, Tison T, Girolami A. Thrombosis and hemorrhage in thrombocytosis: evaluation of a large cohort of patients (357 cases). J Med. 1991;22 :213–223.1787383\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1179-1438", "issue": "13()", "journal": "Clinical pharmacology : advances and applications", "keywords": "anticoagulation; enoxaparin; heparin; platelet count; thrombocytosis", "medline_ta": "Clin Pharmacol", "mesh_terms": null, "nlm_unique_id": "101564865", "other_id": null, "pages": "203-207", "pmc": null, "pmid": "34703325", "pubdate": "2021", "publication_types": "D002363:Case Reports", "references": "7819073;20008195;8647928;3865532;20331456;10650852;17064215;34039362;8200167;15151480;20367573;10392483;1787383", "title": "A Case of Thrombocytosis Associated with Enoxaparin Therapy in an Adolescent.", "title_normalized": "a case of thrombocytosis associated with enoxaparin therapy in an adolescent" }

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{ "abstract": "OBJECTIVE\nImproved survival in testicular cancer has been accompanied by concern about long-term side effects of therapy. We assessed the evolution of second cancer (SC) risk over a prolonged follow-up period, which has been rarely studied in large patient series.\n\n\nMETHODS\nWe estimated the risk of SCs in 1,909 patients with testicular cancer diagnosed in the Netherlands from 1971 to 1985. Complete medical information was obtained up to at least January 1988 for 92% of patients. Median follow-up was 7.7 years. For 89% of second tumors the diagnosis was confirmed through review of histologic slides; for an additional 8%, the diagnosis was verified by pathology reports only.\n\n\nRESULTS\nSeventy-eight patients developed a SC 1 year or more after start of treatment, as compared with 47.6 expected on the basis of incidence rates in the general population (relative risk [RR], 1.6; 95% confidence interval [CI], 1.3 to 2.1). The mean 15-year actuarial risk of all SCs was 9.8% (95% CI, 7.5% to 12.8%). Significantly increased RRs were observed for all gastrointestinal cancers combined (RR, 2.6; 95% CI, 1.7 to 3.9), stomach cancer (RR, 3.7; 95% CI, 1.8 to 6.8), contralateral testicular cancer (CLTC) (RR, 35.7; 95% CI, 21.8 to 55.2), and leukemia (RR, 5.1; 95% CI, 1.4 to 13.0). Patients who had received irradiation to the paraaortic lymph nodes and who survived testicular cancer for more than 5 years were at particularly high risk of developing stomach cancer (RR, 6.9; 95% CI, 3.3 to 12.7). The median interval between the diagnosis of testicular cancer and stomach cancer was 12.4 years. Patients treated with chemotherapy (CT) did not experience an increase in SCs in general. Indeed, CT-treated patients, as compared with those who received radiotherapy (RT), or surgery alone, had significantly reduced risk of CLTC. This finding might be attributed to an eradicating effect of CT on carcinoma in situ or subclinical CLTC. The excess risk of leukemia was not found to be clearly related to CT.\n\n\nCONCLUSIONS\nTesticular cancer patients who receive RT experience elevated risk of gastrointestinal tumors. CT does not seem to increase SC risk and may even decrease the risk of a CLTC. Following testicular cancer, the 15-year actuarial risk of all SCs is only about half the risk experienced by patients with Hodgkin's disease.", "affiliations": "Department of Epidemiology, Netherlands Cancer Institute, Amsterdam.", "authors": "van Leeuwen|F E|FE|;Stiggelbout|A M|AM|;van den Belt-Dusebout|A W|AW|;Noyon|R|R|;Eliel|M R|MR|;van Kerkhoff|E H|EH|;Delemarre|J F|JF|;Somers|R|R|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1200/JCO.1993.11.3.415", "fulltext": null, "fulltext_license": null, "issn_linking": "0732-183X", "issue": "11(3)", "journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", "keywords": null, "medline_ta": "J Clin Oncol", "mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D003131:Combined Modality Therapy; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009381:Neoplasms, Radiation-Induced; D016609:Neoplasms, Second Primary; D009919:Orchiectomy; D011878:Radiotherapy; D012042:Registries; D013223:Statistics as Topic; D013736:Testicular Neoplasms", "nlm_unique_id": "8309333", "other_id": null, "pages": "415-24", "pmc": null, "pmid": "8445415", "pubdate": "1993-03", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Second cancer risk following testicular cancer: a follow-up study of 1,909 patients.", "title_normalized": "second cancer risk following testicular cancer a follow up study of 1 909 patients" }

[ { "companynumb": "NL-PFIZER INC-2016447562", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DACTINOMYCIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TESTIS CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DACTINOMYCIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MECHLORETHAMINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TESTIS CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MECHLORETHAMINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINBLASTINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TESTIS CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINBLASTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TESTIS CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE SULFATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BLEOMYCIN SULFATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TESTIS CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BLEOMYCIN SULFATE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute lymphocytic leukaemia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VAN LEEUWEN, F.. SECOND CANCER RISK FOLLOWING TESTICULAR CANCER: A FOLLOW-UP STUDY OF 1,909 PATIENTS. JOURNAL OF CLINICAL ONCOLOGY. 1993;11 (3):415-424", "literaturereference_normalized": "second cancer risk following testicular cancer a follow up study of 1 909 patients", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20170410", "receivedate": "20161005", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12815248, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" } ]

{ "abstract": "OBJECTIVE\nThis study was aimed at evaluating the frequency and describing the adverse drug-drug interactions (DDIs) recorded among elderly patients accessing the emergency department (ED).\n\n\nMETHODS\nPatients aged ≥65 years, accessing the ED of Pisa University Hospital (Italy) from 1 January 2015 to 31 December 2015 within the ANCESTRAL-ED program, were included in this study. 'Expected' DDIs were assessed using Thomson Micromedex®. Each ED admission (discharge diagnosis) consistent with the signs and symptoms of an expected DDI for each patient was classified as an 'actual' DDI.\n\n\nRESULTS\nThroughout the study period, 3473 patients (3812 ED admissions, 58% females, mean age: 80.3) were recorded. The total number of expected DDIs was 12,578 (67 contraindicated; 3334 major; 8878 moderate; 299 minor) detected in 2147 (62%) patients. Overall 464 expected DDIs were found to be consistent with the ED admission in 194 patients (representing 9% of patients with expected DDIs).\n\n\nCONCLUSIONS\nMore than one half of elderly patients admitted to ED presented at least one expected DDI at the time of ED presentation. However, 9% of the expected DDIs were identified as actual DDIs, based on the consistency of the expected event with the ED discharge diagnosis.", "affiliations": "a Department of Clinical and Experimental Medicine , University of Pisa , Pisa , Italy.;a Department of Clinical and Experimental Medicine , University of Pisa , Pisa , Italy.;b Unit of Adverse Drug Reaction Monitoring , University Hospital of Pisa , Pisa , Italy.;c Geriatric Unit, Department of Clinical and Experimental Medicine , University Hospital of Pisa , Pisa , Italy.;c Geriatric Unit, Department of Clinical and Experimental Medicine , University Hospital of Pisa , Pisa , Italy.;a Department of Clinical and Experimental Medicine , University of Pisa , Pisa , Italy.;a Department of Clinical and Experimental Medicine , University of Pisa , Pisa , Italy.;c Geriatric Unit, Department of Clinical and Experimental Medicine , University Hospital of Pisa , Pisa , Italy.;d Emergency Department , University Hospital of Pisa , Pisa , Italy.;d Emergency Department , University Hospital of Pisa , Pisa , Italy.;c Geriatric Unit, Department of Clinical and Experimental Medicine , University Hospital of Pisa , Pisa , Italy.;a Department of Clinical and Experimental Medicine , University of Pisa , Pisa , Italy.", "authors": "Marino|A|A|;Capogrosso-Sansone|A|A|;Tuccori|M|M|;Bini|G|G|;Calsolaro|V|V|;Mantarro|S|S|;Convertino|I|I|;Pasqualetti|G|G|;Orsitto|E|E|;Santini|M|M|;Monzani|F|F|;Blandizzi|C|C|;|||", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1080/14740338.2016.1221400", "fulltext": null, "fulltext_license": null, "issn_linking": "1474-0338", "issue": "15(sup2)", "journal": "Expert opinion on drug safety", "keywords": "Elderly patients; adverse drug reactions; drug-drug interactions; emergency department", "medline_ta": "Expert Opin Drug Saf", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions; D004636:Emergency Service, Hospital; D005260:Female; D006785:Hospitals, University; D006801:Humans; D007558:Italy; D008297:Male; D011446:Prospective Studies", "nlm_unique_id": "101163027", "other_id": null, "pages": "45-50", "pmc": null, "pmid": "27875918", "pubdate": "2016-12", "publication_types": "D016428:Journal Article", "references": null, "title": "Expected and actual adverse drug-drug interactions in elderly patients accessing the emergency department: data from the ANCESTRAL-ED study.", "title_normalized": "expected and actual adverse drug drug interactions in elderly patients accessing the emergency department data from the ancestral ed study" }

[ { "companynumb": "IT-PFIZER INC-2017213192", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASA" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "011153", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." } ], "patientagegroup": "6", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal ulcer", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MARINO, A.. EXPECTED AND ACTUAL ADVERSE DRUG-DRUG INTERACTIONS IN ELDERLY PATIENTS ACCESSING THE EMERGENCY DEPARTMENT: DATA FROM THE ANCESTRAL-ED STUDY. EXPERT OPINION ON DRUG SAFETY. 2016;15 (S2):45-50", "literaturereference_normalized": "expected and actual adverse drug drug interactions in elderly patients accessing the emergency department data from the ancestral ed study", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20170517", "receivedate": "20170517", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13553666, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170830" }, { "companynumb": "IT-PFIZER INC-2017213195", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "011153", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASA" } ], "patientagegroup": "6", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Gastrointestinal ulcer", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MARINO, A.. EXPECTED AND ACTUAL ADVERSE DRUG-DRUG INTERACTIONS IN ELDERLY PATIENTS ACCESSING THE EMERGENCY DEPARTMENT: DATA FROM THE ANCESTRAL-ED STUDY. EXPERT OPINION ON DRUG SAFETY. 2016;15 (S2):45-50", "literaturereference_normalized": "expected and actual adverse drug drug interactions in elderly patients accessing the emergency department data from the ancestral ed study", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20170517", "receivedate": "20170517", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13553660, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170830" }, { "companynumb": "IT-PFIZER INC-2017213193", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASA" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "011153", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." } ], "patientagegroup": "6", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal ulcer", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MARINO, A.. EXPECTED AND ACTUAL ADVERSE DRUG-DRUG INTERACTIONS IN ELDERLY PATIENTS ACCESSING THE EMERGENCY DEPARTMENT: DATA FROM THE ANCESTRAL-ED STUDY. EXPERT OPINION ON DRUG SAFETY. 2016;15 (S2):45-50", "literaturereference_normalized": "expected and actual adverse drug drug interactions in elderly patients accessing the emergency department data from the ancestral ed study", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20170517", "receivedate": "20170517", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13553665, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170830" }, { "companynumb": "IT-PFIZER INC-2017213194", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "011153", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASA" } ], "patientagegroup": "6", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal ulcer", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MARINO, A.. EXPECTED AND ACTUAL ADVERSE DRUG-DRUG INTERACTIONS IN ELDERLY PATIENTS ACCESSING THE EMERGENCY DEPARTMENT: DATA FROM THE ANCESTRAL-ED STUDY. EXPERT OPINION ON DRUG SAFETY. 2016;15 (S2):45-50", "literaturereference_normalized": "expected and actual adverse drug drug interactions in elderly patients accessing the emergency department data from the ancestral ed study", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20170517", "receivedate": "20170517", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13553663, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170830" }, { "companynumb": "IT-TAKEDA-2017TJP010780", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LANSOPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "020406", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LANSOPRAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": "6", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "International normalised ratio increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MARINO A.. EXPECTED AND ACTUAL ADVERSE DRUG-DRUG INTERACTIONS IN ELDERLY PATIENTS ACCESSING THE EMERGENCY DEPARTMENT: DATA FROM THE ANCESTRAL-ED STUDY. EXPERT OPINION ON DRUG SAFETY. 2016;15 (S2):45-50", "literaturereference_normalized": "expected and actual adverse drug drug interactions in elderly patients accessing the emergency department data from the ancestral ed study", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20170525", "receivedate": "20170524", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13578553, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" } ]

{ "abstract": "OBJECTIVE\nTo investigate the therapeutic efficacy and side effects of treating patients with myelodysplastic syndrome-RAEB (MDS-RAEB) and with refractory acute myeloid leukemia (AML) by using decitabine combined with CAG regimen.\n\n\nMETHODS\nClinical data of 21 patients with MDS-RAEB or refractory AML from July 2011 to July 2014 were analyzed retrospectively. Among 21 patients there were 4 cases of MDS-RAEB and 17 cases of refractory AML; 12 cases were beyond 60 years old; 13 cases had high-risk karyotypes. All the patients received decitabine combined with CAG regimen consisting of decitabine 20 mg/(m(2) · d), d 1-5; aclarubicin 10 mg/d, d 6-13; cytarabine 20 mg/d, d 6-19; G-CSF 300 µg/d, d 6-19.\n\n\nRESULTS\nAfter 1 cycle of treatment with DCAG regimen, the outcome of 21 patients showed that 8 cases achieved complete remission (42.1%), 8 cases achieved partial remission (42.1%), 2 cases achieved hematologic improvement, 1 cases achieved non-remission and 2 cases died; and the 1 year overall survival rate was 67.5%. The outcome of 12 patients beyond 60 years old showed that 6 cases achieved complete renission (60%, 6/10), and the 1 year overall survival rate was 62.5%. The outcome of 13 patients with high-risk karytype showed that 6 cases achieved complete renission (54.5%, 6/11), and the 1 year overall survival rate was 61.5%. The main adverse event was myelosuppression, and non-hematological toxicity included liver dysfunction and gastrointestinal tract reaction.\n\n\nCONCLUSIONS\nDecitabine combined with CAG regimen is effective and safe for treatment of MDS-RAEB and refractory AML patients, which can prolong lives of patiens with refractory hematological diseases.", "affiliations": "Department of Hematology, The First Affiliated Hospital of Chinese PLA General Hospital, Beijing 100048, China.;Department of Hematology, The First Affiliated Hospital of Chinese PLA General Hospital, Beijing 100048, China.;Department of Hematology, The First Affiliated Hospital of Chinese PLA General Hospital, Beijing 100048, China.;Department of Hematology, The First Affiliated Hospital of Chinese PLA General Hospital, Beijing 100048, China.;Department of Hematology, The First Affiliated Hospital of Chinese PLA General Hospital, Beijing 100048, China.;Department of Hematology, The First Affiliated Hospital of Chinese PLA General Hospital, Beijing 100048, China.;Department of Hematology, The First Affiliated Hospital of Chinese PLA General Hospital, Beijing 100048, China.;Department of Hematology, The First Affiliated Hospital of Chinese PLA General Hospital, Beijing 100048, China.;Department of Hematology, The First Affiliated Hospital of Chinese PLA General Hospital, Beijing 100048, China.;Department of Hematology, Chinese PLA General Hospital, Beijing 100853, China.;Department of Hematology, The First Affiliated Hospital of Chinese PLA General Hospital, Beijing 100048, China. E-mail: xiongwuxiao@sohu.com.", "authors": "Yang|Xue-Liang|XL|;Wu|Ya-Mei|YM|;Cao|Yong-Bin|YB|;Li|Xiao-Hong|XH|;Xu|Li-Xin|LX|;Liu|Zhou-Yang|ZY|;Liu|Bei|B|;Yan|Bei|B|;Li|Song-Wei|SW|;DA|Wan-Ming|WM|;Wu|Xiao-Xiong|XX|", "chemical_list": "C011157:aclacinomycins; D003561:Cytarabine; D016179:Granulocyte Colony-Stimulating Factor; D015250:Aclarubicin; D000077209:Decitabine; D001374:Azacitidine", "country": "China", "delete": false, "doi": "10.7534/j.issn.1009-2137.2015.04.030", "fulltext": null, "fulltext_license": null, "issn_linking": "1009-2137", "issue": "23(4)", "journal": "Zhongguo shi yan xue ye xue za zhi", "keywords": null, "medline_ta": "Zhongguo Shi Yan Xue Ye Xue Za Zhi", "mesh_terms": "D015250:Aclarubicin; D000971:Antineoplastic Combined Chemotherapy Protocols; D001374:Azacitidine; D003561:Cytarabine; D000077209:Decitabine; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D059785:Karyotype; D015470:Leukemia, Myeloid, Acute; D009190:Myelodysplastic Syndromes; D010198:Pancytopenia; D012008:Recurrence; D012074:Remission Induction; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome", "nlm_unique_id": "101084424", "other_id": null, "pages": "1056-61", "pmc": null, "pmid": "26314446", "pubdate": "2015-08", "publication_types": "D016428:Journal Article", "references": null, "title": "Clinical Efficacy of Decitabine Combined with CAG Regimen for Myelodysplastic Syndrome-RAEB and Refractory Acute Myeloid Leukemia.", "title_normalized": "clinical efficacy of decitabine combined with cag regimen for myelodysplastic syndrome raeb and refractory acute myeloid leukemia" }

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{ "abstract": "We present a case of drug-induced myocarditis manifesting as acute heart failure in a young patient with bipolar disorder being treated for depression. The case describes a 20-year-old man being treated in the psychiatry ward for worsening depression when he started complaining of chest pain and shortness of breath. His list of medications included clozapine, lithium, lorazepam, and haloperidol. The main findings on physical examination were tachycardia, low-grade fever, crackles in both lung bases on auscultation, and the absence of any notable edema. Abnormal labs included a troponin of 0.9, with a CK of 245 and CK-MB of 3.1. An ECG revealed sinus tachycardia and left anterior fascicular block (LAFB). An echocardiogram revealed global hypokinesis, severe left ventricular dysfunction with an ejection fraction estimated at 20%. The patient had an admitting diagnosis of acute left ventricular systolic dysfunction likely secondary to drug-induced myocarditis (suspect clozapine) versus acute coronary syndrome. He was managed conservatively and transferred to another facility for endomyocardial biopsy confirming myocarditis. This case is an example of one of the most typical presentations of suspected drug-induced acute myocarditis and will hopefully prompt the reader to think of this underdiagnosed entity in the right clinical setting.", "affiliations": "Chief of Cardiology, Woodhull Medical Center, 760 Broadway, Brooklyn, NY 11206, USA.;Pharmacy Department, Woodhull Medical Center, 760 Broadway, Brooklyn, NY 11206, USA.;Department of Medicine, Woodhull Medical Center, 760 Broadway, Brooklyn, NY 11206, USA.;Division of Cardiology, Woodhull Medical Center, 760 Broadway, Brooklyn, NY 11206, USA.;Department of Medicine, Woodhull Medical Center, 760 Broadway, Brooklyn, NY 11206, USA.;Department of Internal Medicine, Yale-New Haven Hospital, 20 York Street, New Haven, CT 06510, USA.;Woodhull Medical Center, 760 Broadway, Brooklyn, NY 11206, USA.", "authors": "Cohen|Ronny|R|;Lysenko|Alla|A|;Mallet|Thierry|T|;Mirrer|Brooks|B|;Gale|Michael|M|;Loarte|Pablo|P|;McCue|Robert|R|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1155/2015/283156", "fulltext": "\n==== Front\nCase Rep CardiolCase Rep CardiolCRICCase Reports in Cardiology2090-64042090-6412Hindawi Publishing Corporation 10.1155/2015/283156Case ReportA Case of Clozapine-Induced Myocarditis in a Young Patient with Bipolar Disorder Cohen Ronny \n1\n\n*\nLysenko Alla \n2\nMallet Thierry \n3\nMirrer Brooks \n4\nGale Michael \n3\nLoarte Pablo \n5\nMcCue Robert \n6\n1Chief of Cardiology, Woodhull Medical Center, 760 Broadway, Brooklyn, NY 11206, USA2Pharmacy Department, Woodhull Medical Center, 760 Broadway, Brooklyn, NY 11206, USA3Department of Medicine, Woodhull Medical Center, 760 Broadway, Brooklyn, NY 11206, USA4Division of Cardiology, Woodhull Medical Center, 760 Broadway, Brooklyn, NY 11206, USA5Department of Internal Medicine, Yale-New Haven Hospital, 20 York Street, New Haven, CT 06510, USA6Woodhull Medical Center, 760 Broadway, Brooklyn, NY 11206, USA*Ronny Cohen: ronny.cohen@nychhc.orgAcademic Editor: Konstantinos P. Letsas\n\n2015 30 8 2015 2015 2831565 5 2015 31 7 2015 17 8 2015 Copyright © 2015 Ronny Cohen et al.2015This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.We present a case of drug-induced myocarditis manifesting as acute heart failure in a young patient with bipolar disorder being treated for depression. The case describes a 20-year-old man being treated in the psychiatry ward for worsening depression when he started complaining of chest pain and shortness of breath. His list of medications included clozapine, lithium, lorazepam, and haloperidol. The main findings on physical examination were tachycardia, low-grade fever, crackles in both lung bases on auscultation, and the absence of any notable edema. Abnormal labs included a troponin of 0.9, with a CK of 245 and CK-MB of 3.1. An ECG revealed sinus tachycardia and left anterior fascicular block (LAFB). An echocardiogram revealed global hypokinesis, severe left ventricular dysfunction with an ejection fraction estimated at 20%. The patient had an admitting diagnosis of acute left ventricular systolic dysfunction likely secondary to drug-induced myocarditis (suspect clozapine) versus acute coronary syndrome. He was managed conservatively and transferred to another facility for endomyocardial biopsy confirming myocarditis. This case is an example of one of the most typical presentations of suspected drug-induced acute myocarditis and will hopefully prompt the reader to think of this underdiagnosed entity in the right clinical setting.\n==== Body\n1. Introduction\nMyocarditis is an inflammatory disease of the myocardium that may lead to serious complications. The condition presents with a wide range of symptoms, some of which are remarkably nonspecific [1], while others point in the direction of myocyte injury. One of the more typical presentations of myocarditis is acute heart failure related to nonischemic severe systolic dysfunction in patients between 20 and 50 years old, with progression to dilated cardiomyopathy. The symptomatology is highly dependent on the causality and severity of the inflammation. The most common etiology is viral; others include bacterial, fungal, drug-induced, and hypereosinophilic syndrome [2]. In general, patients with fulminant myocarditis tend to be sicker but also recuperate more quickly with a good prognosis. However, patients with the chronic form of myocarditis can slowly develop their symptoms within weeks or months but will tend to develop a lingering disease requiring prolonged treatment and sometimes leading to end-stage CHF dilated cardiomyopathy requiring cardiac transplantation [3].\n\n2. Case Presentation\nA 20-year-old Hispanic male with past medical history significant for obesity (Body Mass Index 34), abnormal LFTs, and bipolar disorder was admitted to the psychiatric ward for worsening depression likely related to noncompliance. His home medications included benztropine, lithium, zolpidem, and chlorpromazine. On admission, the patient had a trial of aripiprazole and haloperidol without any significant improvement. Because of the patient's deteriorating psychiatric condition and the ineffectiveness of the previous antipsychotics, the decision was made to start the patient on clozapine 25 mg daily. The clozapine dosage was progressively titrated up over two weeks to a total daily dosage of 250 mg. On day 14 following the initiation of clozapine, the patient complained of chest pain. He described the chest pain as sharp, aching in nature, located in the center of his chest, and nonradiating, with an intensity of 7/10 on the pain scale. The chest pain was exacerbated with deep inspiration and lying supine. The patient also had mild shortness of breath, nausea, vomiting, dizziness, headache, palpitations, and nonproductive cough. The pain was not alleviated by any measures. The patient was transferred to the telemetry unit for close monitoring.\n\nVital signs were blood pressure of 103/61 mm Hg, heart rate of 100 bpm, respiratory rate of 19, and body temperature of 97.2 F with later maximal temperature of 101.8 F. Physical examination was unremarkable for icterus or redness or swelling in the oropharynx; the neck was supple; there was no JVD; auscultation of the heart revealed the presence of normal S1 and S2, with no additional heart sounds or murmurs; lungs were clear to auscultation bilaterally; the abdomen was soft, nontender, and nondistended; there was no edema of the extremities; and no rash was noted.\n\nLaboratory evaluation revealed a BNP of 121 pg/mL (normal < 100 pg/mL); initial troponin was 0.949 [nl] with peak of 0.976 and troponin of 0.333 was noted more than 24 hours later. Total CK was 245 and CK-MB was 3.1, [nl]. Cardio-CRP of 58.2, [nl], was suggestive of infection or inflammation. Basic chemistries were normal; CBC was unremarkable except for a slightly elevated eosinophil count. Urine drug screen and hepatitides B and C were all negative. Blood cultures showed no growth. Ferritin, ceruloplasmin, and alpha-1-antitrypsin were all normal. The electrocardiogram (Figure 1) showed sinus tachycardia, left axis deviation with left anterior fascicular block, and QTC prolongation (486 ms).\n\nTransthoracic echocardiogram revealed four-chamber dilatation, biventricular failure, left ventricular apical akinesis, global hypokinesis, concentric LV hypertrophy, severely depressed LV systolic function with an ejection fraction of 20%, mild mitral and tricuspid regurgitation, and estimated pulmonary artery systolic pressure of 35 mm Hg.\n\nAs Acute Coronary Syndrome was a less likely possibility, the diagnosis of myocarditis presenting as nonischemic dilated cardiomyopathy was strongly considered. Clozapine was held due to this high suspicion and its association with drug-induced myocarditis. The patient was managed with furosemide, ramipril, and carvedilol; the doses of the medications were adjusted based on the patient's clinical response. Nonsteroidal anti-inflammatory drugs and acetaminophen were not given due to the history of abnormal liver function tests and given the acute phase of myocarditis with risk of possible viral agent propagation. Slight clinical improvement was observed, and the patient was ultimately transferred to another facility for endomyocardial biopsy confirming the diagnosis of myocarditis. He eventually did well with supportive treatment and was discharged home.\n\n3. Discussion\n3.1. Definition and Clinical Features\nMyocarditis is an inflammatory disease of the myocardium. The initial criteria for the definition of myocarditis were based on the standard Dallas pathological criteria and required an inflammatory cellular infiltrate with or without associated myocyte necrosis to be present on conventionally stained heart tissue sections [4]. However, because of limitations in the interpretation and prognostic value, new criteria that rely on cell-specific immunoperoxidase stains for surface antigens, such as anti-CD3, anti-CD4, anti-CD20, anti-CD8, and anti-HLA, were developed [5]. Both criteria may be used for the diagnosis.\n\nAcute myocarditis is frequently first diagnosed as nonischemic cardiomyopathy. Clinical manifestations are variable and can range from subclinical disease to sudden death [3]. Although a viral prodrome with fever, myalgia, and respiratory or gastrointestinal symptoms is classically associated with myocarditis, reported symptoms are highly variable [2, 3]. Cardiac symptoms are also variable and may include fatigue, decreased exercise tolerance, palpitations, precordial chest pain, syncope, dyspnea, and arrhythmias [3]. There seems to be a slight preponderance in male patients, which may be due to a protective effect of natural hormone variations on immune responses in women [3, 6].\n\nTwo main clinicopathological forms of acute myocarditis are generally described: fulminant lymphocytic myocarditis and acute lymphocytic myocarditis. The fulminant lymphocytic myocarditis has a distinct onset with a viral prodrome within two weeks before the onset of symptoms and hemodynamic compromise, but with generally a good prognosis. The acute lymphocytic myocarditis frequently does not have a distinct onset or hemodynamic compromise but more frequently results in death or the need for cardiac transplantation [3]. However, both forms of myocarditis are rare and prognostic data are only limited to relatively few patients.\n\nAdditionally, two chronic clinicopathological forms of myocarditis are recognized: chronic active myocarditis occurs with frequent clinical and histologic relapses, with ventricular systolic dysfunction associated with fibrosis and chronic inflammation on biopsy. The second one is chronic persistent myocarditis with biopsy showing persistent inflammatory infiltrate and small foci myonecrosis, with concomitant symptoms of chest pain or palpitation, despite normal and stable ventricular systolic function.\n\n3.2. Causative Agents/Clozapine as a Cause of Myocarditis\nViruses remain the major causes of myocarditis. Historically, outbreaks of myocarditis have been linked to Coxsackievirus B from the 1950s through the 1990s and then to adenovirus in the late 1990s and more recently to parvovirus B19 [3, 7]. Other viruses, like hepatitis C, EBV, CMV, HHV-6, and HIV, have also been incriminated [3]. In addition to viruses, other infections, such as Borrelia burgdorferi and Trypanosoma cruzi, should also be considered. Drug-induced hypersensitivity reactions and systemic hypereosinophilic syndromes can also cause myocarditis. Among medications, anticonvulsants, antibiotics, and antipsychotics, as with clozapine, are the main culprits [3].\n\nMyocarditis is one of the most publicized cardiac complications of clozapine treatment. Clozapine is a second-generation antipsychotic agent that has been shown to be effective in patients with schizophrenia and other psychotic disorders who have not responded adequately to other antipsychotic agents [8]. According to clinical research, clozapine is more effective than other antipsychotics and is associated with a significant decrease in suicidality in the treated patients [9–11]. Despite its efficacy, the general use of clozapine in clinical practice is limited because of the risk of several serious adverse effects such as agranulocytosis, neutropenia, and, rarely, cardiomyopathy.\n\nClozapine is the only antipsychotic known to cause myocarditis. Case series on clozapine-induced myocarditis by Kilian et al. [12] provided strong evidence that association was causal with the substantial incidence of 1 in 500 in the first month of clozapine use. More evidence came from subsequent publications by Coulter et al. [13], where the incidence was more than 2% of patients starting clozapine. Another study by Hägg et al. suggests that, in more than 85% of the cases, it typically occurs within the first 2 months and up to 75% within 3 weeks of treatment [14]. Nevertheless, infrequently, the symptoms of clozapine-induced myocarditis may develop more than two years into the treatment [15].\n\n3.3. Pathogenesis\nAlthough data is scarce on the pathophysiology of clozapine-induced myocarditis, there are a few proposed mechanisms. One hypothesis states that clozapine-induced myocarditis likely results from a type I Ig E-mediated acute hypersensitivity reaction. The time of onset of clozapine-induced myocarditis and peripheral eosinophilia along with eosinophilic myocardial infiltrates frequently observed in the course of disease all support this hypothesis [12, 16]. This has been seen in the observations of peripheral eosinophilia and eosinophilic inclusions within endomyocardial biopsy samples of affected patients, but findings are inconsistent. Other possible mechanisms of clozapine-induced myocarditis involve clozapine-induced cytokine release and hypercatecholaminemia [17]. When in vivo, it was noted that clozapine leads to release of tumor necrosis factor alpha and various interleukins. These proinflammatory cytokines have been found to mediate autoimmune myocarditis and may act similarly in clozapine-induced myocarditis [18]. Clozapine is known to increase serum catecholamine levels; cocaine has a similar effect and has been shown to exacerbate viral myocarditis, suggesting a role for catecholamines in the development of the disorder [19]. Elevated levels of norepinephrine have also been linked to the therapeutic efficacy of clozapine [12, 16]. It has been noted that patients treated with clozapine had higher noradrenaline levels than patients treated with other antipsychotics [17].\n\n3.4. Diagnosis\nA few diagnostic studies might guide us in making the diagnosis of myocarditis. Biomarkers of cardiac injury are elevated in a minority of patients with acute myocarditis but may help confirm the diagnosis [3]. Experimental data suggest that increased levels of troponin I are more common than increased levels of creatine kinase MB in acute myocarditis [20].\n\nThe electrocardiogram (EKG) may show sinus tachycardia with nonspecific ST-segment and T-wave abnormalities. Occasionally, the EKG changes might be suggestive of either an acute MI or pericarditis, with ST-segment elevation, ST-segment depression, or pathologic Q waves [3].\n\nEchocardiography is useful primarily to rule out other causes of heart failure, since there are no specific features of acute myocarditis. Various echocardiographic patterns have been described. Wall motion abnormalities can simulate MI, but the loss of right ventricular function was the most powerful predictor of death or the need for cardiac transplantation in patients with biopsy-proven myocarditis [3, 21].\n\nCardiac MRI is being used with increasing frequency to evaluate suspected acute myocarditis, notably to localize suitable sites for an eventual endomyocardial biopsy [3, 22]. The latter should be performed in patients with unexplained, new-onset heart failure of less than two weeks' duration in association with a normal-size or dilated left ventricle and hemodynamic compromise for suspected fulminant myocarditis. Endomyocardial biopsy should also be performed if heart failure is associated with arrhythmias, high degree heart block, or failure to respond to usual care within one to two weeks [3]. It is preferable that those biopsies are performed in specialized centers with sufficient expertise in their interpretation.\n\n3.5. Treatment\nPatients presenting with myocarditis and acute dilated cardiomyopathy should be managed according to the latest 2013 Heart Failure Practice Guidelines of the American College of Cardiology, American Heart Association [23]. Most patients will improve with a standard heart failure regimen that includes ACE inhibitors or ARBs, beta blockers, and diuretics. For patients who fail to improve with optimal medical management, a role for mechanical circulatory support, such as Ventricular Assist Device, has been suggested as a bridge to transplantation or recovery [24]. Patients recovering from acute myocarditis should refrain from aerobic activity for a period of months, depending on the severity of left ventricular dysfunction and the extent of recovery. The use of NSAIDs was associated with increased mortality [3]. If a medication is thought to be the likely culprit, like clozapine in our case, it should be discontinued.\n\nIn patients with acute myocarditis, therapy for arrhythmias is supportive, since such arrhythmias usually resolve after the acute phase of the disease. Temporary pacemakers may be required for patients with symptomatic bradycardia or complete heart block [3].\n\nThe finding of viral genomes on endomyocardial biopsy has been used to guide treatment. However, because most patients with acute myocarditis are diagnosed weeks after viral infection, it is unlikely that antiviral therapy would be provided early enough to be of benefit in acute viral myocarditis. In contrast, interferon beta has been used successfully in patients with viral persistence in chronic, stable dilated cardiomyopathy, with viral clearance being achieved in all patients and with significant increase in the left ventricular function [3, 25]. Studies done to evaluate the effect of immunosuppression with Intravenous Immune Globulin (IVIG) did not reach similar conclusions, and therefore the use of IVIG is not recommended [26]. More investigations are being done to evaluate if changes in immune regulation might be beneficial, particularly in patients with more chronic cardiomyopathy.\n\n4. Conclusion\nOur case presentation represents, most likely, drug-induced myocarditis with clozapine as the likely culprit. The clinical manifestations leading to the diagnosis were mainly chest pain and shortness of breath, but also confounding nonspecific symptoms. Diagnostic findings were suggestive of an inflammatory process affecting the myocardium, with elevated cardiac biomarkers, elevated CRP, sinus tachycardia, and dilated cardiomyopathy. Clozapine was discontinued and the patient was appropriately treated with ACE inhibitors, beta blockers, and diuretics, which resulted in clinical improvement. The patient was transferred to a specialized center where he had an endomyocardial biopsy, which confirmed the diagnosis of myocarditis. The roles of cardiac MRI and endomyocardial biopsy in the diagnosis were reviewed. New diagnostic modalities are being sought to try to reduce the role of endomyocardial biopsy, as it is an invasive measure. Most of the treatment is supportive, but new therapeutic modalities, particularly in terms of antiviral and immunomodulatory therapies, are being investigated.\n\nDisclosure\nThis is an original paper of original research and discussion presented for review and possible publication for advancement of medical education. It has not been submitted to any other journal.\n\nConflict of Interests\nThere are no financial interests tied to this original research, neither is there any other side support. The authors listed have no conflict of interests.\n\nAuthors' Contribution\nThe authors listed originally prepared all materials. The authors listed have contributed to, read, and approved the paper.\n\nFigure 1 ECG sinus tachycardia. Left axis deviation late precordial lead transition.\n==== Refs\n1 Pastor C. A. Mehta M. Masked clozapine-induced cardiomyopathy Journal of the American Board of Family Medicine 2008 21 1 70 74 10.3122/jabfm.2008.01.070091 2-s2.0-38549145941 18178706 \n2 Magnani J. W. Dec G. W. Myocarditis: current trends in diagnosis and treatment Circulation 2006 113 6 876 890 10.1161/circulationaha.105.584532 2-s2.0-33644850082 16476862 \n3 Cooper L. T. Jr. Myocarditis The New England Journal of Medicine 2009 360 15 1526 1538 10.1056/nejmra0800028 19357408 \n4 Aretz H. T. Billingham M. E. Edwards W. D. Myocarditis. a histopathologic definition and classification The American Journal of Cardiovascular Pathology 1987 1 1 3 14 2-s2.0-0023069681 3455232 \n5 Maisch B. Portig I. Ristic A. Hufnagel G. Pankuweit S. Definition of inflammatory cardiomyopathy (myocarditis): on the way to consensus: a status report Herz 2000 25 3 200 209 10.1007/s000590050007 2-s2.0-0033931349 10904839 \n6 Schwartz J. Sartini D. Huber S. Myocarditis susceptibility in female mice depends upon ovarian cycle phase at infection Virology 2004 330 1 16 23 10.1016/j.virol.2004.06.051 2-s2.0-7444233126 15527830 \n7 Kühl U. Pauschinger M. Noutsias M. High prevalence of viral genomes and multiple viral infections in the myocardium of adults with ‘idiopathic’ left ventricular dysfunction Circulation 2005 111 7 887 893 10.1161/01.cir.0000155616.07901.35 2-s2.0-14044279226 15699250 \n8 McEvoy J. P. Lieberman J. A. Stroup T. S. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment American Journal of Psychiatry 2006 163 4 600 610 10.1176/appi.ajp.163.4.600 2-s2.0-33646839961 16585434 \n9 Lewis S. W. Barnes T. R. E. Davies L. Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia Schizophrenia Bulletin 2006 32 4 715 723 10.1093/schbul/sbj067 2-s2.0-33748768220 16540702 \n10 Walker A. M. Lee Lanza L. Arellano F. Rothman K. Mortality in current and former users of clozapine Epidemiology 1997 8 6 671 677 10.1097/00001648-199710000-00010 2-s2.0-0030778896 9345668 \n11 Green A. Burgees E. Dawson R. Zimmet S. V. Strous R. D. Alcohol and cannabis use in schizophrenia: effects of clozapine vs. risperidone Schizophrenia Research 2003 60 1 81 85 12505141 \n12 Kilian J. G. Kerr K. Lawrence C. Celermajer D. S. Myocarditis and cardiomyopathy associated with clozapine The Lancet 1999 354 9193 1841 1845 10.1016/s0140-6736(99)10385-4 2-s2.0-0033610722 \n13 Coulter D. M. Bate A. Meyboom R. H. B. Lindquist M. Edwards I. R. Antipsychotic drugs and heart muscle disorder in international pharmacovigilance: data mining study British Medical Journal 2001 322 7296 1207 1209 10.1136/bmj.322.7296.1207 2-s2.0-0035912544 11358771 \n14 Hägg S. Spigset O. Bahons A. B. Söderström T. G. Myocarditis related to clozapine treatment Journal of Clinical Psychopharmacology 2001 21 4 382 388 10.1097/00004714-200108000-00005 2-s2.0-0034919108 11476122 \n15 Haas S. J. Hill R. Krum H. Clozapine-associated myocarditis: a review of 116 cases of suspected myocarditis associated with the use of clozapine in Australia during 1993–2003 Drug Safety 2007 30 1 47 57 10.2165/00002018-200730010-00005 2-s2.0-33846074353 17194170 \n16 Merrill D. B. Ahmari S. E. Bradford J.-M. E. Lieberman J. A. Myocarditis during clozapine treatment The American Journal of Psychiatry 2006 163 2 204 208 10.1176/appi.ajp.163.2.204 2-s2.0-33645000404 16449471 \n17 Elman I. Goldstein D. S. Eisenhofer G. Mechanism of peripheral noradrenergic stimulation by clozapine Neuropsychopharmacology 1999 20 1 29 34 10.1016/S0893-133X(98)00047-5 2-s2.0-0032943627 9885782 \n18 Burian J. Buser P. Eriksson U. Myocarditis: the immunologist's view on pathogenesis and treatment Swiss Medical Weekly 2005 135 25-26 359 364 2-s2.0-23344442150 16106325 \n19 Wang J.-F. Zhang J. Min J.-Y. Cocaine enhances myocarditis induced by encephalomyocarditis virus in murine model The American Journal of Physiology—Heart and Circulatory Physiology 2002 282 3 H956 H963 10.1152/ajpheart.00648.2001 2-s2.0-0036085085 11834492 \n20 Lauer B. Niederau C. Kühl U. Cardiac troponin T in patients with clinically suspected myocarditis Journal of the American College of Cardiology 1997 30 5 1354 1359 10.1016/S0735-1097(97)00317-3 2-s2.0-0030771670 9350939 \n21 Mendes L. A. Dec G. W. Picard M. H. Palacios I. F. Newell J. Davidoff R. Right ventricular dysfunction: an independent predictor of adverse outcome in patients with myocarditis American Heart Journal 1994 128 2 301 307 10.1016/0002-8703(94)90483-9 2-s2.0-0028124478 8037097 \n22 Laissy J.-P. Messin B. Varenne O. MRI of acute myocarditis: a comprehensive approach based on various imaging sequences Chest 2002 122 5 1638 1648 10.1378/chest.122.5.1638 2-s2.0-0036435873 12426265 \n23 2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Circulation 2013 127 23 e663 e828 10.1161/cir.0b013e31828478ac 23630129 \n24 Topkara V. K. Dang N. C. Barili F. Ventricular assist device use for the treatment of acute viral myocarditis Journal of Thoracic and Cardiovascular Surgery 2006 131 5 1190 1191 10.1016/j.jtcvs.2005.08.073 2-s2.0-33646180830 16678619 \n25 Kühl U. Pauschinger M. Schwimmbeck P. L. Interferon-β treatment eliminates cardiotropic viruses and improves left ventricular function in patients with myocardial persistence of viral genomes and left ventricular dysfunction Circulation 2003 107 22 2793 2798 10.1161/01.cir.0000072766.67150.51 2-s2.0-0038120010 12771005 \n26 McNamara D. M. Holubkov R. Starling R. C. Controlled trial of intravenous immune globulin in recent-onset dilated cardiomyopathy Circulation 2001 103 18 2254 2259 10.1161/01.CIR.103.18.2254 2-s2.0-0006518635 11342473\n\n", "fulltext_license": "CC BY", "issn_linking": "2090-6404", "issue": "2015()", "journal": "Case reports in cardiology", "keywords": null, "medline_ta": "Case Rep Cardiol", "mesh_terms": null, "nlm_unique_id": "101576452", "other_id": null, "pages": "283156", "pmc": null, "pmid": "26413355", "pubdate": "2015", "publication_types": "D016428:Journal Article", "references": "18178706;9350939;16106325;11342473;15527830;17194170;15699250;16540702;9885782;3455232;12426265;19357408;12771005;9345668;16449471;23630129;10584719;12505141;10904839;11834492;11358771;16585434;16476862;8037097;11476122;16678619", "title": "A Case of Clozapine-Induced Myocarditis in a Young Patient with Bipolar Disorder.", "title_normalized": "a case of clozapine induced myocarditis in a young patient with bipolar disorder" }

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{ "abstract": "Von Willebrand disease (VWD) is a bleeding disorder caused by qualitative or quantitative defects of von Willebrand factor (VWF). This case report of a patient with systemic sclerosis and gastrointestinal bleeding from angiodysplasias seeks to address the key clinical question of a useful diagnostic and therapeutic approach in this setting. The extent of vascular malformations and the frequency of bleeding episodes were unusually severe, and we reached a diagnosis of inherited type 2A VWD. After an insufficient effect of treatment with factor VIII (FVIII)/VWF, prophylactic administration of vonicog alfa, a recombinant VWF preparation without FVIII, was initiated. This therapy led to a substantial reduction of transfusion requirements and the improvement of angiodysplasias. In refractory gastrointestinal bleeding, hemostaseological evaluation is crucial, as inherited disorders of hemostasis may go unnoticed, especially in patients with underlying autoimmune diseases, where complications may be ascribed to the underlying disease.", "affiliations": "Department of Nephrology and Rheumatology University Medical Center Göttingen Göttingen Germany.;Department of Nephrology and Rheumatology University Medical Center Göttingen Göttingen Germany.;Department of Hematology and Medical Oncology University Medical Center Göttingen Göttingen Germany.", "authors": "Korsten|Peter|P|https://orcid.org/0000-0001-6065-5680;Wallbach|Manuel|M|;Binder|Claudia|C|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1002/rth2.12426", "fulltext": "\n==== Front\nRes Pract Thromb Haemost\nRes Pract Thromb Haemost\n10.1002/(ISSN)2475-0379\nRTH2\nResearch and Practice in Thrombosis and Haemostasis\n2475-0379 John Wiley and Sons Inc. Hoboken \n\n10.1002/rth2.12426\nRTH212426\nCase Report\nCase Report\nType 2A von Willebrand disease and systemic sclerosis: Vonicog alfa reduced gastrointestinal bleeding\nKORSTEN et al.Korsten Peter MDhttps://orcid.org/0000-0001-6065-5680\n1\npeter.korsten@med.uni-goettingen.de@pekor002 Wallbach Manuel MD\n1\n Binder Claudia MD\n2\n \n1 \nDepartment of Nephrology and Rheumatology\nUniversity Medical Center Göttingen\nGöttingen\nGermany\n\n\n2 \nDepartment of Hematology and Medical Oncology\nUniversity Medical Center Göttingen\nGöttingen\nGermany\n\n* Correspondence\n\nPeter Korsten, Department of Nephrology and Rheumatology, University Medical Center Göttingen, Robert‐Koch‐Str. 40, D‐37075 Göttingen, Germany.\n\nEmail: peter.korsten@med.uni-goettingen.de\n\n10 9 2020 \n10 2020 \n4 7 10.1002/rth2.v4.71230 1234\n27 7 2020 11 8 2020 12 8 2020 © 2020 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH)This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Abstract\nVon Willebrand disease (VWD) is a bleeding disorder caused by qualitative or quantitative defects of von Willebrand factor (VWF). This case report of a patient with systemic sclerosis and gastrointestinal bleeding from angiodysplasias seeks to address the key clinical question of a useful diagnostic and therapeutic approach in this setting. The extent of vascular malformations and the frequency of bleeding episodes were unusually severe, and we reached a diagnosis of inherited type 2A VWD. After an insufficient effect of treatment with factor VIII (FVIII)/VWF, prophylactic administration of vonicog alfa, a recombinant VWF preparation without FVIII, was initiated. This therapy led to a substantial reduction of transfusion requirements and the improvement of angiodysplasias. In refractory gastrointestinal bleeding, hemostaseological evaluation is crucial, as inherited disorders of hemostasis may go unnoticed, especially in patients with underlying autoimmune diseases, where complications may be ascribed to the underlying disease.\n\nangiodysplasiasAutoimmune Diseasessclerodermasystemicvascular malformationsvon Willebrand diseases source-schema-version-number2.0cover-dateOctober 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.3 mode:remove_FC converted:27.10.2020\n\n\nKorsten \nP \n, \nWallbach \nM \n, \nBinder \nC \n. Type 2A von Willebrand disease and systemic sclerosis: Vonicog alfa reduced gastrointestinal bleeding\n. Res Pract Thromb Haemost . 2020 ;4 :1230 –1234\n. 10.1002/rth2.12426 \n\n\n\nPeter Korsten and Manuel Wallbach equal contribution of both authors.\n\nHandling Editor: Pantep Angchaisuksiri.\n\n\nFunding information\n\n\nThe authors have not declared a specific grant for this research from any funding agency in public, commercial, or not‐for‐profit sectors.\n==== Body\nEssentials\n\nAngiodysplasias are a common source of refractory gastrointestinal bleeding.\n\nWe report a case of a patient with inherited von Willebrand disease and systemic sclerosis.\n\nA hemostaseological evaluation is crucial in the setting of refractory bleeding.\n\nVonicog alfa was used as prophylactic therapy and led to a reduction of angiodysplasias.\n\n\n\n\n\n\n\n1 INTRODUCTION\nVon Willebrand disease (VWD) is an inherited platelet‐derived bleeding disorder caused by quantitative or qualitative defects of the von Willebrand factor (VWF).\n1\n Primary and secondary (acquired) forms of VWD exist.\n1\n The latter can be associated with various underlying conditions, such as autoimmune diseases, where VWF function is impaired by binding to autoantibodies.\n2\n Apart from its role in primary hemostasis, VWF participates in the regulation of angiogenesis. Its lack induces gastrointestinal vascular malformations in a subset of patients with VWD leading to recurrent and often therapy‐resistant gastrointestinal bleeding.\n\nSystemic sclerosis (SSc) is a rare autoimmune disease and mainly manifests as either diffuse or limited type.\n3\n Limited SSc (lcSSc) is characterized by the presence of anticentromere antibodies and a higher prevalence of vascular sequelae, such as pulmonary arterial hypertension, compared to the diffuse form.\n3\n Gastrointestinal involvement in SSc is frequent in both subtypes and most often manifests as gastroesophageal reflux disease, small intestinal bacterial overgrowth, diarrhea, or constipation.\n4\n More severe disease can lead to malnutrition, intestinal pseudo‐obstruction, or significant weight loss, and is associated with increased mortality.\n5\n\n\n\nVascular abnormalities are less commonly reported: Telangiectasias are frequently localized in the skin of patients with lcSSc; however, some patients develop disseminated angiodysplasias throughout the gastrointestinal tract with subsequent life‐threatening bleeding.\n6\n Gastrointestinal angiodysplasias are found in ~1%‐5% of all patients undergoing endoscopic studies and are frequently located in the small bowel.\n7\n They account for ~10% of all gastrointestinal bleedings and ~50% of all small bowel gastrointestinal bleeding episodes.\n7\n\n\n\nWith this case report, we seek to address the key clinical question of the appropriate diagnostic testing and subsequent management of severe gastrointestinal bleeding in the setting of a known underlying autoimmune condition.\n\n2 CASE REPORT\nA 54‐year‐old female patient with a history of lcSSc since 2001 was hospitalized at our center. Throughout the disease course, she developed severe Raynaud phenomenon (RP), pulmonary arterial hypertension (PAH), and autoamputation of several fingertips secondary to calcinosis and digital ulcers with finger necrosis and tissue loss (Figure 1A). Her past medical history was significant for a smoking history of 25 pack‐years and hypothyroidism. She had been treated with various immunosuppressive treatments for her skin manifestation and deforming arthritis. Her current treatment included intravenous rituximab 500 mg every 3 months with a notable improvement in her skin disease, which was paused because of frequent hospitalizations and anemia. She had received the last of rituximab 3 months before the current admission. Her disease had most notably been complicated by recurrent and severe gastrointestinal bleeding secondary to gastric, small and large intestinal angiodysplasias, eventually leading to the persistent need for blood transfusions with frequent hospitalizations and endoscopic interventions over the past months before the current admission to our center.\n\nFigure 1 (A) Clinical images of the patient with severe deforming arthritis and autoamputation of several digits. (B) Endoscopy studies of the stomach before (left) and 5 months after the initiation of vonicog alfa treatment (right) with significant improvement of angiodysplasias. (C) The course of the hematocrit levels over time in relation to treatment. Treatment with plasma‐derived FVIII/VWF led to improved bleeding control and reduced the number of RBC transfusions. A significant improvement of bleeding ensued after initiation of treatment with Vonicog alfa. FVIII, factor VIII; VWF, von Willebrand factor\n\nImmediately before being transferred to our center, she had been admitted to another hospital for severe gastrointestinal bleeding. At that hospital, a minimum hemoglobin level of 5.8 g/dL had been detected, and a computed tomography angiography was performed without an identifiable bleeding source. She received eight red blood cell (RBC) transfusions and 2 units of fresh‐frozen plasma. On admission, we measured a hemoglobin level of 7.0 g/dL (normal range, 11.5‐15.0 g/dL), and she was transferred to the intensive care unit because of daily RBC transfusion requirements, impending hemodynamic instability and persistent gastrointestinal bleeding despite normal platelet counts and routine tests of coagulation (partial thrombin time and international normalized ratio). An endoscopic intervention with argon plasma coagulation of gastric and colonic angiodysplasias was again performed but did not lead to lasting improvement. Additional laboratory investigations confirmed the presence of antinuclear antibodies and anticentromere antibodies, as described previously. Because the current bleeding episode was life threatening and refractory to supportive and endoscopic treatments, a multidisciplinary approach between critical care, rheumatology, and hematology ensued.\n\nIt was deemed unlikely that the severity of bleeding from angiodysplasias could be ascribed to the underlying autoimmune disease alone, and further hemostaseological workup was performed. At this point, the differential diagnoses favored acquired forms of VWD, which are rare but have been reported in autoimmune diseases. We measured factor VIII (FVIII) activity, VWF antigen, ristocetin cofactor (ACL TOP Analyzer, Instrumentation Lab., Werfen, Vienna, Austria), in‐vitro bleeding time (Innovance PFA 200 System, Siemens Healthcare GmbH, Erlangen, Germany), and platelet aggregometry (APACT 4004, LabiTec GmbH, Ahrensburg, Germany). Additionally, collagen‐binding activity and multimer analysis were performed (Prof. Budde, MediLys, Hamburg, Germany). Based on the results given in Table 1 and the detected loss of large VWF multimers and the absence of platelet aggregation under low doses of ristocetin, we reached a diagnosis of type 2A VWD according to the current classification.\n8\n, \n9\n Subsequent further history taking and investigations revealed the same disease in the patient’s older brother, who reported frequent epistaxis and prolonged bleeding after minor trauma. The condition was likely inherited in an autosomal‐dominant trait by the patient’s mother, who had reportedly suffered heavy, and at times, life‐threatening menstrual bleeding. She was deceased at the time, which precluded further analyses. Another sister of the patient reported no history of bleeding. Overall, the family history confirmed the diagnosis of inherited VWD (Figure 2).\n\nTable 1 Results of coagulation studies\n\nAssay\tBefore vonicog alfa treatment\tDuring vonicog alfa treament\tNormal range\t\nFVIII:C activity\t88%\t101%\t70%‐170%\t\nVWF antigen\t103%\t176%\t66%‐176%\t\nRistocetin cofactor\t\n28%\n\t109%\t61%‐239%\t\nRatio\t\n0.27\n\t\t>0.6\t\nCollagen binding activity\t\n4.3%\n\t\t50%‐250%\t\nPFA 200 COL/EPI\t\n>300 s\n\t\t85‐165 s\t\nPFA 200 COL/ADP\t\n160 s\n\t\t71‐118 s\t\n\nAbbreviations: ADP, adenosine diphosphate; COL, collagen; EPI, epinephrine; FVIII, factor VIII; FVIII:C, factor VIII clotting activity; PFA, platelet function analyzer; VWF, von Willebrand factor.\n\nBold entries denote abnormal values.\n\nJohn Wiley & Sons, LtdFigure 2 Pedigree of the patient. The patient’s mother (deceased) reportedly suffered from heavy menstrual bleeding. The patient’s older brother experienced frequent epistaxis and prolonged bleeding after minor trauma. Another older sister is unaffected\n\nWe initiated treatment with the usual on‐demand administration of plasma‐derived VWF/FVIII concentrates, which had no long‐lasting effect and led to recurrent transfusion requirements and endoscopic interventions with argon plasma coagulation. Therefore, prophylaxis with plasma‐derived VWF/FVIII concentrates was administered, which led to a partial response with an improvement of gastrointestinal bleeding but the persistent need for RBC transfusions. However, this therapy was complicated because factor VIII clotting activity (FVIII:C) plasma levels reached values far above the normal range, further deteriorating the patient’s underlying RP and PAH. Consequently, treatment with the endothelin receptor antagonist ambrisentan was begun concomitantly with the ongoing substitution of plasma‐derived VWF/FVIII. Unfortunately, ambrisentan had to be discontinued due to developing medication‐induced anemia.\n\nSince it proved impossible to control the bleeding episodes without worsening the SSc‐related sequelae sufficiently, we decided to commence treatment with the only available VWF preparation devoid of FVIII, the recombinant VWF concentrate vonicog alfa. Prophylactic (off‐label) administration three times per week (8450 IU/week, 50 IU/kg), significantly reduced bleeding episodes and stabilized hematocrit levels without any adverse events. The number of RBC transfusions could be substantially reduced (Figure 1C). An endoscopic investigation 5 months after vonicog alfa treatment initiation showed a clearly diminished number of angiodysplasias (Figure 1B). Nevertheless, hematocrit levels remain below 35% despite vonicog alfa treatment. We assume that small bowel angiodysplasias persist and may lead to occult bleeding. However, the overt gastric and colonic angiodysplasias have improved.\n\n3 DISCUSSION\nWe report the unusual case of a patient with SSc and inherited VWD with an insufficient response to conventional treatment. We successfully treated her with vonicog alfa as repeated administration three times per week. Vonicog alfa contains high amounts of ultra‐large VWF multimers,\n10\n which are essential for hemostasis and particularly for angiogenesis regulation. The Food and Drug Administration has approved vonicog alfa for on‐demand treatment, control of bleeding episodes, and perioperative bleeding management in patients with VWD.\n11\n\n\n\nContinuous prophylaxis with vonicog alfa stabilized haemostasis and positively influenced the vascular malformations without the undesirable effects resulting from high FVIII:C levels. The mechanism of vascular homeostasis regulation by VWF is complex: Its binding to integrin avß3 in endothelial cells can activate angiogenesis while at the same time counteracting vessel maturation in vascular smooth muscle cells (reviewed in Randi and Laffan\n12\n). Since this is predominantly mediated by the ultra‐large VWF multimers, vonicog alfa may have effectively interfered with the disrupted vessel formation in this case. An antiangiodysplastic effect of rituximab seems unlikely, as it had been administered for years until 3 months before the current admission without improving the bleeding frequency.\n\nThe exact mechanism of how vonicog alfa led to better control of the gastrointestinal bleeding than a plasma‐derived VWF/FVIII‐containing preparation, which led to only a partial improvement, remains elusive. In this particular patient with concomitant SSc and PAH, we observed worsening of PAH, presumably due to high levels of FVIII. Higher levels of FVIII have been described in patients with chronic thromboembolic pulmonary hypertension and PAH compared to healthy controls.\n13\n\n\n\nBecause acquired functional VWF defects are increasingly recognized in autoimmune and other diseases,\n14\n a thorough hemostaseological evaluation is highly recommendable in systemic diseases because patients who are potentially jeopardized by a further increase of FVIII activity through plasma‐derived VWF/FVIII concentrates may particularly benefit from the administration of FVIII‐free VWF preparations. Also, the testing of VWD‐associated abnormalities is an area of active research.\n15\n\n\n\nOf note, the patient and her siblings had not been aware of an inherited coagulation disorder, which underscores the importance of history taking in bleeding disorders. This is especially true in patients with an autoimmune disorder because severe complications, as in the presented case, may be falsely ascribed to the underlying condition and preclude appropriate testing.\n\nIn conclusion, this is the first reported case of the administration of vonicog alfa as prophylactic therapy in a patient with a combination of SSc‐associated gastrointestinal bleeding and inherited type 2A VWD as a result of multidisciplinary care between critical care, rheumatology, and hematology.\n\nAUTHOR CONTRIBUTIONS\nPK treated the patient, collected and analyzed data, wrote the manuscript, and created the figures. MW treated the patient, analyzed data and cowrote the manuscript. CB treated the patient, collected and analyzed data, and edited the manuscript.\n\nRELATIONSHIP DISCLOSURE\nPK declared personal fees, travel support, or honoraria from Abbvie, Bristol‐Myers Squibb, Chugai, Gilead, Glaxo Smith Kline, Novartis, and Pfizer, all unrelated to this manuscript. MW and CB declared no competing interests.\n\nACKNOWLEDGMENTS\nThe authors are indebted to the patient for providing written informed consent to publish this case report and for the contribution of valuable supporting information from her medical records. Open access funding enabled and organized by Projekt DEAL.\n==== Refs\nREFERENCES\n1 \n\nLeebeek \nFWG \n, \nEikenboom \nJCJ \n. Von Willebrand’s disease. Longo DL, editor\n. N Engl J Med . 2016 ;375 (21 ):2067 –80\n.27959741 \n2 \n\nTiede \nA \n, \nZieger \nB \n, \nLisman \nT \n. Acquired bleeding disorders\n. Haemophilia . 2020 . [Epub ahead of print].\n3 \n\nGabrielli \nA \n, \nAvvedimento \nEV \n, \nKrieg \nT \n. Scleroderma\n. N Engl J Med . 2009 ;360 (19 ):1989 –2003\n.19420368 \n4 \n\nShreiner \nAB \n, \nMurray \nC \n, \nDenton \nC \n, \nKhanna \nD \n. Gastrointestinal manifestations of systemic sclerosis\n. 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Res Pract Thromb Haemost . 2020 ;4 (6 ):1024 –34\n.32864553\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2475-0379", "issue": "4(7)", "journal": "Research and practice in thrombosis and haemostasis", "keywords": "Autoimmune Diseases; angiodysplasias; scleroderma; systemic; vascular malformations; von Willebrand diseases", "medline_ta": "Res Pract Thromb Haemost", "mesh_terms": null, "nlm_unique_id": "101703775", "other_id": null, "pages": "1230-1234", "pmc": null, "pmid": "33134789", "pubdate": "2020-10", "publication_types": "D002363:Case Reports", "references": "30517716;16889557;27778439;21540459;32476241;31210709;12958604;31902122;24889779;27959741;28133631;28276537;32864553;19420368", "title": "Type 2A von Willebrand disease and systemic sclerosis: Vonicog alfa reduced gastrointestinal bleeding.", "title_normalized": "type 2a von willebrand disease and systemic sclerosis vonicog alfa reduced gastrointestinal bleeding" }

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TYPE 2A VON WILLEBRAND DISEASE AND SYSTEMIC SCLEROSIS: VONICOG ALFA REDUCED GASTROINTESTINAL BLEEDING. RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS. 2020?1?5", "literaturereference_normalized": "type 2a von willebrand disease and systemic sclerosis vonicog alfa reduced gastrointestinal bleeding", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": null, "receiptdate": "20210107", "receivedate": "20210107", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18713769, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210419" }, { "companynumb": "DE-BEH-2020122852", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "AMBRISENTAN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "NOT REPORTED", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201909", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMBRISENTAN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "HUMAN COAGULATION FACTOR VIII/VON WILLEBRAND FACTOR COMPLEX" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "103960", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, PRN", "drugenddate": null, "drugenddateformat": null, "drugindication": "VON WILLEBRAND^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201905", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HUMAN FACTOR VIII VWF (INN)" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "HUMAN COAGULATION FACTOR VIII/VON WILLEBRAND FACTOR COMPLEX" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "103960", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "PROPHYLAXIS", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201905", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HUMAN FACTOR VIII VWF (INN)" } ], "patientagegroup": "5", "patientonsetage": "54", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Raynaud^s phenomenon", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary arterial hypertension", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Coagulation factor VIII level increased", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2019" } }, "primarysource": { "literaturereference": "KORSTEN P., WALLBACH M., BINDER C.. TYPE 2A VON WILLEBRAND DISEASE AND SYSTEMIC SCLEROSIS: VONICOG ALFA REDUCED GASTROINTESTINAL BLEEDING. RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS. 2020?00:1-5", "literaturereference_normalized": "type 2a von willebrand disease and systemic sclerosis vonicog alfa reduced gastrointestinal bleeding", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20201215", "receivedate": "20201002", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18337301, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210113" } ]

{ "abstract": "Introduction. There is no information regarding the pattern of inpatient referrals to drug allergy units in Kuwait. Objectives. The main goal of this study is to clarify the pattern of inpatient referrals to a drug allergy unit in terms of incidence, drugs implicated and allergy evaluation outcomes in comparison with studies in other countries. Patients and Methods. A retrospective chart review of inpatient drug allergy consultations at Al-Rashed Allergy Center over a 3-year period was performed. Results. A total of 51 patients were referred for drug allergy consultations, with an estimated incidence of reported drug allergy among inpatients of 0.008%. There is an increasing trend of referrals from public health centres located in proximity to Al-Rashed Allergy Center. Beta-lactams, contrast media, and general anaesthetics were the most common drugs leading to referrals. In total, 30% of patients were diagnosed with an allergy to the offending drug after a full allergy evaluation. Conclusion. Inpatient drug allergy referrals are highly underreported in Kuwait.", "affiliations": "Department of Microbiology, Faculty of Medicine, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait Phone: +965-24636515 Fax: +965-25332719 E-mail: Alahmadm@hsc.edu.kw; Drug Allergy Unit, Department of Allergy, Al-Rashed Allergy Center, Ministry of Health, Kuwait.;Drug Allergy Unit, Department of Allergy, Al-Rashed Allergy Center, Ministry of Health, Kuwait.", "authors": "Al-Ahmad|M|M|;Rodriguez Bouza|T|T|", "chemical_list": null, "country": "Italy", "delete": false, "doi": "10.23822/EurAnnACI.1764-1489.18", "fulltext": null, "fulltext_license": null, "issn_linking": "1764-1489", "issue": "49(6)", "journal": "European annals of allergy and clinical immunology", "keywords": "Kuwait; drug hypersensitivity; inpatients; referral and consultation", "medline_ta": "Eur Ann Allergy Clin Immunol", "mesh_terms": "D000328:Adult; D000368:Aged; D002648:Child; D004342:Drug Hypersensitivity; D005260:Female; D006757:Hospital Units; D006801:Humans; D007159:Immunologic Tests; D015994:Incidence; D007297:Inpatients; D007730:Kuwait; D008297:Male; D008875:Middle Aged; D010818:Practice Patterns, Physicians'; D011237:Predictive Value of Tests; D011379:Prognosis; D012017:Referral and Consultation; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D055815:Young Adult", "nlm_unique_id": "101466614", "other_id": null, "pages": "276-280", "pmc": null, "pmid": "29249136", "pubdate": "2017-11", "publication_types": "D016428:Journal Article", "references": null, "title": "Pattern of inpatient referrals to a drug allergy unit in Kuwait.", "title_normalized": "pattern of inpatient referrals to a drug allergy unit in kuwait" }

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PATTERN OF INPATIENT REFERRALS TO A DRUG ALLERGY UNIT IN KUWAIT. EUROPEAN ANNALS OF ALLERGY AND CLINICAL IMMUNOLOGY. 2017?49 (6):276-280.", "literaturereference_normalized": "pattern of inpatient referrals to a drug allergy unit in kuwait", "qualification": "3", "reportercountry": "KW" }, "primarysourcecountry": null, "receiptdate": "20181010", "receivedate": "20171219", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14306027, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190204" }, { "companynumb": "KW-PHARMACEUTICS INTERNATIONAL, INC. (PII)-2017PII000013", "fulfillexpeditecriteria": "1", "occurcountry": "KW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "207029", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE USP" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Angioedema", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urticaria", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "AL-AHMAD M, RODRIGUEZ BOUZA T.. PATTERN OF INPATIENT REFERRALS TO A DRUG ALLERGY UNIT IN KUWAIT. EUROPEAN ANNALS OF ALLERGY AND CLINICAL IMMUNOLOGY. 2017;49:6:276-280", "literaturereference_normalized": "pattern of inpatient referrals to a drug allergy unit in kuwait", "qualification": "3", "reportercountry": "KW" }, "primarysourcecountry": "KW", "receiptdate": "20171228", "receivedate": "20171228", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14331377, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" }, { "companynumb": "KW-ALLERGAN-1771035US", "fulfillexpeditecriteria": "1", "occurcountry": "KW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE UNK" } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug hypersensitivity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urticaria", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Angioedema", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "AL-AHMAD M, RODRIGUEZ BOUZA T.. PATTERN OF INPATIENT REFERRALS TO A DRUG ALLERGY UNIT IN KUWAIT. EUROPEAN ANNALS OF ALLERGY AND CLINICAL IMMUNOLOGY. 2017?49(6):276-280", "literaturereference_normalized": "pattern of inpatient referrals to a drug allergy unit in kuwait", "qualification": "1", "reportercountry": "KW" }, "primarysourcecountry": "KW", "receiptdate": "20181005", "receivedate": "20171215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14293026, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190204" }, { "companynumb": "KW-GLENMARK PHARMACEUTICALS-2017GMK030071", "fulfillexpeditecriteria": "1", "occurcountry": "KW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROCORTISONE BUTYRATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "202145", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE BUTYRATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Angioedema", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug hypersensitivity", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urticaria", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "AL-AHMAD M, RODRIGUEZ BOUZA T.. PATTERN OF INPATIENT REFERRALS TO A DRUG ALLERGY UNIT IN KUWAIT. 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PATTERN OF INPATIENT REFERRALS TO A DRUG ALLERGY UNIT IN KUWAIT. EUROPEAN ANNALS OF ALLERGY AND CLINICAL IMMUNOLOGY. 2017?49(6):276-80", "literaturereference_normalized": "pattern of inpatient referrals to a drug allergy unit in kuwait", "qualification": "3", "reportercountry": "KW" }, "primarysourcecountry": "KW", "receiptdate": "20190329", "receivedate": "20171212", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14279000, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20190417" }, { "companynumb": "KW-APOTEX-2017AP022830", "fulfillexpeditecriteria": "1", "occurcountry": "KW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBAMAZEPINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "075948", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBAMAZEPINE." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Anaphylactic reaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "AL-AHMAD M., RODRIGUEZ BOUZA T.. PATTERN OF INPATIENT REFERRALS TO A DRUG ALLERGY UNIT IN KUWAIT. 10.23822/EURANNACI.1764-1489.18. EUR ANN ALLERGY CLIN IMMUNOL. 2017;49(6):276-280", "literaturereference_normalized": "pattern of inpatient referrals to a drug allergy unit in kuwait", "qualification": "3", "reportercountry": "KW" }, "primarysourcecountry": "KW", "receiptdate": "20171215", "receivedate": "20171215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14290381, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20180321" }, { "companynumb": "KW-MYLANLABS-2017M1078923", "fulfillexpeditecriteria": "1", "occurcountry": "KW", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CARBAMAZEPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "076697", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBAMAZEPINE." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Anaphylactic reaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "AL-AHMAD M, RODRIGUEZ BOUZA T. PATTERN OF INPATIENT REFERRALS TO A DRUG ALLERGY UNIT IN KUWAIT. EUR-ANN-ALLERGY-CLIN-IMMUNOL 2017;49(6):276-280.", "literaturereference_normalized": "pattern of inpatient referrals to a drug allergy unit in kuwait", "qualification": "3", "reportercountry": "KW" }, "primarysourcecountry": "KW", "receiptdate": "20171227", "receivedate": "20171227", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14329343, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" } ]

{ "abstract": "Recently, studies on whole-exome sequencing (WES) of large cohorts of people with periventricular heterotopia (PVH) have reported an association with loss-of-function variants in the MAP1B gene. However, neurological phenotypes of these patients remain poorly characterized. Four family members with seizures beginning in early childhood were evaluated. Integrated genomic analysis with WES and microarray was performed. Affected family members had various combinations of: febrile, fever-triggered and afebrile seizures; photo-sensitivity; comorbid mild developmental delays; obsessive-compulsive behaviors; and poor attention span. Neuroimaging showed PVH, corpus callosum abnormalities, and perisylvian polymicrogyria. A novel heterozygous frameshift variant in MAP1B was found in all affected family members. This report extends the clinical and neuroimaging phenotypes associated with MAP1B pathogenic variants. MAP1B variants may be considered in patients with febrile and afebrile seizures if characteristic neuroimaging, particularly PVH, is observed.", "affiliations": "Comprehensive Epilepsy Center, Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.;Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.;Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA, Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.", "authors": "Arya|Ravindra|R|;Spaeth|Christine|C|;Zhang|Wenying|W|", "chemical_list": null, "country": "France", "delete": false, "doi": "10.1684/epd.2021.1258", "fulltext": null, "fulltext_license": null, "issn_linking": "1294-9361", "issue": "23(2)", "journal": "Epileptic disorders : international epilepsy journal with videotape", "keywords": "genetic epilepsy; perisylvian polymicrogyria; periventricular heterotopia", "medline_ta": "Epileptic Disord", "mesh_terms": null, "nlm_unique_id": "100891853", "other_id": null, "pages": "392-396", "pmc": null, "pmid": "33772511", "pubdate": "2021-04-01", "publication_types": "D016428:Journal Article", "references": null, "title": "Epilepsy phenotypes associated with MAP1B-related brain malformations.", "title_normalized": "epilepsy phenotypes associated with map1b related brain malformations" }

[ { "companynumb": "US-CIPLA LTD.-2021US07215", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "078234", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Seizure", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVETIRACETAM" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Arya R, Spaeth C, Zhang W.. Epilepsy phenotypes associated with MAP1B related brain malformations. Epileptic Disord. 2021;23 (2):392 to 396", "literaturereference_normalized": "epilepsy phenotypes associated with map1b related brain malformations", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211102", "receivedate": "20211102", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20022506, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" } ]

{ "abstract": "Antipsychotic use is associated with risk of falls among older persons, but we are not aware of previous studies investigating risk of head injuries. We studied the association of antipsychotic use and risk of head injuries among community dwellers with Alzheimer's disease (AD).\n\n\n\nNationwide register-based cohort study.\n\n\n\nMedication Use and Alzheimer's Disease (MEDALZ) cohort, Finland.\n\n\n\nThe MEDALZ cohort includes Finnish community dwellers who received clinically verified AD diagnosis in 2005 to 2011. Incident antipsychotic users were identified from the Prescription Register and matched with nonusers by age, sex, and time since AD diagnosis (21 795 matched pairs). Persons with prior head injury or history of schizophrenia were excluded.\n\n\n\nOutcomes were incident head injuries (International Classification of Diseases, Tenth Revision [ICD-10] codes S00-S09) and traumatic brain injuries (TBIs; ICD-10 codes S06.0-S06.9) resulting in a hospital admission (Hospital Discharge Register) or death (Causes of Death Register). Inverse probability of treatment (IPT) weighted Cox proportional hazard models were used to assess relative risks.\n\n\n\nAntipsychotic use was associated with an increased risk of head injuries (event rate per 100 person-years = 1.65 [95% confidence interval {CI} = 1.50-1.81] for users and 1.26 [95% CI = 1.16-1.37] for nonusers; IPT-weighted hazard ratio [HR] = 1.29 [95% CI = 1.14-1.47]) and TBIs (event rate per 100 person-years = 0.90 [95% CI = 0.79-1.02] for users and 0.72 [95% CI = 0.65-0.81] for nonusers; IPT-weighted HR = 1.22 [95% CI = 1.03-1.45]). Quetiapine users had higher risk of TBIs (IPT-weighted HR = 1.60 [95% CI = 1.15-2.22]) in comparison to risperidone users.\n\n\n\nThese findings imply that in addition to previously reported adverse events and effects, antipsychotic use may increase the risk of head injuries and TBIs in persons with AD. Therefore, their use should be restricted to most severe neuropsychiatric symptoms, as recommended by the AGS Beers Criteria®. Additionally, higher relative risk of TBIs in quetiapine users compared to risperidone users should be confirmed in further studies. J Am Geriatr Soc 68:595-602, 2020.", "affiliations": "School of Pharmacy, University of Eastern Finland, Kuopio, Finland.;School of Pharmacy, University of Eastern Finland, Kuopio, Finland.;School of Pharmacy, University of Eastern Finland, Kuopio, Finland.;School of Pharmacy, University of Eastern Finland, Kuopio, Finland.;Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.;Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.;School of Pharmacy, University of Eastern Finland, Kuopio, Finland.;School of Pharmacy, University of Eastern Finland, Kuopio, Finland.", "authors": "Tapiainen|Vesa|V|0000-0002-5467-361X;Lavikainen|Piia|P|;Koponen|Marjaana|M|;Taipale|Heidi|H|;Tanskanen|Antti|A|;Tiihonen|Jari|J|;Hartikainen|Sirpa|S|;Tolppanen|Anna-Maija|AM|0000-0001-9270-9268", "chemical_list": "D014150:Antipsychotic Agents", "country": "United States", "delete": false, "doi": "10.1111/jgs.16275", "fulltext": null, "fulltext_license": null, "issn_linking": "0002-8614", "issue": "68(3)", "journal": "Journal of the American Geriatrics Society", "keywords": "Alzheimer's disease; antipsychotics; dementia; risk factors; traumatic brain injury", "medline_ta": "J Am Geriatr Soc", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease; D014150:Antipsychotic Agents; D015331:Cohort Studies; D006259:Craniocerebral Trauma; D005260:Female; D005387:Finland; D006760:Hospitalization; D006801:Humans; D057187:Independent Living; D008297:Male; D012042:Registries; D012306:Risk", "nlm_unique_id": "7503062", "other_id": null, "pages": "595-602", "pmc": null, "pmid": "31912482", "pubdate": "2020-03", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "The Risk of Head Injuries Associated With Antipsychotic Use Among Persons With Alzheimer's disease.", "title_normalized": "the risk of head injuries associated with antipsychotic use among persons with alzheimer s disease" }

[ { "companynumb": "FI-JNJFOC-20170104614", "fulfillexpeditecriteria": "1", "occurcountry": "FI", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "020272", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "MEDIAN DOSE: 0.7 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEMENTIA ALZHEIMER^S TYPE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DEMENTIA ALZHEIMER^S TYPE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Craniocerebral injury", "reactionmeddraversionpt": "23.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Fall", "reactionmeddraversionpt": "23.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Hip fracture", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Head injury", "reactionmeddraversionpt": "23.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VESA T, HEIDI T, SIRPA H. THE RISK OF HEAD INJURIES ASSOCIATED WITH ANTIPSYCHOTIC USE AMONG PERSONS WITH ALZHEIMER^S DISEASE. J AM GERIATR. 2020?68:595-602.", "literaturereference_normalized": "the risk of head injuries associated with antipsychotic use among persons with alzheimer s disease", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "FI", "receiptdate": "20200407", "receivedate": "20170109", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13098923, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" } ]

{ "abstract": "Metastatic germ cell tumors remain potentially curable when treated with salvage chemotherapy at first relapse. In the present phase I/II study, we sought to improve on the response rate and duration of the TIP (paclitaxel, ifosfamide, cisplatin) regimen by adding gemcitabine (Gem-TIP).\n\n\n\nTwenty patients were recruited after failure of first-line cisplatin-containing chemotherapy. The primary objectives were to determine the maximum tolerated dose of gemcitabine when combined with TIP and to establish the dose intensity of the TIP drugs in this combination. The secondary objectives were the response rates, failure-free survival, and overall survival.\n\n\n\nThe maximum tolerated dose of gemcitabine was 1200 mg/m2. The mean relative dose intensity was 95% (95% confidence interval [CI], 90.2%-99.2%) for gemcitabine, 96% (95% CI, 92.9%-98.7%) for paclitaxel, 92% (95% CI, 84.5%-98.8%) for ifosfamide, and 94% (95% CI, 89.3%-99.0%) for cisplatin. The overall complete response rate was 50%; another 30% of the patients achieved a partial response. The 1-year failure-free survival and overall survival rates were 68% (95% CI, 43%-84%) and 89.5% (95% CI, 64%-97%), respectively.\n\n\n\nGemcitabine can be added to TIP chemotherapy at the full dose, with manageable toxicity and no detrimental effect on the dose intensity of the TIP drugs. The response rate and duration were improved compared with those reported from the Medical Research Council TIP trial; further evaluation is warranted.", "affiliations": "University Hospital Southampton NHS Foundation Trust, Southampton General Hospital, Southampton, United Kingdom. Electronic address: h.s.mckenzie@soton.ac.uk.;University Hospital Southampton NHS Foundation Trust, Southampton General Hospital, Southampton, United Kingdom.;The Royal Marsden NHS Foundation Trust, The Royal Marsden Hospital, Sutton, United Kingdom.;Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom.;Mount Vernon Cancer Centre, Mount Vernon Hospital, Northwood, United Kingdom.;Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, United Kingdom.;Southampton Clinical Trials Unit, University of Southampton, Southampton General Hospital, Southampton, United Kingdom.;Southampton Clinical Trials Unit, University of Southampton, Southampton General Hospital, Southampton, United Kingdom.;Southampton Clinical Trials Unit, University of Southampton, Southampton General Hospital, Southampton, United Kingdom.;University Hospital Southampton NHS Foundation Trust, Southampton General Hospital, Southampton, United Kingdom.", "authors": "McKenzie|Hayley S|HS|;Mead|Graham|G|;Huddart|Robert|R|;White|Jeff D|JD|;Rustin|Gordon J S|GJS|;Hennig|Ivo M|IM|;Cozens|Kelly|K|;Cross|Nadia|N|;Bowers|Megan|M|;Wheater|Matthew J|MJ|", "chemical_list": "D043823:Taxoids; D003841:Deoxycytidine; C056507:gemcitabine; D002945:Cisplatin; D007069:Ifosfamide", "country": "United States", "delete": false, "doi": "10.1016/j.clgc.2018.07.006", "fulltext": null, "fulltext_license": null, "issn_linking": "1558-7673", "issue": "16(6)", "journal": "Clinical genitourinary cancer", "keywords": "Antineoplastic combined chemotherapy protocols; Germ cell and embryonal; Neoplasms; Salvage therapy; TIP regimen", "medline_ta": "Clin Genitourin Cancer", "mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D003841:Deoxycytidine; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007069:Ifosfamide; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009373:Neoplasms, Germ Cell and Embryonal; D016879:Salvage Therapy; D015996:Survival Rate; D043823:Taxoids; D017211:Treatment Failure; D055815:Young Adult", "nlm_unique_id": "101260955", "other_id": null, "pages": "458-465.e2", "pmc": null, "pmid": "30115544", "pubdate": "2018-12", "publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Salvage Chemotherapy With Gemcitabine, Paclitaxel, Ifosfamide, and Cisplatin for Relapsed Germ Cell Cancer.", "title_normalized": "salvage chemotherapy with gemcitabine paclitaxel ifosfamide and cisplatin for relapsed germ cell cancer" }

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SALVAGE CHEMOTHERAPY WITH GEMCITABINE, PACLITAXEL, IFOSFAMIDE, AND CISPLATIN FOR RELAPSED GERM CELL CANCER.. CLIN. GENITOURIN. 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"drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PEGFILGRASTIM" }, "drugadditional": "3", "drugadministrationroute": "058", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GERM CELL CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PEGFILGRASTIM" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MCKENZIE H.S., MEAD G., HUDDART R., WHITE J.D., RUSTIN G.J.S., HENNIG I.M., COZENS K., CROSS N., BOWERS M., WHEATER M.J.. SALVAGE CHEMOTHERAPY WITH GEMCITABINE, PACLITAXEL, IFOSFAMIDE, AND CISPLATIN FOR RELAPSED GERM CELL CANCER.. CLIN. GENITOURIN. CANCER.. 2018?16(6):458-465.E2.", "literaturereference_normalized": "salvage chemotherapy with gemcitabine paclitaxel ifosfamide and cisplatin for relapsed germ cell cancer", "qualification": "1", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190812", "receivedate": "20190812", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16693562, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20191004" }, { "companynumb": "GB-HQ SPECIALTY-GB-2019INT000208", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PEGFILGRASTIM" }, "drugadditional": "3", "drugadministrationroute": "058", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GERM CELL CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PEGFILGRASTIM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GEMCITABINE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, 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METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IFOSFAMIDE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GERM CELL CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IFOSFAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "018057", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GERM CELL CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, 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SALVAGE CHEMOTHERAPY WITH GEMCITABINE, PACLITAXEL, IFOSFAMIDE, AND CISPLATIN FOR RELAPSED GERM CELL CANCER.. CLIN. GENITOURIN. CANCER.. 2018?16(6):458-465.E2.", "literaturereference_normalized": "salvage chemotherapy with gemcitabine paclitaxel ifosfamide and cisplatin for relapsed germ cell cancer", "qualification": "1", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190812", "receivedate": "20190812", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16693570, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20191004" } ]

{ "abstract": "OBJECTIVE\nTo obtain reliable information about the incidence of adverse drug reactions, and identify potential areas where intervention may reduce the burden of ill-health.\n\n\nMETHODS\nProspective observational study.\n\n\nMETHODS\nA large tertiary children's hospital providing general and specialty care in the UK.\n\n\nMETHODS\nAll acute paediatric admissions over a one year period.\n\n\nMETHODS\nAny medication taken in the two weeks prior to admission.\n\n\nMETHODS\nOccurrence of adverse drug reaction.\n\n\nRESULTS\n240/8345 admissions in 178/6821 patients admitted acutely to a paediatric hospital were thought to be related to an adverse drug reaction, giving an estimated incidence of 2.9% (95% CI 2.5, 3.3), with the reaction directly causing, or contributing to the cause, of admission in 97.1% of cases. No deaths were attributable to an adverse drug reaction. 22.1% (95% CI 17%, 28%) of the reactions were either definitely or possibly avoidable. Prescriptions originating in the community accounted for 44/249 (17.7%) of adverse drug reactions, the remainder originating from hospital. 120/249 (48.2%) reactions resulted from treatment for malignancies. The drugs most commonly implicated in causing admissions were cytotoxic agents, corticosteroids, non-steroidal anti-inflammatory drugs, vaccines and immunosuppressants. The most common reactions were neutropenia, immunosuppression and thrombocytopenia.\n\n\nCONCLUSIONS\nAdverse drug reactions in children are an important public health problem. Most of those serious enough to require hospital admission are due to hospital-based prescribing, of which just over a fifth may be avoidable. Strategies to reduce the burden of ill-health from adverse drug reactions causing admission are needed.", "affiliations": "Department of Women's and Children's Health, University of Liverpool, Liverpool, United Kingdom. ruairi.gallagher@nhs.net", "authors": "Gallagher|Ruairi M|RM|;Mason|Jennifer R|JR|;Bird|Kim A|KA|;Kirkham|Jamie J|JJ|;Peak|Matthew|M|;Williamson|Paula R|PR|;Nunn|Anthony J|AJ|;Turner|Mark A|MA|;Pirmohamed|Munir|M|;Smyth|Rosalind L|RL|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1371/journal.pone.0050127", "fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, USA 23226510PONE-D-12-1956610.1371/journal.pone.0050127Research ArticleMedicineDrugs and DevicesAdverse ReactionsPharmacoepidemiologyEpidemiologyPharmacoepidemiologyNon-Clinical MedicineHealth Care PolicyChild and Adolescent Health PolicyHealth StatisticsHealth Services ResearchPediatricsPublic HealthChild HealthAdverse Drug Reactions Causing Admission to a Paediatric Hospital Drug Reactions Causing Paediatric AdmissionGallagher Ruairi M. \n1\n\n*\nMason Jennifer R. \n2\nBird Kim A. \n2\nKirkham Jamie J. \n3\nPeak Matthew \n2\nWilliamson Paula R. \n3\nNunn Anthony J. \n4\nTurner Mark A. \n1\nPirmohamed Munir \n5\nSmyth Rosalind L. \n1\n\n1 \nDepartment of Women’s and Children’s Health, University of Liverpool, Liverpool, United Kingdom\n\n2 \nResearch and Development, Alder Hey Children’s Hospital NHS Foundation Trust, Liverpool, United Kingdom\n\n3 \nDepartment of Biostatistics, University of Liverpool, Liverpool, United Kingdom\n\n4 \nNational Institute for Health Research Medicines for Children Research Network, University of Liverpool, Alder Hey Hospital (previously: Department of Pharmacy, Alder Hey Children’s NHS Foundation Trust), Liverpool, United Kingdom\n\n5 \nDepartment of Pharmacology, University of Liverpool, Liverpool, United Kingdom\nChoonara Imti Editor\nNottingham University, United Kingdom\n* E-mail: ruairi.gallagher@nhs.netCompeting Interests: The authors have declared that no competing interests exist. Munir Pirmohamed is NHS Chair of Pharmacogenetics (funded by Department of Health (England)). Rosalind Smyth and Munir Pirmohamed are members of the Commission on Human Medicines. Munir Pirmohamed Chairs the Pharmacovigilance Expert Advisory Group, while Rosalind Smyth Chairs the Paediatric Medicines Expert Advisory Group.\n\nConceived and designed the experiments: RMG JRM KAB JJK M. Peak PRW AJN MAT M. Pirmohamed RLS. Performed the experiments: RMG JRM KAB AJN MAT M. Pirmohamed RLS. Analyzed the data: RMG JJK PRW. Wrote the paper: RMG JRM KAB JJK M. Peak PRW AJN MAT M. Pirmohamed RLS.\n\n2012 4 12 2012 7 12 e501277 7 2012 15 10 2012 © 2012 Gallagher et al2012Gallagher et alThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.Objective(s)\nTo obtain reliable information about the incidence of adverse drug reactions, and identify potential areas where intervention may reduce the burden of ill-health.\n\nDesign\nProspective observational study.\n\nSetting\nA large tertiary children’s hospital providing general and specialty care in the UK.\n\nParticipants\nAll acute paediatric admissions over a one year period.\n\nMain Exposure\nAny medication taken in the two weeks prior to admission.\n\nOutcome Measures\nOccurrence of adverse drug reaction.\n\nResults\n240/8345 admissions in 178/6821 patients admitted acutely to a paediatric hospital were thought to be related to an adverse drug reaction, giving an estimated incidence of 2.9% (95% CI 2.5, 3.3), with the reaction directly causing, or contributing to the cause, of admission in 97.1% of cases. No deaths were attributable to an adverse drug reaction. 22.1% (95% CI 17%, 28%) of the reactions were either definitely or possibly avoidable. Prescriptions originating in the community accounted for 44/249 (17.7%) of adverse drug reactions, the remainder originating from hospital. 120/249 (48.2%) reactions resulted from treatment for malignancies. The drugs most commonly implicated in causing admissions were cytotoxic agents, corticosteroids, non-steroidal anti-inflammatory drugs, vaccines and immunosuppressants. The most common reactions were neutropenia, immunosuppression and thrombocytopenia.\n\nConclusions\nAdverse drug reactions in children are an important public health problem. Most of those serious enough to require hospital admission are due to hospital-based prescribing, of which just over a fifth may be avoidable. Strategies to reduce the burden of ill-health from adverse drug reactions causing admission are needed.\n\nThis paper presents independent research commissioned by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme (RP-PG-0606-1170). The views expressed are those of the author(s) and not necessarily those of the National Health Service, the NIHR or the Department of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n==== Body\nIntroduction\nChildren are vulnerable to adverse drug reactions (ADRs). [1], [2], [3], [4], [5], [6] Spontaneous reporting systems, such as the UK Yellow Card scheme, [7] are subject to under reporting of ADRs, even those which are severe. [8] To obtain reliable information about the incidence of ADRs prospective studies are needed. A systematic review of observational studies of ADRs causing paediatric hospital admissions, between 1976 to 1996, estimated the rate of ADR admissions to be 2.1% (95% CI 1.0, 3.8). [9] A further review of prospective paediatric studies published between 2001 and 2007 did not identify any large studies of the incidence and nature of ADRs causing hospital admission. [10]\n\n\nSome results of the present study, prior to publication, were included in a recent systematic review by Smyth et al in 2011 [11]. The authors reviewed prospective studies researching ADRs in three settings; ADRs in-patients, those causing acute admission to hospital and those occurring in out-patients. Incidence rates for ADRs causing hospital admission ranged from 0.4% to 10.3% of all children (pooled estimate of 2.9% (2.6%, 3.1%)). Only 19/102 studies, from all three settings, assessed avoidability.\n\n10.1371/journal.pone.0050127.t001Table 1 Univariate analyses of ADRs by age.\nAge (years, months)[Median; Q1, Q3]\tAll\tNo ADR\tADR\tMann–Whitney U\tP–value\t\n\nAll\n\t[3y 1m; 9m, 9y] (n = 4656)\t[3y 0m; 9m, 9y] (n = 4514)\t[6y 0m; 2y 4m, 11y] (n = 142)\t244161\t<0.001\t\n\nOncology\n\t[6y; 3y 6m, 12y] (n = 74)\t[6y; 3y 6m, 13y] (n = 33)\t[6y; 3y 0m, 10y] (n = 41)\t580.5\t0.296\t\n\nNon–Oncology\n\t[3y; 9m, 9y] (n = 4582)\t[2y 11m; 9m, 9y] (n = 4481)\t[6y; 1y 7m, 11y] (n = 101)\t178319.5\t<0.001\t\nThe aim of this study was to prospectively identify ADRs in children causing hospital admission during a one year period in order to quantify the burden of ADRs and characterise their features. The investigators aimed to determine the avoidability of identified ADRs and detail the reasons for determining reactions as avoidable. This aspect of ADRs causing admission in children has not been fully addressed in previous studies.\n\n10.1371/journal.pone.0050127.t002Table 2 Univariate analyses of ADRs by number of medicines taken.\nDrug Count [Median; Q1, Q3]\tAll\tNo ADR\tADR\tMann–Whitney U\tP–value\t\n\nAll\n\t\n[2]; [1], [3] (n = 4656)\t\n[2]; [1], [3] (n = 4514)\t\n[6]; [3], [9] (n = 142)\t115391.5\t<0.001\t\n\nOncology\n\t\n[6]; [4], [9] (n = 74)\t\n[4]; [3], [7] (n = 33)\t\n[8]; [5], [10] (n = 41)\t380.5\t0.001\t\n\nNon–Oncology\n\t\n[2]; [1], [3] (n = 4582)\t\n[2]; [1], [3] (n = 4481)\t\n[5]; [3], [9] (n = 101)\t100371.5\t<0.001\t\nMethods\nWe prospectively screened all unplanned admissions to a tertiary paediatric hospital for ADRs over a one year period, including weekends and holidays, from 1st July 2008 to 30th June 2009. Admissions were excluded if they were planned, or occurred as a result of accidental or intentional overdose. Patients admitted to an Accident and Emergency (A&E) department short-stay ‘observation ward’ were not included. [12] The definition of ADR used was that of Edwards and Aronson which is “an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product.” [13] This definition was chosen as it describes only clinically significant adverse reactions that cause harm and it includes the concept of preventive action.\n\n10.1371/journal.pone.0050127.t003Table 3 Multivariate logistic regression analysis for risk factors for occurrence of ADR admission.\nParameter\tOdds Ratio (OR)\t95% CI for OR\tP–value\t\nGender\t0.77\t0.52, 1.12\t0.17\t\nAge\t1.04\t1, 1.08\t0.03\t\nOncology\t29.71\t17.35, 50.88\t<0.01\t\nNumber of medicines\t1.24\t1.19, 1.29\t<0.01\t\na Variable(s) entered on step 1: Gender (Male), Age, Oncology, Number of medicines.\n\nBefore the study began, an educational program was undertaken amongst clinicians of all grades to raise awareness about the importance of taking detailed medication histories. A structured medication history section was added to medical admission documentation to ensure details were taken about medication in the preceding two weeks. We identified all unplanned admissions in the previous 24 hours daily from hospital information systems. The study team collected the following information from case notes: age, sex, presenting complaint, clinical history, diagnosis (if available), and medications, including over-the-counter drugs, taken in the preceding two weeks. If any information was unclear, study team members interviewed the family to clarify the history.\n\n10.1371/journal.pone.0050127.t004Table 4 Classification of drugs associated with ADR admissions.\nDrug class(No. of cases)\tNo of drugs\tDrugs\tADRs\t\nCytotoxics (110)\t275\tVincristine 51, Doxorubicin 38, Methotrexate 35, Etoposide 30,Mercaptopurine 27, Cytarabine 24, Ifosfamide 18, Cyclophosphamide15, Carboplatin 7, Vinblastine 5, Pegasparaginase 5, Dactinomycin 5,Daunorubicin 4, Cisplatin 3, Irinotecan 3, Temozolomide 2,Fludarabine 1, Amsacrine 1, Imatinib 1\tNeutropenia 89, Thrombocytopenia 55, Anaemia 38, Vomiting 8, Mucositis 8, Deranged Liver Function Tests 7, Immunosuppression 7, Diarrhoea 5, Nausea 4, Constipation 3, Headache 2, Abdominal pain 1, Back pain 1, Haematuria 1, Leukencephalopathy 1, Deranged renal function 1\t\nCorticosteroids (102)\t107\tDexamethasone 68, Prednisolone 33, Hydrocortisone 2,Betamethasone 1, Mometasone 1,Methylprednisolone 1, Fluticasone 1\tImmunosuppression 71, Post–op bleeding 23, Hyperglycaemia 3, Hypertension 1, Gastritis 1, Increased appetite 1, Impaired healing 1, Adrenal suppression 1\t\nNSAIDs (31)\t43\tIbuprofen 28, Diclofenac 15\tPost–op bleeding 27, Haematemesis 2, Constipation 1, Abdominal pain 1\t\nVaccines (22)\t37\tDiphtheria Tetanus Pertussis Inactivated polio HaemophilusInfluenza vaccine 11, Pneumococcal conjugate 9,Meningococcal C 8, MMR 7, Haemophilus Influenza B 1, Influenza 1\tFever 8, Rash 5, Irritability 4, Seizure 4, Vomiting 3, Pallor 1, Apnoea 1, Limb swelling 1, Lethargy 1, Thrombocytopenia 1, Diarrhoea 1, Abdominal pain 1, Respiratory distress 1, Kawasaki disease 1\t\nDrugs affecting theimmune response (18)\t26\tTacrolimus 15, Mycophenolate 7, Azathioprine 2,Methotrexate 1, Infliximab 1\tImmunosuppression 18\t\nAnti–bacterial (16)\t17\tCo–amoxiclav 4, Penicillin V 3, Amoxicillin 3, Flucloxacillin 2,Cefaclor 1, Cefalexin 1, Cefotaxime 1, Teicoplanin 1, Erythromycin 1\tDiarrhoea 7, Rash 4, Vomiting 4, Lip swelling 1, Deranged LFTs 1, Thrush 1\t\nDrugs used indiabetes (9)\t13\tInsulin detemir 4, Insulin aspart 3, Isophane insulin 2,Biphasic isophane 2, Human insulin 2,\tHypoglycaemia 9\t\nDrugs used in status epilepticus (8)\t12\tLorazepam 5, Diazepam 5, Midazolam 2\tRespiratory depression 8\t\nOpioid analgesia (6)\t7\tDihydrocodeine 3, Codeine phosphate 3, Fentanyl 1\tConstipation 4, Ileus 1, Decreased conscious level 1\t\nDrugs used in nausea (4)\t4\tOndansetron 4\tConstipation 4\t\nAnti–epileptic drugs (2)\t2\tCarbamazepine 1, Nitrazepam 1\tConstipation 1, Respiratory depression 1\t\nDrugs that suppress rheumatic disease (2)\t2\tMethotrexate 1, Anakinra 1\tImmunosuppression 2\t\nOther (16)\t4\tCalcium carbonate and Amlodipine 1, Oxybutynin 1, Baclofen 1\tConstipation 3\t\n\t2\tDimeticone 1, Carbocysteine 1\tRash 2\t\n\t2\tDesmopressin acetate 1, Alimemazine 1\tSeizure 2\t\n\t10\tGlucose and Dextrose 1, Propanolol 1, Acetazolomide 1,Spironolactone 1, Loperamide 1, Macrogols 1, Captopril 1,Alfacalcidol 1, Ethinylestradiol 1\tHyperglycaemia 1, Wheeze/Difficulty in breathing 1, Headache 1, Hyperkalaemia 1, Intestinal obstruction 1, Diarrhoea 1, Renal dysfunction 1, Hypercalcaemia 1, Inter–menstrual bleed 1\t\nWe cross-referenced presenting symptoms/signs against the medication history for each patient using the ADR profile for relevant drugs from the Summary of Product Characteristics (SPC) [14] in the Medicines Compendium or, if not available, the British National Formulary (BNF) [15]. We identified possible ADRs using this information combined with the clinical history and temporal relationships of the medication(s) taken. We reported all possible ADRs to the responsible clinicians and to the Yellow Card scheme.\n\n10.1371/journal.pone.0050127.g001Figure 1 Number of ADRs per patient with ≥ one ADR according to origin of prescription.\nWe assessed the origin of prescription for drugs thought to be associated with ADRs using classifications of:\n\n\nCommunity – drugs where prescriptions originated in community settings, for example general practice, or where administration took place prior to hospital admission (e.g. paramedic administered)\n\n\nHospital – drugs where the prescription originated, or administration took place, in hospital and then may or may not have been continued in community or outpatient settings\n\n\nOncology – all drugs prescribed, or administered, from the oncology ward.\n\n10.1371/journal.pone.0050127.t005Table 5 Possibly and definitely avoidable cases and explanation of assessment result.\nAvoidable\tFrequency\tADR(s)\tDrug Classes\tReason for potential avoidability\t\nDefinitely\t3\tDiarrhoea and/or vomiting\tAnti-bacterial\tInappropriate indication, signs/symptoms of viral illness\t\nDefinitely\t2\tConstipation\tCytotoxics, Drugs used in nausea,Opioid analgesia\tAppropriate prophylaxis not used\t\nDefinitely\t1\tLip swelling, rash\tAnti-bacterial\tSame ADR previously to same medication\t\nDefinitely\t1\tSeizure\tAntihistamine\tSame ADR previously to similar medication\t\nDefinitely\t1\tAdrenal suppression\tCorticosteroids\tAvoidable with more rational prescribing (prolonged use of drugs) and improved monitoring\t\nDefinitely\t1\tIntestinal obstruction\tAnti-motility drugs\tCould be prevented by improved parent/patient education\t\nDefinitely\t1\tDeranged renal function\tDrugs affecting the renin-angiotensin system\tAvoidable with improved monitoring\t\nPossibly\t9\tHypoglycaemia\tDrugs used in diabetes\tAvoidable with improved patient education (e.g. insulin use when unwell) and more rational prescribing\t\nPossibly\t8\tRespiratory depression\tDrugs used in status epilepticus, Hypnotics\tAlternative medicine available, Multiple doses given - avoidable with more rational prescribing\t\nPossibly\t6\tDiarrhoea/vomiting\tAnti-bacterial\tInappropriate indication, symptoms suggested viral infection\t\nPossibly\t5\tConstipation\tAntiepileptic drugs, Opioid analgesia,Drugs used in nausea, NSAIDs,Cytotoxics, Calcium-channel blockers,Calcium supplements\tProphylaxis not used\t\nPossibly\t4\tImmunosuppression\tDrugs affecting the immuneresponse, Corticosteroids\tPossibly Avoidable with improved monitoring of drug levels, Avoidable with more rational prescribing\t\nPossibly\t2\tHaematemesis\tNSAIDs\tAvoidable with improved patient education/more rational prescribing (less NSAID use)\t\nPossibly\t1\tNeutropenia\tCytotoxics\tSame ADR previously at same dose of medication\t\nPossibly\t1\tNeutropenia,thrombocytopenia, anaemia\tCytotoxics\tSuperficial infection after recent admission with febrile neutropenia. Possibly avoidable by prolonging antibiotic use or commencing GCSF\t\nPossibly\t1\tHyperglycaemia\tCorticosteroids\tAvoidable with more rational prescribing (prolonged course steroids used)\t\nPossibly\t1\tHyperglycaemia\tParenteral preparations\tAvoidable with more rational prescribing (more judicial use) or improved monitoring\t\nPossibly\t1\tSeizure\tPosterior pituitary hormones\tPossibly inappropriate medication used for a patient with seizures\t\nPossibly\t1\tDiarrhoea\tLaxatives\tAvoidable with improved patient education\t\nPossibly\t1\tIleus\tOpioid analgesia\tAvoidable with more rational prescribing (possibly use alternative analgesia)\t\nPossibly\t1\tCNS depression\tOpioid analgesia\tAvoidable with improved patient education\t\nPossibly\t1\tVomiting\tCytotoxics\tPossibly avoidable with more appropriate anti-emetic prophylaxis\t\nPossibly\t1\tGastritis\tCorticosteroids\tPrevious gastritis. Possibly avoidable with improved prophylaxis\t\nPossibly\t1\tHypercalcaemia\tVitamins\tAvoidable with improved monitoring\t\nDrug class, according to BNF classification, was recorded for drugs implicated in causing ADRs. We performed assessment of causality using the Liverpool ADR Causality Assessment Tool, an algorithm developed by the investigators. [16] A novel aspect of the tool, which allows for a case to be classified as ‘definite’ causality, is that prior drug exposure that led to the same ADR was judged as being equivalent to a prospective re-challenge. Three investigators (RG, MT, AN) independently assessed causality for all ADR cases. Agreement on causality between all three investigators was taken as accepted consensus. Where the investigators did not achieve consensus, a fourth investigator (MuP) assessed cases to decide on causality.\n\nThe investigating group met to assess avoidability of the ADRs by consensus using the definitions developed by Hallas et al. [17] We determined the type of ADR (using the Rawlins and Thompson classification) [18] and severity using the Hartwig scale. [19] We chose these assessment tools to describe the ADRs in our study as they have been used in ADR studies by other investigators and can be completed quickly. Three investigators (AN, MuP, RLS) independently assessed 217/4514 (4.8%) reports of admissions exposed to medication, but deemed not to have had an ADR, to assess for occurrence of possible ADR cases wrongly classified by the study team.\n\nWe calculated the mean cost of ADR admissions to the study hospital, using information provided by the finance department for the cost of each case. Paediatric emergency admission data from the Health and Social Care Information Centre (National Health Service (NHS)), between 2009/2010, was used to estimate the total cost of ADR admissions annually in England.\n\nEthics Statement\nThe Liverpool Paediatric Research Ethics Committee issued a formal opinion that this study was audit and informed consent from individual patients was not necessary.\n\nStatistical Analysis\nAnalyses of the rates of ADRs were based on the number of admissions with the rate expressed as ADR per 100 admissions, together with 95% confidence intervals. Other results are presented as medians and interquartile ranges or percentage frequencies and 95% percent confidence intervals. The formal statistical analysis was based on the data obtained at the first admission for patients exposed to a medication. Univariate statistical analyses were performed using the Mann-Whitney U test except for frequency data, which were analysed using a chi-square test. A multivariate logistic regression analysis was undertaken to calculate odds ratios for possible risk factors for ADR. A P-value <0.05 was regarded as being significant. All data were analyzed anonymously.\n\nResults\nOver the study period, there were 6821 patients (3961 boys and 2860 girls) admitted 8345 times to the study hospital. The median number of admissions per patient was one, with 932 patients having more than one acute admission, up to a maximum of fifteen. 178 patients (94 boys, 84 girls) experienced 240 admissions with an ADR. This gives an incidence of 2.9 ADRs per 100 admissions (95% CI 2.5, 3.3). In 233 of 240 (97.1%) admissions an ADR was deemed to have directly caused, or contributed to, admission. There were 249 ADRs in 240 admissions, with nine admissions having two separate ADRs. 35/178 (19.7%) patients had more than one admission (maximum seven) with an ADR. Assessment of a sample of non-ADR cases (n = 217) confirmed that no admissions were due to ADRs.\n\nThere were 4656 patients exposed to medication in the two weeks prior to acute hospital admission. Of these, 142 (3%) had a suspected ADR on their first hospital admission. There was no significant difference between the proportion of boys (76/2677, 2.8%) and girls (66/1979, 3.3%) experiencing an ADR on their first admission, for the group as a whole or oncology patients studied separately. For non-oncology patients, there was a slightly higher proportion of girls admitted with an ADR (boys 48/2627 (1.8%), girls 53/1955 (2.7%), P = 0.044), although overall more boys than girls were admitted.\n\nThe median age of the 4656 patients who had been exposed to a drug on their first admission was 3 years 1 month (IQR 9 months, 9 years). Patients with an ADR (6y; 2y 4m, 11y) were significantly older (P<0.01) than those without (3y; 9m, 9y) (Table 1). There was no age difference between 41 oncology patients admitted with an ADR (6y; 3y, 10y) and 33 oncology patients admitted without an ADR (6y; 3y 6m, 13y). There was a significant age difference (P<0.01) between 101 non-oncology patients admitted with ADR (6y; 1y 7m, 11y) and 4481 admitted without ADR (2y 11m; 9m, 9y).\n\nPatients admitted with an ADR had taken a greater number of drugs than those admitted for other reasons (Table 2). For patients admitted with an ADR (n = 142), the number of medicines taken was higher (6; 3, 9, P<0.001) than those for other reasons (n = 4514) (2; 1, 3). The number of medicines taken by oncology patients admitted with an ADR (8; 5, 10) was higher than those admitted without an ADR (4; 3, 7) and this difference was also found for non-oncology patients (with ADR 5; 3, 9: without ADR 2; 1, 3).\n\nLogistic regression analysis showed a trend towards boys being less likely to experience an ADR than girls, with an odds ratio (OR) of 0.77 (95% CI 0.52, 1.12, P = 0.17) (Table 3). There was an increased likelihood of ADRs with increasing age (OR 1.04, 95% CI 1.003, 1.08, P = 0.03). No children were admitted with an ADR in the first month of life. Oncology patients were much more likely to have an ADR causing admission (OR 29.71, 95% CI 17.35, 50.88, P<0.001). The likelihood of a child being admitted with an ADR increased with the number of medicines taken (OR 1.24, 95% CI 1.19, 1.29, P<0.001). Therefore, for each additional medicine taken the risk of an ADR occurring increases by almost 25%.\n\nDrug Class\nThe main class of drugs contributing to ADR-related admissions (n = 110; 44.2%) was cytotoxic drugs (Table 4). Corticosteroids (n = 102, 41%), non-steroidal anti-inflammatory drugs (NSAIDs) (n = 31, 12.4%), vaccines (n = 22, 8.8%) and immunosuppressants (n = 18, 7.2%) were the next most commonly implicated drug classes causing ADR-related hospital admissions.\n\nADRs\nThe most common ADRs were oncology related including neutropenia (89), thrombocytopenia (55) and anaemia (38). The next most common ADR was immunosuppression (74), occurring in both oncology and non-oncology patients. Post-operative bleeding, linked to peri-operative corticosteroid administration and/or NSAIDs, caused 28 admissions (26 post-tonsillectomy). Vomiting (15), diarrhoea (14), rash (11) and constipation (9) were all common ADRs causing admission. Hypoglycaemia in diabetic patients treated with regular insulin caused nine admissions. Respiratory depression following treatment for status epilepticus caused eight admissions to the hospital’s paediatric intensive care unit (PICU).\n\nOrigin of Prescriptions\n44/249 (17.7%) of ADRs were associated with prescriptions from the community, 85/249 (34.1%) with prescriptions originating in hospital for treatment of conditions other than oncology; 120/249 (48.2%) with prescriptions originating from oncology. Of the patients with one ADR (n = 140) in the study period, 39 (27.9%) occurred with community prescriptions, 71 (50.7%) with hospital prescriptions and 30 (21.4%) with oncology prescriptions; hospital-based prescriptions, particularly oncology, predominated in patients who had more than one ADR (Figure 1).\n\nADR Assessments (Reaction Type, Causality, Severity, Avoidability)\n238/249 (95.6%) ADRs were classified as type A (predictable from the known pharmacology) with 11/249 (4.4%) being type B (not predictable). Assessment of causality showed the majority of cases (94/249, 37.8%) to be in the ‘definite’ category. Oncology cases accounted for 80 of these 94 definite cases (Table S1). 92/238 (39.1%) type A reactions were assessed to be of definite causality. 8/11 (72.7%) type B reactions were assessed to be ‘possible.’\n\n223/249 (89.6%) of the ADRs were classified as grade 3 (‘required treatment or drug administration discontinued’) according to the Hartwig severity scale, as we defined anyone requiring admission to hospital as ‘needing treatment.’ 14 (5.6%) were classified as grade 4 (‘resulted in patient transfer to higher level of care’) including respiratory depression (8), immunosuppression (4), neutropenia (1), fever/seizure (1) and leukencephalopathy (1). Three ADRs were classified as grade 5 (‘caused permanent harm or significant haemodynamic instability’). Two of these most severe ADRs occurred in oncology patients with febrile neutropenia and septicaemia and the remaining case was a child who required bowel resection for ileus following treatment with loperamide. No ADRs contributed to death. The majority (16/17, 94.1%) of the more severe reactions (≥ Grade 4 Hartwig severity score) were assessed to have definite or probable causality.\n\nWe determined 112/120 (93.3%) of the oncology patient admission ADRs to be unavoidable, with a further six being possibly avoidable and two definitely avoidable. These ‘definitely avoidable’ cases were oncology patients with constipation following treatment with vincristine and ondansetron (with one also having dihydrocodeine) without laxative prophylaxis.\n\nOf the ADR admissions not associated with oncology patients, 82/129 ADRs (63.6%) were classified as unavoidable, 39 (30.2%) as possibly avoidable (14/39 prescribed from the community) and 8 (7.6%) as definitely avoidable (5/8 prescribed from the community). The eight ‘definitely avoidable’ comprised four patients prescribed antibiotics where the antibiotic choice or indication was deemed to be inconsistent with good practice, one patient with intestinal obstruction being treated with loperamide who had not passed stool for two days prior to admission, one patient who had a seizure after alimemazine having had two previous occurrences of seizure following anti-histamine use, one patient with deranged renal function which improved after cessation of captopril where improved renal function monitoring may have avoided the ADR, and one patient who presented with adrenal suppression following two years of continuous treatment with intranasal corticosteroids. The possibly avoidable cases and the reasons for their allocation are summarised in Table 5. 41/55 (74.5%) of possibly or definitely avoidable cases were classified as ‘definite’ or ‘probable’ causality.\n\nCost of ADRs\nWe calculated the mean cost of 238/240 ADR admissions to the study hospital, using information provided by the finance department, to be £4753 per admission (95% CI £3439, £6066). Cost data were missing for two ADR admissions. Data from the Health and Social Care Information Centre (National Health Service (NHS)) [20] showed, in one year between 2009/2010, the total number of paediatric emergency admissions in England was approximately 597,800 (includes paediatrics and paediatric surgery, cardiology and neurology). We estimate the annual mean cost of ADR admissions to the NHS in England to be £82.4M. Using the upper and lower confidence intervals for our estimate of ADR incidence (2.5%, 3.3%), and study hospital costs, we estimate the cost to the NHS in England to be between £51.4–119.7M.\n\nDiscussion\nThis prospective observational study is the largest of its kind in children and the only one to comprehensively assess causality, type of reaction, severity, avoidability and risk factors. In our setting, the majority of admissions associated with ADRs in children occurred as a result of prescriptions originating in hospital. Potential preventative strategies for ADRs causing admission in children should therefore be targeted at hospital prescribing. Our analysis of the ‘definitely avoidable’ ADRs in our study suggests careful attention to practical aspects of care, such as improved monitoring, following prescribing guidelines, patient education, and heightened suspicion about potential reactions could lead to a reduction in the frequency of this important problem.\n\nThis study gave an estimated ADR admission incidence of 2.9% (95% CI 2.5, 3.3), which is similar to a pooled estimate of 2.9% (2.6%, 3.1%) from a recent comprehensive systematic review. [11] The incidence of ADRs in this study was significantly less than that of a large US study published in 1988 (3.96%, 95%CI 3.52, 4.43). [2] In that study the top three drugs causing ADRs were phenobarbital, aspirin and phenytoin, all of which are used in children much less now because of safety concerns and because better alternatives are available. The majority of ADRs that were seen during our study were oncology related. Oncology patients are often exposed to medications causing ADRs, including neutropenia, nausea, vomiting, diarrhoea and thrombocytopenia, all of which may require admission. [21] These ADRs are expected and may be unavoidable given the underlying illness and the treatment options available. Although several studies have evaluated a potential preventative strategy for neutropenia [22], no definite evidence exists regarding the use of granulocyte-colony stimulating factors (GCSF) to prevent such ADRs [23].\n\nSteroids, along with other immunosuppressants, increase risk of infection. [24] These ADR admissions were children taking steroids, admitted with proven bacterial, or viral infections associated with immunosuppression, such as shingles. Although such infections occur in healthy children, immunosuppressive therapy may be causal and this may be an under-recognised ADR.\n\nThe majority of admissions for post-operative bleeding (23/28) occurred in patients exposed to intravenous dexamethasone for anti-emetic prophylaxis, and non-steroidal anti-inflammatory drugs (NSAIDs). A few patients received either steroid or NSAIDs. Dexamethasone has been linked to post-tonsillectomy bleeding [25] but its role, and the role of NSAIDs, in causing secondary haemorrhage is yet to be determined. [26], [27] However, intra-operative steroids have played a major role in improving post-operative nausea and vomiting in children. [26], [28]\n\n\nRespiratory depression following treatment of seizures with benzodiazepines, a well recognised event, [29] was the cause of eight PICU admissions, some of whom were transfers from other district general hospitals. Some occurred as a result of rectal diazepam used by paramedics in out-of-hospital care. The benefit/risk ratio of drugs used to treat seizures has been the objective of a number of clinical studies [30], [31], and there may be better drugs to treat seizures in children. [32]\n\n\nAssessment of avoidability was undertaken by consensus approach using the definitions by Hallas. The definitions, which are based on avoidability linked to standards of care, are wide and may lead to variability in assessor rating. The Hallas criteria are less prescriptive than some other avoidability tools but there is little evidence to suggest preference for the use of any one avoidability tool. [33]\n\n\nWhile this study has highlighted important ADRs, we cannot be certain of the aetiological fraction (the risk of an event occurring in the presence of a risk factor) for some of the drugs in their contribution to the ADRs. Further prospective, cohort studies that capture benefits and harms using validated tools and all medication exposures with adequate sample size are needed to assess this accurately and to estimate more precisely risks compared to benefits.\n\nWe calculated the cost of ADRs to the NHS in England using knowledge of the cost of admissions to the study hospital, our estimate of the incidence of ADRs causing admission and an estimate of total paediatric admissions annually to hospitals in England, although this may be an underestimate, as the multiplier which we used (total paediatric emergency admissions), did not include admissions of children from other specialities.\n\nConclusion\nWe have demonstrated that ADRs cause a small but substantial proportion of admissions to hospital and some of these are serious and potentially avoidable. The results of this study should be used to inform paediatric pharmacovigilance practice. Preventing avoidable ADRs will require careful attention to good prescribing practice.\n\nSupporting Information\nTable S1 Origin of prescription of ADR drugs by type of reaction, severity score, avoidability and causality assessment.\n\n(DOCX)\n\nClick here for additional data file.\n==== Refs\nReferences\n1 \nMcKenzie MW , Marchall GL , Netzloff ML , Cluff LE (1976 ) Adverse drug reactions leading to hospitalization in children . Journal of Pediatrics \n89 : 487 –490 .986429 \n2 \nMitchell AA , Lacouture PG , Sheehan JE , Kauffman RE , Shapiro S (1988 ) Adverse drug reactions in children leading to hospital admission . Pediatrics \n82 : 24 –29 .3380598 \n3 \nMartinez-Mir I , Garcia-Lopez M , Palop V , Ferrer JM , Estan L , et al (1997 ) A prospective study of adverse drug reactions as a cause of admission to a paediatric hospital . 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The Lancet \n366 : 205 –210 .\n31 \nMcMullan J , Sasson C , Pancioli A , Silbergleit R (2010 ) Midazolam Versus Diazepam for the Treatment of Status Epilepticus in Children and Young Adults: A Meta-analysis . Academic Emergency Medicine \n17 : 575 –582 .20624136 \n32 Appleton R, Macleod S, Martland T (2008) Drug management for acute tonic-clonic convulsions including convulsive status epilepticus in children. Cochrane Database of Systematic Reviews: Art. No.: CD001905. doi:001910.001002/14651858.CD14001905.pub14651852.\n33 \nFerner RE , Aronson JK (2010 ) Preventability of drug-related harms part I: A systematic review . Drug Safety \n33 : 985 –994 .20925436\n\n", "fulltext_license": "CC BY", "issn_linking": "1932-6203", "issue": "7(12)", "journal": "PloS one", "keywords": null, "medline_ta": "PLoS One", "mesh_terms": "D002648:Child; D002675:Child, Preschool; D064420:Drug-Related Side Effects and Adverse Reactions; D006776:Hospitals, Pediatric; D006801:Humans; D010343:Patient Admission; D011446:Prospective Studies; D006113:United Kingdom", "nlm_unique_id": "101285081", "other_id": null, "pages": "e50127", "pmc": null, "pmid": "23226510", "pubdate": "2012", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "986429;12193434;15064936;19531524;16023510;12535500;8877022;3380598;1524068;20479291;19066382;15310780;20624136;11112957;18646081;15089814;21366649;11851647;22194808;16034921;20925436;16689555;2394974;11453893;22403604;11072960;16882807", "title": "Adverse drug reactions causing admission to a paediatric hospital.", "title_normalized": "adverse drug reactions causing admission to a paediatric hospital" }

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"drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE" } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Metrorrhagia", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intestinal obstruction", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Immunosuppression", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Back pain", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Renal impairment", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hyperkalaemia", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Constipation", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Impaired healing", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Depressed level of consciousness", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypertension", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Wheezing", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haematuria", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Adrenal suppression", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lip swelling", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Febrile neutropenia", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypercalcaemia", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Headache", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Post procedural haemorrhage", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Candida infection", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ileus", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haematemesis", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mucosal inflammation", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Liver function test abnormal", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abdominal pain", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hyperglycaemia", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastritis", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Increased appetite", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GALLAGHER RM, MASON JR, BIRD KA, KIRKHAM JJ, PEAK M, WILLIAMSON PR, ET AL. ADVERSE DRUG REACTIONS CAUSING ADMISSION TO A PAEDIATRIC HOSPITAL. PLOS ONE 04-DEC-2012;7 (12):1-8.", "literaturereference_normalized": "adverse drug reactions causing admission to a paediatric hospital", "qualification": "1", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20140723", "receivedate": "20130108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 9005252, "safetyreportversion": 13, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": 1, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150326" } ]

{ "abstract": "Microsphaeropsis arundinis, a dematiaceous mold, is emerging as a cause of skin and soft tissue infection in immunocompromised hosts. Diagnosis is challenging because of the difficulty in identifying Microsphaeropsis species morphologically and few data are available to guide optimal management. We report 3 renal transplant recipients with M. arundinis soft tissue infection, where the etiological agent was diagnosed using DNA sequencing, and who were successfully treated with prolonged courses of extended-spectrum triazole antifungal agents.", "affiliations": "Infectious Diseases Department, Wollongong Hospital, Wollongong, New South Wales, Australia.;Centre for Infectious Diseases and Microbiology Laboratory Services, Institute for Clinical Pathology and Medical Research - Pathology West, Westmead Hospital, Westmead, New South Wales, Australia.;Centre for Infectious Diseases and Microbiology Laboratory Services, Institute for Clinical Pathology and Medical Research - Pathology West, Westmead Hospital, Westmead, New South Wales, Australia.;Department of Renal Medicine, Westmead Hospital, Westmead, New South Wales, Australia.;Department of Infectious Diseases and Microbiology, Concord Hospital, Concord, New South Wales, Australia.;Infectious Diseases Department, Wollongong Hospital, Wollongong, New South Wales, Australia.", "authors": "Crawford|S J|SJ|;Chen|S C-A|SC|;Halliday|C|C|;Rangan|G K|GK|;Gottlieb|T|T|;Reid|A B|AB|", "chemical_list": "D000935:Antifungal Agents", "country": "Denmark", "delete": false, "doi": "10.1111/tid.12464", "fulltext": null, "fulltext_license": null, "issn_linking": "1398-2273", "issue": "17(6)", "journal": "Transplant infectious disease : an official journal of the Transplantation Society", "keywords": "Microsphaeropsis arundinis; fungi; immunocompromised host; molecular typing; opportunistic infection; phaeohyphomycosis; renal transplantation; skin diseases, infectious; soft tissue infections", "medline_ta": "Transpl Infect Dis", "mesh_terms": "D000328:Adult; D000368:Aged; D000935:Antifungal Agents; D001203:Ascomycota; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D016030:Kidney Transplantation; D008297:Male; D009181:Mycoses; D018461:Soft Tissue Infections", "nlm_unique_id": "100883688", "other_id": null, "pages": "915-20", "pmc": null, "pmid": "26437250", "pubdate": "2015-12", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Microsphaeropsis arundinis skin and soft tissue infection in renal transplant recipients: three case reports and a review of the literature.", "title_normalized": "microsphaeropsis arundinis skin and soft tissue infection in renal transplant recipients three case reports and a review of the literature" }

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TRANSPL INFECT DIS. 2015;17:915-920", "literaturereference_normalized": "microsphaeropsis arundinis skin and soft tissue infection in renal transplant recipients three case reports and a review of the literature", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20171205", "receivedate": "20171205", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14249642, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" }, { "companynumb": "AU-APOTEX-2017AP021935", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090419", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "43", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cellulitis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Soft tissue infection", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Fungal infection", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Fungal skin infection", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CRAWFORD SJ, CHEN SC-A, HALLIDAY C, RANGAN GK, GOTTLIEB T, REID AB. MICROSPHAEROPSIS ARUNDINIS SKIN AND SOFT TISSUE INFECTION IN RENAL TRANSPLANT RECIPIENTS: THREE CASE REPORTS AND A REVIEW OF THE LITERATURE. DOI: 10.1111/TID.12464. TRANSPL INFECT DIS. 2015;17:915-920", "literaturereference_normalized": "microsphaeropsis arundinis skin and soft tissue infection in renal transplant recipients three case reports and a review of the literature", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20171206", "receivedate": "20171206", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14253245, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" } ]

{ "abstract": "L-Asparaginase has significantly improved outcome for children with acute lymphoblastic leukemia and has become an essential component of multiagent chemotherapy. However, there are many adverse events due to L-asparaginase, including acute pancreatitis. The pathology of L-asparaginase-associated pancreatitis (AAP) remains unclear. We compared patients who developed AAP (n=29) and random matched controls (n=36) who had been enrolled in the Japan Association of Childhood Leukemia Study of the ALL-02 protocol. AAP and control patients were matched for age, sex, treatment, and protocol risk. We examined correlations between AAP development and clinical symptoms, laboratory data, and concomitant medication. Abdominal pain and nausea were common presenting symptoms for AAP. There was an increased risk of AAP in patients using gastric acid-suppressing agents and antithrombin (AT) supplementation. Mean fibrinogen and AT levels before the onset of AAP were lower in AAP patients than in controls. Decreased AT and fibrinogen levels resulting from the strong suppression of protein synthesis by L-asparaginase were predictive signs for AAP. Our epidemiological approach should prove clinically useful for the diagnosis the AAP as early as possible.", "affiliations": "Department of Pediatrics, Osaka University Graduate School of Medicine.;Department of Pediatrics, Asahikawa Medical University, Asahikawa.;Department of Pediatrics, Osaka City General Hospital, Osaka.;Department of Pediatrics, Hiroshima University Hospital, Hiroshima.;Department of Pediatrics, Osaka General Medical Center, Osaka.;Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya.;Department of Pediatrics, Kyoto University Hospital, Kyoto, Japan.", "authors": "Hashii|Yoshiko|Y|;Yoshida|Makoto|M|;Hara|Junichi|J|;Nishimura|Shinichiro|S|;Yumura-Yagi|Keiko|K|;Horibe|Keizo|K|;Nakahata|Tatsutoshi|T|", "chemical_list": "D005343:Fibrinolytic Agents; D054328:Proton Pump Inhibitors; D001215:Asparaginase", "country": "United States", "delete": false, "doi": "10.1097/MPH.0000000000001193", "fulltext": null, "fulltext_license": null, "issn_linking": "1077-4114", "issue": "40(5)", "journal": "Journal of pediatric hematology/oncology", "keywords": null, "medline_ta": "J Pediatr Hematol Oncol", "mesh_terms": "D015746:Abdominal Pain; D000208:Acute Disease; D000293:Adolescent; D001215:Asparaginase; D002648:Child; D002675:Child, Preschool; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D007223:Infant; D007564:Japan; D007938:Leukemia; D008297:Male; D009325:Nausea; D010195:Pancreatitis; D054328:Proton Pump Inhibitors", "nlm_unique_id": "9505928", "other_id": null, "pages": "374-378", "pmc": null, "pmid": "29697579", "pubdate": "2018-07", "publication_types": "D016430:Clinical Trial; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial", "references": null, "title": "Acid-suppressing Drugs and a Low 1 Level of Antithrombin as Risk Factors for L-Asparaginase-associated Pancreatitis: A Case-control Study in the Japan Association of Childhood Leukemia Study (JACLS).", "title_normalized": "acid suppressing drugs and a low 1 level of antithrombin as risk factors for l asparaginase associated pancreatitis a case control study in the japan association of childhood leukemia study jacls" }

[ { "companynumb": "JP-JAZZ-2018-JP-011246", "fulfillexpeditecriteria": "2", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "84,000 U/M2 IN STANDARD-RISK (SR)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "880,000 U/M2 IN HIGH-RISK (HR)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "1,254,000 U/M2 IN EXTREMELY HIGH-RISK (ER)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "660,000 U/M2 IN T PROTOCOLS", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pancreatitis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HASHII Y, YOSHIDA M, HARA J, NISHIMURA S, YUMURA-YAGI K, HORIBE K, ET AL.. ACID-SUPPRESSING DRUGS AND A LOW 1 LEVEL OF ANTITHROMBIN AS RISK FACTORS FOR L-ASPARAGINASE-ASSOCIATED PANCREATITIS: A CASE-CONTROL STUDY IN THE JAPAN ASSOCIATION OF CHILDHOOD LEUKEMIA STUDY (JACLS). J PEDIATR HEMATOL ONCOL. 2018?40:374?378", "literaturereference_normalized": "acid suppressing drugs and a low 1 level of antithrombin as risk factors for l asparaginase associated pancreatitis a case control study in the japan association of childhood leukemia study jacls", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20181004", "receivedate": "20181004", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15465188, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190204" } ]

{ "abstract": "BACKGROUND\nIbuprofen is a nonsteroidal anti-inflammatory drug available over the counter and on prescription for the management of pain and inflammation. Severe toxicity is rare following deliberate self-poisoning with ibuprofen, and patients are usually either asymptomatic or develop only mild gastrointestinal toxicity. Although there have been nine other reported fatalities, co-existent factors have probably contributed to all of these deaths. We report here a fatality from isolated toxicity following self-poisoning with sustained-release ibuprofen.\n\n\nMETHODS\nA 26-year-old female presented after deliberate ingestion of up to 105 g sustained-release ibuprofen, with a reduced level of consciousness, severe metabolic acidosis and haemodynamic compromise. Despite intensive supportive management, gut decontamination with multidose activated charcoal and correction of the metabolic acidosis with sodium bicarbonate and haemofiltration, the patient did not survive. The ibuprofen concentration ante mortem on presentation in peripheral blood was 760 mg/l and the concentrations post mortem were 518 mg/l in peripheral blood, 74 mg/kg in liver extract and 116 mg/l in the gastric contents.\n\n\nCONCLUSIONS\nMost patients with ibuprofen poisoning are either asymptomatic or have mild gastrointestinal symptoms; severe poisoning with ibuprofen is rare. We report the first death related to isolated sustained-release ibuprofen poisoning.", "affiliations": "Guy's and St Thomas' Poisons Unit, Guy's and St Thomas' NHS Foundation Trust, London, UK. David.Wood@gstt.nhs.uk", "authors": "Wood|David Michael|DM|;Monaghan|Jane|J|;Streete|Peter|P|;Jones|Alison Linda|AL|;Dargan|Paul Ivor|PI|", "chemical_list": "D003692:Delayed-Action Preparations; D007052:Ibuprofen", "country": "England", "delete": false, "doi": "10.1186/cc4850", "fulltext": "\n==== Front\nCrit CareCritical Care1364-85351466-609XBioMed Central London cc48501654248710.1186/cc4850ResearchFatality after deliberate ingestion of sustained-release ibuprofen: a case report Wood David Michael 1David.Wood@gstt.nhs.ukMonaghan Jane 1Jane.Monaghan@gstt.nhs.ukStreete Peter 1Peter.Streete@gstt.nhs.ukJones Alison Linda 1Alison.Jones@gstt.nhs.ukDargan Paul Ivor 1Paul.Dargan@gstt.nhs.uk1 Guy's and St Thomas' Poisons Unit, Guy's and St Thomas' NHS Foundation Trust, London, UK2006 8 3 2006 10 2 R44 R44 6 1 2006 23 1 2006 9 2 2006 10 2 2006 Copyright © 2006 Wood et al.; licensee BioMed Central Ltd.2006Wood et al.; licensee BioMed Central Ltd.This is an open access article distributed under the terms of the Creative Commons Attribution License (), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\n\nIntroduction\nIbuprofen is a nonsteroidal anti-inflammatory drug available over the counter and on prescription for the management of pain and inflammation. Severe toxicity is rare following deliberate self-poisoning with ibuprofen, and patients are usually either asymptomatic or develop only mild gastrointestinal toxicity. Although there have been nine other reported fatalities, co-existent factors have probably contributed to all of these deaths. We report here a fatality from isolated toxicity following self-poisoning with sustained-release ibuprofen.\n\nCase report\nA 26-year-old female presented after deliberate ingestion of up to 105 g sustained-release ibuprofen, with a reduced level of consciousness, severe metabolic acidosis and haemodynamic compromise. Despite intensive supportive management, gut decontamination with multidose activated charcoal and correction of the metabolic acidosis with sodium bicarbonate and haemofiltration, the patient did not survive. The ibuprofen concentration ante mortem on presentation in peripheral blood was 760 mg/l and the concentrations post mortem were 518 mg/l in peripheral blood, 74 mg/kg in liver extract and 116 mg/l in the gastric contents.\n\nDiscussion\nMost patients with ibuprofen poisoning are either asymptomatic or have mild gastrointestinal symptoms; severe poisoning with ibuprofen is rare. We report the first death related to isolated sustained-release ibuprofen poisoning.\n==== Body\nIntroduction\nIbuprofen is a nonsteroidal anti-inflammatory drug (NSAID) commonly used as an analgesic, as an anti-inflammatory agent and as an anti-pyretic agent [1,2]. The predominant pharmacological action of ibuprofen is to inhibit the activity of cyclooxygenase, an enzyme crucial for the synthesis of prostaglandins. The subsequent inhibition of prostaglandin production leads to a reduction in inflammation, temperature and pain, both centrally and peripherally. Ibuprofen is manufactured and marketed as a 'normal' release preparation at a dose of 400 mg three times a day or a sustained-release preparation at a dose of 800–1600 mg once a day. In the United Kingdom the 'normal'-release preparation is available on general sales licence, pharmacy and prescription, but the sustained-release preparation is available only as a 'prescription only medication'.\n\nThere have been only nine previously reported fatalities following ibuprofen intoxication, although in eight of these cases other co-existent factors have probably contributed to death [3-11]. We report here the first case report of a fatality following isolated ingestion of sustained-release ibuprofen that did not respond to maximal supportive care with ante mortem and post mortem ibuprofen concentrations.\n\nCase report\nA 26-year-old woman with no significant past medical history presented after ingestion of up to 132 tablets of 800 mg sustained-release ibuprofen, equivalent to approximately 105 g. This estimate of the amount ingested was based on empty ibuprofen packets found near her. The patient was bought into the Emergency Department having been found collapsed and unconscious at home by her family, who had last seen her well approximately five hours previously. There was no history of vomiting, gastrointestinal haemorrhage or seizures prior to presentation at hospital. Her initial Glasgow Coma Scale was 3/15 and the patient was therefore intubated and ventilated to provide a protected airway. On presentation she was haemodynamically compromised with a systolic blood pressure of 80 mmHg. The patient's initial electrocardiogram showed sinus rhythm, normal QRS duration and normal QT duration, but widespread myocardial ischaemia was noted. Initial biochemistry blood test results were sodium 132 mmol/l, potassium 4.7 mmol/l, urea 4.8 mmol/l, creatinine 159 μmol/l and venous blood glucose 4.7 mmol/l. Paracetamol and salicylate concentrations were not detected on her admission blood samples. Arterial blood gases showed a severe metabolic acidosis with pH 6.99, base excess of -21 and lactate of 17 mmol/l. The patient was commenced on epinephrine and norepinephrine for inotropic support in view of the significant hypotension, and the Guy's and St Thomas' Poisons Unit was contacted for further advice on management.\n\nSince this was potentially a life-threatening ingestion of a sustained-release preparation of ibuprofen, it was recommended that multidose activated charcoal (50 g activated charcoal every 3–4 hours) should be given via a nasogastric tube to try and reduce further absorption of ibuprofen from the gastrointestinal tract. The patient's severe metabolic acidosis should be corrected with repeated doses of intravenous boluses of 8.4% sodium bicarbonate, and haemofiltration with a bicarbonate buffer if the metabolic acidosis did not respond to intravenous sodium bicarbonate. Other potential common drug and toxicological causes of a high anion gap lactic acidosis are summarised in Table 1. It should be ensured that the patient is adequately filled with intravenous fluid to sustain blood pressure prior to the commencement of any additional inotropic support.\n\nDespite fluid resuscitation and maximal infusion doses of epinephrine and norepinephrine, the patient remained hypotensive with a systolic blood pressure of 80 mmHg. Additionally her metabolic acidosis remained resistant to intravenous sodium bicarbonate and haemofiltration with a bicarbonate buffer, with only minor improvement to pH 7.00. Her clinical condition continued to deteriorate and approximately five hours post-presentation to the Emergency Department the patient suffered a ventricular tachycardia/ventricular fibrillation cardiac arrest, which did not respond to standard Advanced Life Support protocol cardiopulmonary resuscitation.\n\nResults\nSerum toxicology screening\nSamples of ante mortem serum were obtained following admission and were analysed for ibuprofen by the Medical Toxicology Laboratory in London. Post mortem samples of peripheral whole blood, urine, gastric contents and liver extract were analysed at the local toxicology laboratory for ibuprofen and other drugs. Ibuprofen concentrations were measured by high-pressure liquid chromatography with ultraviolet detection. Ante mortem serum ibuprofen concentrations were 760 mg/l on presentation, rising to a peak concentration of 1,050 mg/l 90 minutes after presentation. Post mortem ibuprofen concentrations were 518 mg/l, 264 mg/l, 116 mg/l and 74 mg/kg in the peripheral whole blood, urine, gastric contents and liver extract, respectively. No other drugs were detected in a broad toxicology screen; analysis of the ante mortem and post mortem serum samples only detected atracurium and lignocaine given following admission to the hospital.\n\nPost mortem\nThe cause of death was probably directly related to the ibuprofen overdose, since there was no evidence of another cause of death at the post mortem examination. Of particular note there was no evidence of cerebral oedema, no underlying artherosclerotic disease of the coronary arteries and no evidence of previous myocardial infarction. Although there was altered blood in the gastric fluid, there was no evidence of oesophageal or gastric erosions.\n\nDiscussion\nSevere poisoning and death following poisoning with ibuprofen is extremely uncommon. Most cases are either asymptomatic or experience mild gastrointestinal symptoms only [4,5]. In the case presented here the patient presented after ingestion of up to 105 g sustained-release ibuprofen with a reduced Glasgow Coma Scale, a severe metabolic acidosis and significant haemodynamic compromise. Despite meticulous supportive care initially in the Emergency Department and subsequently in the intensive care unit, attempted correction of her metabolic acidosis and the use of multidose activated charcoal to reduce further ibuprofen absorption from the gastrointestinal tract, the patient did not survive. This is the first reported case of fatality following ingestion of sustained-release ibuprofen and the first fatality following isolated ibuprofen toxicity.\n\nIbuprofen is a NSAID commonly used as an analgesic, as an anti-pyretic agent and as an anti-inflammatory agent [1,2]. The predominant pharmacological effect of ibuprofen, similar to other NSAIDs, is to inhibit the activity of cyclooxygenase (both COX-1 and COX-2), leading to an inhibition of prostaglandin synthesis. Following a therapeutic dose of 400 mg, the serum ibuprofen concentration is approximately 28 mg/l (range 17–36 mg/l) [12]. Clinical features of toxicity of ibuprofen and other NSAIDs are predictable and occur due to an inhibition of cyclooxygenase activity.\n\nThe American Academy of Clinical Toxicology and European Association of Poisons Centres and Clinical Toxicologists have published a position statement on the use of multidose activated charcoal [13]. This position statement, however concentrated on the evidence base for the increased elimination of drugs undergoing enterohepatic/enteric circulation, rather than reducing the absorption of sustained-release or modified-release preparations.\n\nIn the case reported here a sustained-release preparation of ibuprofen was ingested, and therefore multidose activated charcoal was recommended to try and reduce further absorption of ibuprofen. The post mortem gastric content ibuprofen concentration was 116 mg/l, suggesting a significant amount of ibuprofen had still not been absorbed more than five hours post-presentation to the Emergency Department. Another patient who was found dead who had recently been prescribed an 800 mg preparation of ibuprofen, presumed to be a sustained-release preparation, had a post mortem total ibuprofen concentration of 131 mg in the gastric contents [8]. Both our case and the other presumed sustained-release case would support the use of multidose activated charcoal in the management of patients who have ingested a sustained-release preparation of ibuprofen in any subsequent cases.\n\nThe toxicity of ibuprofen following self-poisoning has been reported in five large case series [3-5,10,14]. Between 80% and 90% of the patients in these case series were either asymptomatic or had mild gastrointestinal symptoms, such as nausea, vomiting and diarrhoea, following ibuprofen intoxication [3-5]. Several case series have demonstrated that, in patients with a history of ingestion of less than approximately 100 mg/kg ibuprofen, symptoms did not occur [4,5,15] and that symptoms of ibuprofen toxicity following ingestion of a standard release preparation usually occur within four hours of ingestion [4,5].\n\nSevere toxicity is uncommon following ibuprofen self-poisoning, and in general less than 10% of patients develop 'life-threatening' symptoms such as coma, seizures, respiratory arrest, hypotension or anuric renal failure [3-5,10]. Life-threatening features of ibuprofen toxicity have been shown only to occur in patients who have ingested greater than 400 mg/kg ibuprofen [15]. Histories in patients presenting with an overdose have been shown to be unreliable [16], however, so to try and predict those patients who are at risk of severe ibuprofen-induced toxicity, a nomogram based on the time since ingestion and the serum ibuprofen concentration, similar to that used for paracetamol (acetaminophen), has been developed [4]. Subsequent studies have shown conflicting results as to whether this nomogram is accurate [5] or inaccurate [10] at predicting those at risk of severe toxicity. Since ibuprofen concentrations are not routinely available in most emergency departments or hospitals, there are concerns about the accuracy of the nomogram, the toxic effects of ibuprofen are predictable and (unlike paracetamol poisoning) there is no effective antidote, we would not recommend use of the ibuprofen nomogram in routine clinical practice.\n\nManagement of patients presenting following deliberate self-poisoning with ibuprofen consists of gut decontamination with activated charcoal, if they present within one hour of a potentially toxic overdose, and generalised supportive care [17,18]. As already discussed, multidose activated charcoal may be appropriate in patients who have ingested a potentially toxic amount of a sustained-release preparation. Other more severe features of ibuprofen toxicity should be managed appropriately. Ibuprofen-induced seizures that are nonself-limiting should initially be managed with intravenous diazepam (0.1–0.2 mg/kg). Significant metabolic acidosis (pH < 7.0) that does not respond to adequate intravenous fluid resuscitation, and maintenance of the blood pressure, with intropic support if appropriate, should be corrected with intravenous 50–100 ml boluses of 8.4% sodium bicarbonate. For resistant metabolic acidosis that is not responding, then haemofiltration with a nonlactate bicarbonate buffer may be beneficial. Although ibuprofen has a relatively low volume of distribution (0.1 l/kg), its high protein binding to albumin (99%) limits removal by extracorporeal treatments such as haemodialysis or haemofiltration [19].\n\nPrevious studies have demonstrated no accumulation of ibuprofen in patients with renal impairment [20] and, in functionally anephric patients undergoing renal replacement therapy with haemodialysis, no accumulation of ibuprofen was seen and there was no detectable ibuprofen in the dialysate, indicating that the ibuprofen was eliminated through metabolism [21]. This provides further support that extracorporeal treatments will probably not be beneficial in increasing the clearance of ibuprofen in overdose, and there have been no previous reported cases of their attempted use in patients with ibuprofen toxicity. There have been no published studies on the routine prophylactic use of H2 histamine receptor antagonists or proton pump inhibitors in trying to reduce the risk of ibuprofen or other NSAID-related gastrointestinal toxicity. Our current practice in patients with significant epigastric pain/tenderness after ibuprofen poisoning is to treat them with 1 week of a proton pump inhibitor such as lansoprazole 30 mg once daily.\n\nThere have been nine reported cases of fatality following ibuprofen self-poisoning in the literature to date, although other factors probably contributed to death in eight of these cases [3-11]. The co-ingestion of other drugs at the time of the overdose, such as aspirin, paracetamol, theophylline and cyclobenzaprine, contributed to death in four cases [3,6,7,9]. Aspiration pneumonia that developed as a complication of ibuprofen-induced apnoeic episodes [4] and septic shock, thought to be unrelated to ibuprofen toxicity [10], contributed to two deaths. Refusal of treatment of ibuprofen-induced oliguric renal failure and sepsis, felt by the authors to be survivable, significantly contributed to one death [5]. The circumstances surrounding one death are unclear as the patient was found dead near their home [8]. There are limited details of and no confirmatory ibuprofen concentrations for the final death, which has been reported in abstract form only [11].\n\nIbuprofen concentrations have been measured in four of the previous fatalities [6,8-10]. One of the previously reported fatalities had an ante mortem ibuprofen concentration of 72 mg/l; although few details of the case were given, the authors concluded that the cause of death was septic shock and respiratory failure unrelated to the ibuprofen intoxication [10]. Peripheral blood post mortem ibuprofen concentrations of 81 mg/l, 130 mg/l and 348 mg/l have been reported in a 48-year-old male [6], a 19-year-old male [9] and a 26-year-old male [8], respectively.\n\nAdditionally, post mortem ibuprofen concentrations of 942 mg/kg [8] and 238 mg/kg [6] were reported in liver extract in two cases. In the case reported here, the post mortem ibuprofen concentrations were 518 mg/l in peripheral blood and 74 mg/kg in liver extract. The main differences between our reported case and the other two cases with previous reported post mortem ibuprofen concentrations is that our case had higher peripheral blood and lower liver extract concentrations. Since the exact timing of ingestion was not known in our case and was not reported in the other two cases, the differences in peripheral blood and liver extract ibuprofen concentrations may be due to differences in distribution and metabolism. It is therefore probable, given the post mortem ibuprofen concentrations in our reported case, that our patient died sooner after ingestion than the other two reported cases, as peripheral blood concentrations had not had sufficient time to fall and the liver had not started to metabolise as much ibuprofen. The other unknown factor in all of these cases is the impact of impaired haemodynamics, renal dysfunction and metabolic acidosis on ibuprofen kinetics.\n\nConclusion\nWe have described the case of a fatality following severe poisoning with sustained-release ibuprofen. The patient presented with a reduced Glasgow Coma Scale, severe metabolic acidosis and haemodynamic compromise that did not respond to meticulous supportive care, to treatment with sodium bicarbonate, to haemofiltration and to inotropic support. There were no other toxicological or medical causes for the patient's clinical presentation. Multidose activated charcoal was utilised in this patient due to the ingestion of a sustained-release preparation, and its use was supported by elevated ibuprofen concentrations in the gastric contents following death.\n\nKey messages\n• \tIbuprofen is a NSAID used as an analgesic, as an anti-pyretic agent and as an anti-inflammatory agent.\n\n• \tMost patients with ibuprofen overdoses are usually asymptomatic or have mild gastrointestinal symptoms.\n\n• \tSymptoms are unlikely if less than 100 mg/kg ibuprofen has been ingested.\n\n• \tSymptoms of severe ibuprofen toxicity, including metabolic acidosis, seizures, renal impairment and cardiovascular collapse, occur after >400 mg/kg has been ingested.\n\n• \tPatients require meticulous supportive care and management of ibuprofen-induced complications.\n\nAbbreviations\nNSAID = nonsteroidal anti-inflammatory drug.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors' contributions\nDMW, PID, ALJ and JM provided toxicology advice on the management of the patient. PS analysed the ibuprofen samples. DMW and PID drafted the first draft of this manuscript. All authors contributed to the final draft of the manuscript.\n\nAcknowledgements\nThe authors acknowledge Mr Frank Tames, University Hospital, Aintree, Liverpool for post mortem ibuprofen concentration analysis.\n\nFigures and Tables\nTable 1 Common toxicological causes of a high anion gap lactate acidosis (adapted from 22)\n\nBiguanides (for example, metformin)\t\nCyanide\t\nIron\t\nSalicylates\t\nTheophylline\t\nType B lactic acidosis (for example, from hypotension related to any significant poisoning)\n==== Refs\nNazu K Ibuprofen: highly potent inhibitor of prostaglandin synthesis Biochim Biophys Acta 1978 529 493 494 96864 \nAdams SS McCullough KF Nicholson JS The pharmacological properties of ibuprofen, an anti-inflammatory, analgesic and antipyretic agent Arch Int Pharmacodyn Ther 1969 178 115 129 5353466 \nCourt H Streete P Volans GN Acute poisoning with ibuprofen Hum Toxicol 1983 2 381 384 6862484 \nHall AH Smolinske SC Conrad FL Wruk KM Kulig KW Dwelle TL Rumack BH Ibuprofen overdose: 126 cases Ann Emerg Med 1986 15 1308 1313 3777588 10.1016/S0196-0644(86)80617-5 \nHall AH Smolinske SC Kulig KW Rumack BH Ibuprofen overdose – a prospective study West J Med 1988 148 653 656 3176471 \nSteinmetz JC Lee CY Wu AY Tissue levels of ibuprofen after fatal overdosage of ibuprofen and acetaminophen Vet Hum Toxicol 1987 29 381 383 3686818 \nBernstein G Jehle D Bernaski E Braen GR Failure of gastric emptying and charcoal administration in fatal sustained-release theophylline overdose: pharmacobezoar formation Ann Emerg Med 1992 21 1388 1390 1416337 10.1016/S0196-0644(05)81907-9 \nKunsman GW Rohrig TP Tissue distribution of ibuprofen in a fatal overdose Am J Forensic Med Pathol 1993 14 48 50 8493969 \nLevine B Jones R Smith ML Gudewicz TM Peterson B A multiple drug intoxication involving cyclobenzaprine and ibuprofen Am J Forensic Med Pathol 1993 14 246 248 8311059 \nMcElwee NE Veltri JC Bradford DC Rollins DE A prospective, population-based study of acute ibuprofen overdose: complications are rare and routine serum levels not warranted Ann Emerg Med 1990 19 657 662 2188537 10.1016/S0196-0644(05)82471-0 \nKøenová M Pelclová D Fatal poisoning with ibuprofen [abstract] Clin Toxicol 2005 43 537 \nCollier PS D'Arcy PF Harron DW Morrow N Pharmacokinetic modelling of ibuprofen Br J Clin Pharmacol 1978 5 528 530 656296 \nAmerican Academy of Clinical Toxicology European Association of Poisons Centres and Clinical Toxicologists Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning J Toxicol Clin Toxicol 1999 37 731 751 10584586 10.1081/CLT-100102451 \nPerry SJ Streete PJ Volans GN Ibuprofen overdose: the first two years of over-the-counter sales Hum Toxicol 1987 6 173 178 3557476 \nSmolinske SC Hall AH Vandenberg SA Spoerke DG McBride PV Toxic effects of nonsteroidal anti-inflammatory drugs in overdose. An overview of recent evidence on clinical effects and dose-response relationships Drug Saf 1990 5 252 274 2198051 \nPohjola-Sintonen S Kivisto KT Vuori E Lapatto-Reiniluoto O Tiula E Neuvonen PJ Identification of drugs ingested in acute poisoning: correlation of patient history with drug analyses Ther Drug Monit 2000 22 749 752 11128245 10.1097/00007691-200012000-00016 \nHalpern SM Fitzpatrick R Volans GN Ibuprofen toxicity. A review of adverse reactions and overdose Adverse Drug React Toxicol Rev 1993 12 107 128 8357944 \nLondon: Churchill Livingstone Non-steroidal anti-inflammatory drugs (NSAIDs) Churchill's Pocketbook of Toxicology 2001 1 Jones AL, Dargan PI 65 66 \nDollery C Ibuprofen Therapeutic Drugs 1999 2 2 Edinburgh: Churchill Livingstone 1 3 \nSenekjian HO Lee CS Kuo TH Au DS Krothapalli R Absorption and disposition of ibuprofen in hemodialyzed uremic patients Eur J Rheumatol Inflamm 1983 6 155 162 6673979 \nAntal EJ Wright CE 3rdBrown BL Albert KS Aman LC Levin NW The influence of hemodialysis on the pharmacokinetics of ibuprofen and its major metabolites J Clin Pharmacol 1986 26 184 190 3958223 \nHoffman RS Goldfrank LR, Flomenbaum NE, Lewin NA, Howland MA, Hoffman RS, Nelson LS Fluid, electrolyte, and acid-base principles Goldfrank's Toxicologic Emergencies 2002 7 New York: McGraw-Hill 364 380\n\n", "fulltext_license": "CC BY", "issn_linking": "1364-8535", "issue": "10(2)", "journal": "Critical care (London, England)", "keywords": null, "medline_ta": "Crit Care", "mesh_terms": "D000328:Adult; D003692:Delayed-Action Preparations; D062787:Drug Overdose; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007052:Ibuprofen; D013405:Suicide; D014474:Unconsciousness", "nlm_unique_id": "9801902", "other_id": null, "pages": "R44", "pmc": null, "pmid": "16542487", "pubdate": "2006", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "10584586;8311059;5353466;656296;96864;6862484;6673979;3958223;3777588;3557476;3686818;3176471;2188537;2198051;1416337;8493969;8357944;11128245", "title": "Fatality after deliberate ingestion of sustained-release ibuprofen: a case report.", "title_normalized": "fatality after deliberate ingestion of sustained release ibuprofen a case report" }

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{ "abstract": "[Full article available at http://rimed.org/rimedicaljournal-2017-10.asp].", "affiliations": "Pharmacy Resident, Veterans Affairs (VA) Connecticut Healthcare System, West Haven, CT; at the time of writing, PharmDc, College of Pharmacy, University of Rhode Island.;Department of Medicine, Roger Williams Medical Center, Boston University, Providence, RI.;Department of Medicine, Roger Williams Medical Center, Boston University, Providence, RI.;PharmDc, College of Pharmacy, University of Rhode Island.;Department of Pharmacy, University of Rhode Island College of Pharmacy, Kingston, RI.", "authors": "Bystrak|Tamara|T|;Cervera-Hernandez|Miguel E|ME|;Reddy|Nishitha|N|;King|Zachary|Z|;Bratberg|Jeffrey|J|", "chemical_list": "D019440:Anti-Obesity Agents; D010936:Plant Extracts", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0363-7913", "issue": "100(10)", "journal": "Rhode Island medical journal (2013)", "keywords": "diabetic ketoacidosis; garcinia cambogia; hydroxycitric acid; pancreatitis", "medline_ta": "R I Med J (2013)", "mesh_terms": "D019440:Anti-Obesity Agents; D003922:Diabetes Mellitus, Type 1; D016883:Diabetic Ketoacidosis; D005260:Female; D029761:Garcinia cambogia; D006801:Humans; D008875:Middle Aged; D009765:Obesity; D010195:Pancreatitis; D008517:Phytotherapy; D010936:Plant Extracts", "nlm_unique_id": "101605827", "other_id": null, "pages": "48-50", "pmc": null, "pmid": "28968624", "pubdate": "2017-10-02", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Garcinia Cambogia, Diabetic Ketoacidosis, and Pancreatitis.", "title_normalized": "garcinia cambogia diabetic ketoacidosis and pancreatitis" }

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"reactionmeddrapt": "Mental disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Confusional state", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Diabetic ketoacidosis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pancreatitis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pancreatic atrophy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "BYSTRAK T, CERVERA-HERNANDEZ ME, REDDY N, KING Z, BRATBERG J. GARCINIA CAMBOGIA, DIABETIC KETOACIDOSIS, AND PANCREATITIS. R-I-MED-J 2017?100(10):48-50.", "literaturereference_normalized": "garcinia cambogia diabetic ketoacidosis and pancreatitis", "qualification": "2", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180309", "receivedate": "20180309", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14615731, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" } ]

{ "abstract": "Despite increasingly widespread utilization of direct-acting oral anticoagulants (DOACs), there remains limited experience with the use of these agents following liver transplantation. We performed a single-center, retrospective review of liver transplant recipients prescribed DOACs or warfarin between January 2014 and January 2018. Patients receiving DOACs were matched with warfarin-treated controls based on discrete clinical parameters and followed from the time of anticoagulant prescription, until treatment discontinuation or study conclusion. The primary endpoint for this review was the incidence of clinically relevant major or non-major bleeding among the treatment groups. Twenty-seven patients prescribed DOACs were identified for inclusion in the review, of which 20 could be matched with suitable warfarin controls. At the conclusion of the study, warfarin-treated patients had a significantly higher incidence of clinically relevant bleeding (45% vs 15%; P = .01). No statistically significant differences were found in the rate of new or recurrent thrombotic events. Multivariable logistic regression demonstrated that warfarin treatment was associated with a significantly higher odds of a bleeding event compared to treatment with a DOAC (OR = 6.9; 95% CI, 1.1-44.6). DOAC use appears relatively safe compared with warfarin in select liver transplant recipients. Patient-specific factors still bear consideration when selecting between the various anticoagulant options.", "affiliations": "Recanati-Miller Transplantation Institute, Mount Sinai Hospital, New York, NY, USA.;Department of Population Health Science and Policy, Mount Sinai Hospital, New York, NY, USA.;Recanati-Miller Transplantation Institute, Mount Sinai Hospital, New York, NY, USA.;Recanati-Miller Transplantation Institute, Mount Sinai Hospital, New York, NY, USA.", "authors": "Santeusanio|Andrew D|AD|0000-0002-4575-5330;Weinberg|Alan D|AD|;Florman|Sander S|SS|0000-0002-1635-9136;Schiano|Thomas D|TD|", "chemical_list": "D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D014859:Warfarin", "country": "Denmark", "delete": false, "doi": "10.1111/ctr.13756", "fulltext": null, "fulltext_license": null, "issn_linking": "0902-0063", "issue": "34(1)", "journal": "Clinical transplantation", "keywords": "algorithm; anticoagulants; clotting; hemorrhage; liver transplantation", "medline_ta": "Clin Transplant", "mesh_terms": "D000284:Administration, Oral; D000925:Anticoagulants; D001281:Atrial Fibrillation; D065427:Factor Xa Inhibitors; D006801:Humans; D016031:Liver Transplantation; D012189:Retrospective Studies; D014859:Warfarin", "nlm_unique_id": "8710240", "other_id": null, "pages": "e13756", "pmc": null, "pmid": "31738454", "pubdate": "2020-01", "publication_types": "D016428:Journal Article; D016454:Review", "references": null, "title": "Safety of direct-acting oral anticoagulants relative to warfarin in a matched cohort of liver transplant recipients.", "title_normalized": "safety of direct acting oral anticoagulants relative to warfarin in a matched cohort of liver transplant recipients" }

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{ "abstract": "BACKGROUND\nThe spontaneous rupture of the gallbladder is extremely rare, majority of ruptures occur secondary to traumatic injuries. Here, we report a case of spontaneous rupture of the gallbladder with probably cause of oral anticoagulants.\n\n\nMETHODS\nA 51-year-old woman presented to the emergency room with sudden-onset severe abdominal pain, as well as hypotension and low level of hemoglobin. Abdominal computed tomography (CT) scan showed a 2.5 cm filling defect and discontinuity in the wall of the gallbladder body, and a massive hematocele in the abdominal cavity. Past medical history was significant for hypertension and had been taking daily aspirin for the past three years because of interventional surgery for cerebral aneurysms, but no history of recent abdominal trauma or past episodes of biliary colic. The patient underwent an urgent laparoscopic abdominal exploration and the gallbladder was removed. The pathology just showed chronic cholecystitis and the patient recovered well.\n\n\nCONCLUSIONS\nLong-term use of anticoagulants may increase the risk of gallbladder rupture and hemorrhage, which is a lethal condition. Rapid diagnosis and timely surgical intervention are the most important measures to treat the patient.", "affiliations": "Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.;Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.;Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.;Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.;Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.;Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China. zs_song@hotmail.com.;Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China. Tingsong.yang@tongji.edu.cn.", "authors": "Ma|Zhilong|Z|;Xu|Bin|B|;Wang|Long|L|;Mao|Yukan|Y|;Zhou|Bo|B|;Song|Zhenshun|Z|;Yang|Tingsong|T|", "chemical_list": "D000925:Anticoagulants", "country": "England", "delete": false, "doi": "10.1186/s12893-018-0464-6", "fulltext": "\n==== Front\nBMC Surg\nBMC Surg\nBMC Surgery\n1471-2482 BioMed Central London \n\n30611267\n464\n10.1186/s12893-018-0464-6\nCase Report\nAnticoagulants is a risk factor for spontaneous rupture and hemorrhage of gallbladder: a case report and literature review\nMa Zhilong mazhilong@tongji.edu.cn Xu Bin pfdbsxubin@163.com Wang Long longwang1996@163.com Mao Yukan yukanmao@163.com Zhou Bo surgeonzhoubo@163.com Song Zhenshun +86-21-663067363zs_song@hotmail.com Yang Tingsong +86-21-663067434Tingsong.yang@tongji.edu.cn Department of General Surgery, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 200072 China \n5 1 2019 \n5 1 2019 \n2019 \n19 230 1 2018 20 12 2018 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nThe spontaneous rupture of the gallbladder is extremely rare, majority of ruptures occur secondary to traumatic injuries. Here, we report a case of spontaneous rupture of the gallbladder with probably cause of oral anticoagulants.\n\nCase presentation\nA 51-year-old woman presented to the emergency room with sudden-onset severe abdominal pain, as well as hypotension and low level of hemoglobin. Abdominal computed tomography (CT) scan showed a 2.5 cm filling defect and discontinuity in the wall of the gallbladder body, and a massive hematocele in the abdominal cavity. Past medical history was significant for hypertension and had been taking daily aspirin for the past three years because of interventional surgery for cerebral aneurysms, but no history of recent abdominal trauma or past episodes of biliary colic. The patient underwent an urgent laparoscopic abdominal exploration and the gallbladder was removed. The pathology just showed chronic cholecystitis and the patient recovered well.\n\nConclusion\nLong-term use of anticoagulants may increase the risk of gallbladder rupture and hemorrhage, which is a lethal condition. Rapid diagnosis and timely surgical intervention are the most important measures to treat the patient.\n\nKeywords\nAnticoagulantsGallbladderSpontaneous ruptureissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nThe spontaneous rupture of gallbladder is extremely rare, the majority of cases have followed penetrating war injuries and trauma [1, 2]. Rupture and hemorrhage of gallbladder is a lethal condition, rapid diagnosis and treatment are very virtual. Computed tomography (CT) scans and intravenous contrast association a careful medical history and physical examination frequently could help make an accurately diagnose. With the progress of medicine, the past exploratory laparotomy has been made a secondary consideration, and laparoscopic exploration is widely adopted. Here, we describe the case of gallbladder rupture in a patient with cholelithiasis who has been on anticoagulation therapy for two years.\n\nCase presentation\nA 51-year-old woman presented to the emergency department with sudden-onset severe abdominal pain, as well as hypotension (75/48 mmHg) and diffuse abdominal tenderness with guarding on physical examination. Laboratory tests were significant for downtrending hemoglobin levels (75 g/L). Abdominal computed tomography (CT) scan with intravenous contrast showed a 2.5 cm filling defect and discontinuity in the wall of the gallbladder body, a 1.0 × 0.8 cm stone in the neck of the gallbladder, and a massive hematocele in the abdominal cavity (Fig. 1a). Past medical history was significant for hypertension but no history of recent abdominal trauma or past episodes of biliary colic; social history was not significant for any alcohol or tobacco use. Patient had also been taking daily aspirin (200 mg per day) for the past three years because of interventional surgery for cerebral aneurysms. The patient underwent an urgent laparoscopic abdominal exploration. A 2.0 cm defect was identified in the body of the gallbladder and an active arterial bleeding site was visualized at the edge of the defect. The remainder of the gallbladder wall appeared normal without any hyperaemia and edema. 2500 mL of fresh and clotted blood mixed with bile was evacuated from the gallbladder fossa, right supra-hepatic space, splenic recess and pelvic cavity. Final pathology demonstrated a disruption in the muscularis propria of a portion of the gallbladder wall and the abundance of eosinophils and lymphocytes infiltration in the mucosal layer, associated with chronic cholecystitis (Fig. 1b). The patient was discharged on post-operative day 7 without complications and recovered well.Fig. 1 a, Abdominal CT scan with intravenous contrast showed a 2.5 cm filling defect in the body of gallbladder wall, a 1.0 × 0.8 cm stone in the neck of gallbladder and a massive hematocele in the abdominal cavity. b, Final pathology showed a disruption in the muscularis propria of partial gallbladder wall and plenty of eosinophils and lymphocytes infiltration in the mucous layer, associated with chronic cholecystitis\n\n\n\nDiscussion and conclusions\nThe spontaneous rupture of the gallbladder is extremely rare. While majority of ruptures occur secondary to traumatic injuries, the incidence remains low, at less than 2%, after abdominal trauma [1, 2]. Spontaneous rupture of the gallbladder can occur by the following mechanisms: 1) rupture of the cystic artery due to sclerotic changes in the arterial wall, 2) mechanical irritation of the gallbladder wall due to the presence of a calculus, 3) interference of venous return at the gallbladder neck secondary to an impacted, 4) severe inflammation of the gallbladder mucosa with associated gangrene [3–5]. Long-term use of anticoagulants is also associated with increased risk of spontaneous rupture of the gallbladder [6]. Additional predisposing factors include postprandial gallbladder distention, a thin gallbladder wall, malposition of the gallbladder, and alcohol consumption [7].\n\nIn the present case, the patient suffered from an episode of abrupt and severe abdominal pain without any history of associated trauma, cholecystitis or biliary colic. Imaging was significant only for a small stone in the neck of the gallbladder, which could have caused acute cholecystitis and gallbladder gangrene with subsequent gallbladder rupture. However, there was no evidence of any acute inflammation of the gallbladder on the laparoscopic exploration. Moreover, the pathology also verified only the presence of chronic inflammation of the gallbladder mucosa.\n\nReviewing the patient’s past medical history, the patient had been taking aspirin 200 mg daily for three years after interventional treatment of a cerebral aneurysm. While there was no evidence of any coagulopathies on laboratory examination, aspirin use has been associated with complications including soft tissue edema, skin hemorrhage and hematuria. In the literature, the rupture and hemorrhage from the gallbladder is a rare complication, with only one previously-reported case of a gallbladder hematoma in a patient with hemophilia B. In this previous case, the diagnosis was made on MRI and a cholecystectomy was performed [8].\n\nIn the present case, the chronic inflammation of the gallbladder may have weakened the wall. Moreover, given the lack of collateral vascular supply to the gallbladder, even a small amount of bleeding may lead to gallbladder ischemia and potentially triggering the wall rupture. Furthermore, the calculus in the neck of the gallbladder could have also affected the blood supply of the gallbladder. In addition, the patient has long term use history of aspirin, which has been clarified clearly to prolong bleeding time and inhibit platelet aggregation [9]. Several reports that link coagulopathy and hemorrhagic cholecystitis have been published [10–12]. Thus, in this case, aspirin therapy is thought to be a predisposing factor for gallbladder hemorrhage, and continuous massive bleeding increase the pressure of gallbladder and even have exacerbated to rupture.\n\nIn conclusion, while the exact cause of the rupture of the gallbladder remains unclear in this case, the calculus in the gallbladder neck and the presence of chronic cholecystitis are significant risk factors for rupture. Long-term aspirin use may have further increased this risk. Gallbladder rupture and hemorrhage is a lethal condition, and rapid diagnosis and timely surgical intervention are the most important measures to treat the patient.\n\nAbbreviations\nCTComputed Tomography\n\nZhilong Ma and Bin Xu contributed equally to this work.\n\nAcknowledgements\nThe authors would like to thank Dr. Linda M. Pak from Brigham and Women’s Hospital, Harvard Medical School, for the language editting.\n\nFunding\nThere is no funding to be declared for the preparation of this manuscript. The publication fee will be funded by Shanghai Tenth Peoples’ Hospital.\n\nAvailability of data and materials\nAll patient data and clinical images adopted are contained in the medical files of Shanghai Tenth People’s Hospital affiliated Tongji University in Shanghai. The data supporting the conclusions of this article are included within the article and its figures.\n\nAuthors’ Contributions\nAll authors participated in the management of the patient in this case report. MZL, YTS and XB drafted the manuscript. MYK, WL and ZB collected the clinical data and images. SZS is the chairman of the department and supervised the entire process. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the editor of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Blumgart LH Rupture of gall-bladder associated with intraperitoneal rupture of urinary bladder Br J Surg 1969 56 1 76 77 10.1002/bjs.1800560115 5766326 \n2. Frank DJ Pereiras R Jr Lima MS Taub SJ Schiff ER Traumatic rupture of the gallbladder with massive biliary ascites Jama 1978 240 3 252 253 10.1001/jama.1978.03290030070030 660855 \n3. Barauskas G Pavalkis D Free rupture of the gallbladder in elderly patients Dig Surg 2008 14 3 192 194 10.1159/000172540 \n4. Mason CB Judd CS Jr Hill RL Rupture of the gall bladder with intraperitoneal hemorrhage N Engl J Med 1957 256 13 609 610 10.1056/NEJM195703282561307 13451904 \n5. Parekh J Corvera CU Hemorrhagic cholecystitis Arch Surg 2010 145 2 202 204 10.1001/archsurg.2009.265 20157090 \n6. Onishi S Hojo N Sakai I Yasukawa M Hato T Minamoto Y Yokota E Ito MR Dote K Shimizu I Rupture of the gallbladder in a patient with acquired factor VIII inhibitors and systemic lupus erythematosus Intern Med 2004 43 11 1073 1077 10.2169/internalmedicine.43.1073 15609706 \n7. Liess BD Awad ZT Eubanks WS Laparoscopic cholecystectomy for isolated traumatic rupture of the gallbladder following blunt abdominal injury J Laparoendosc Adv Surg Tech A 2006 16 6 623 625 10.1089/lap.2006.16.623 17243883 \n8. Shimura T Kojima T Tsutsumi S Yoshida T Uchiumi H Kuwano H Gallbladder hematoma in a patient with hemophilia B, report of a case Hepatogastroenterology 2000 47 34 939 941 11020853 \n9. Tamai Y Takami H Nakahata R Ono F Munakata A Comparison of the effects of acetylsalicylic acid, ticlopidine and cilostazol on primary hemostasis using a quantitative bleeding time test apparatus Haemostasis 1999 29 5 269 276 10754379 \n10. Morris DS Porterfield JR Sawyer MD Hemorrhagic cholecystitis in an elderly patient taking aspirin and cilostazol Case reports in gastroenterology 2008 2 2 203 207 10.1159/000135693 21490889 \n11. Pandya R O'Malley C Hemorrhagic cholecystitis as a complication of anticoagulant therapy: role of CT in its diagnosis Abdom Imaging 2008 33 6 652 653 10.1007/s00261-007-9358-2 18629579 \n12. Chen YY Yi CH Chen CL Huang SC Hsu YH Hemorrhagic cholecystitis after anticoagulation therapy Am J Med Sci 2010 340 4 338 339 10.1097/MAJ.0b013e3181e9563e 20601855\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2482", "issue": "19(1)", "journal": "BMC surgery", "keywords": "Anticoagulants; Gallbladder; Spontaneous rupture", "medline_ta": "BMC Surg", "mesh_terms": "D000005:Abdomen; D015746:Abdominal Pain; D000925:Anticoagulants; D002764:Cholecystitis; D004636:Emergency Service, Hospital; D005260:Female; D005704:Gallbladder; D006470:Hemorrhage; D006801:Humans; D008875:Middle Aged; D012307:Risk Factors; D012422:Rupture, Spontaneous; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "100968567", "other_id": null, "pages": "2", "pmc": null, "pmid": "30611267", "pubdate": "2019-01-05", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": "10754379;11020853;13451904;15609706;17243883;18629579;20157090;20601855;21490889;5766326;660855", "title": "Anticoagulants is a risk factor for spontaneous rupture and hemorrhage of gallbladder: a case report and literature review.", "title_normalized": "anticoagulants is a risk factor for spontaneous rupture and hemorrhage of gallbladder a case report and literature review" }

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ANTICOAGULANTS IS A RISK FACTOR FOR SPONTANEOUS RUPTURE AND HEMORRHAGE OF GALLBLADDER: A CASE REPORT AND LITERATURE REVIEW. BMC SURG. 2019?9(1):2", "literaturereference_normalized": "anticoagulants is a risk factor for spontaneous rupture and hemorrhage of gallbladder a case report and literature review", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20190308", "receivedate": "20190308", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16050737, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20190418" }, { "companynumb": "CN-INGENUS PHARMACEUTICALS NJ, LLC-ING201901-000044", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN\\CARISOPRODOL\\CODEINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "040860", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARISOPRODOL, ASPIRIN AND CODEINE PHOSPHATE" } ], "patientagegroup": null, "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Haemoglobin decreased", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Gallbladder rupture", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Abdominal pain", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Haematocoele", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Haemobilia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Arterial haemorrhage", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "MA Z, XU B, WANG L, MAO Y, SONG Z, YANG T. ANTICOAGULANTS IS A RISK FACTOR FOR SPONTANEOUS RUPTURE AND HEMORRHAGE OF GALLBLADDER: A CASE REPORT AND LITERATURE REVIEW. BMC SURGERY (2019). 2019 JAN 05?19 (1):1-3.", "literaturereference_normalized": "anticoagulants is a risk factor for spontaneous rupture and hemorrhage of gallbladder a case report and literature review", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "CN", "receiptdate": "20190128", "receivedate": "20190128", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15880676, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "CN-NOVAST LABORATORIES, LTD-CN-2019NOV000231", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN\\CARISOPRODOL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "040832", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MG PER DAY, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARISOPRODOL\\ASPIRIN" } ], "patientagegroup": null, "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemobilia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Gallbladder rupture", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "MA Z, XU B, WANG L, MAO Y, ZHOU B, SONG Z, ET AL.. ANTICOAGULANTS IS A RISK FACTOR FOR SPONTANEOUS RUPTURE AND HEMORRHAGE OF GALLBLADDER: A CASE REPORT AND LITERATURE REVIEW. BMC-SURG. 2019?19(1):2", "literaturereference_normalized": "anticoagulants is a risk factor for spontaneous rupture and hemorrhage of gallbladder a case report and literature review", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20190411", "receivedate": "20190411", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16184779, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" } ]

{ "abstract": "A 9-year-old girl with a diagnosis of cystinosis since 2 years of age, on cysteamine therapy, presented with complaints of serositis and arthritis, and laboratory tests revealed high antinuclear antibody titers with hypocomplementemia. Kidney biopsy was not consistent with lupus nephritis. With prednisolone treatment her complaints resolved and creatinine level decreased, but on follow-up, serological features of systemic lupus erythematosus (SLE) continued. Six years after cessation of prednisolone, lupus features were reactivated, with positive antihistone antibodies and ANCA. Coincidence of cystinosis and SLE is very rare, and to the best of our knowledge this is the fourth case reported in the literature. Physicians should be aware that cystinosis patients may have some autoimmune manifestations with features of true or drug-induced lupus. In the light of this case, pathophysiology and treatment are discussed.", "affiliations": "Department of Pediatric Nephrology-Rheumatology, Hacettepe University Faculty of Medicine, Turkey fehimekara@yahoo.com.;Department of Pediatric Nephrology-Rheumatology, Hacettepe University Faculty of Medicine, Turkey.;Department of Pediatric Nephrology-Rheumatology, Hacettepe University Faculty of Medicine, Turkey.;Department of Pediatric Nephrology-Rheumatology, Hacettepe University Faculty of Medicine, Turkey.;Department of Pediatric Nephrology-Rheumatology, Hacettepe University Faculty of Medicine, Turkey.", "authors": "Eroglu|F K|FK|;Besbas|N|N|;Ozaltin|F|F|;Topaloglu|R|R|;Ozen|S|S|", "chemical_list": "D000974:Antibodies, Antinuclear", "country": "England", "delete": false, "doi": "10.1177/0961203315598017", "fulltext": null, "fulltext_license": null, "issn_linking": "0961-2033", "issue": "24(13)", "journal": "Lupus", "keywords": "Cystinosis; childhood; cysteamine; lupus", "medline_ta": "Lupus", "mesh_terms": "D000974:Antibodies, Antinuclear; D002648:Child; D003554:Cystinosis; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic", "nlm_unique_id": "9204265", "other_id": null, "pages": "1452-4", "pmc": null, "pmid": "26223294", "pubdate": "2015-11", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Lupus in a patient with cystinosis: is it drug induced?", "title_normalized": "lupus in a patient with cystinosis is it drug induced" }

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"HYDROCHLOROTHIAZIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2001", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCHLOROTHIAZIDE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "CYSTEAMINE BITARTRATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "020392", "drugbatchnumb": null, "drugcharacterization": "1", 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"drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BICARBONATE" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "CYSTEAMINE BITARTRATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "020392", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "60 MG/KG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "201209", "drugstartdateformat": "610", "drugstructuredosagenumb": "60", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYSTAGON" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CALCITRIOL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CALCITRIOL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Systemic lupus erythematosus", "reactionmeddraversionpt": "18.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "EROGLU, FK. LUPUS IN A PATIENT WITH CYSTINOSIS: IS IT DRUG INDUCED? LUPUS 2015; (0) 1-3", "literaturereference_normalized": "lupus in a patient with cystinosis is it drug induced", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20150927", "receivedate": "20150824", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11414116, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20151125" }, { "companynumb": "TR-MYLANLABS-2015M1045716", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "CYSTEAMINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "020392", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "70 MG/KG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYSTINOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTAMINE" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "CYSTEAMINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "020392", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "60 MG/KG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTAMINE" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "CYSTEAMINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "020392", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "90 MG/KG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTAMINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Systemic lupus erythematosus", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2005" } }, "primarysource": { "literaturereference": "EROGLU FK, BESBAS N, OZALTIN F, TOPALOGLU R, OZEN S. LUPUS IN A PATIENT WITH CYSTINOSIS: IS IT DRUG INDUCED?. LUPUS 2015? 24(13):1452-1454.", "literaturereference_normalized": "lupus in a patient with cystinosis is it drug induced", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20151221", "receivedate": "20151221", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11855369, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160305" } ]

{ "abstract": "Hypereosinophilic syndromes are rare in children. Sporadic, mild-severity FIP1L1-platelet-derived growth factor receptor α (PDGFRα) rearrangement cases have been reported, mainly in boys. We present the case of a 5-year-old girl referred from her African country of birth, due to severe constitutional symptoms, multifocal bone pain, headache, gastrointestinal complaints, cardiomyopathy and unexplained hypereosinophilia. She presented multiple end-organ diseases and striking bone involvement. Although she had a positive serology for Strongyloides stercoralis, extensive evaluation detected a FIP1L1-PDGFRA fusion gene. Systemic corticosteroids and low-dose imatinib were started and the child became asymptomatic. After 9 months of treatment, FIP1L1-PDGFRA was no longer detected.", "affiliations": "Women, Child and Adolescents Department, Hospital Dona Estefania, Lisboa, Portugal.;Radiology Department, Hospital Dona Estefania, Lisboa, Portugal.;Pediatric Oncology Department, Instituto Portugues de Oncologia de Lisboa Francisco Gentil EPE, Lisboa, Portugal.;Women, Child and Adolescents Department, Hospital Dona Estefania, Lisboa, Portugal.", "authors": "Bota|Sofia|S|http://orcid.org/0000-0003-4776-1053;Alves|Pedro|P|;Constantino|Claudia|C|;Maia|Raquel|R|", "chemical_list": "D000305:Adrenal Cortex Hormones; D000871:Anthelmintics; D000977:Antiparasitic Agents; D004338:Drug Combinations; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D039221:mRNA Cleavage and Polyadenylation Factors; D007559:Ivermectin; D000068877:Imatinib Mesylate; C479819:FIP1L1-PDGFRA fusion protein, human; D020796:Receptor, Platelet-Derived Growth Factor alpha; D015766:Albendazole", "country": "England", "delete": false, "doi": "10.1136/bcr-2018-227653", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "12(4)", "journal": "BMJ case reports", "keywords": "paediatric oncology; radiology; tropical medicine (infectious disease)", "medline_ta": "BMJ Case Rep", "mesh_terms": "D000305:Adrenal Cortex Hormones; D000349:Africa; D015766:Albendazole; D000818:Animals; D000871:Anthelmintics; D000977:Antiparasitic Agents; D001847:Bone Diseases; D002675:Child, Preschool; D004338:Drug Combinations; D005260:Female; D006801:Humans; D017681:Hypereosinophilic Syndrome; D000068877:Imatinib Mesylate; D007559:Ivermectin; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D035583:Rare Diseases; D020796:Receptor, Platelet-Derived Growth Factor alpha; D017171:Strongyloides stercoralis; D013322:Strongyloidiasis; D016896:Treatment Outcome; D039221:mRNA Cleavage and Polyadenylation Factors", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "31036733", "pubdate": "2019-04-29", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "12660384;18843283;23337549;23982058;27130711;16344672;20589620;22727506;20955401;23350004;18376280;26257279;26523379;26486351;19812425", "title": "Hypereosinophilia and severe bone disease in an African child: an unexpected diagnosis.", "title_normalized": "hypereosinophilia and severe bone disease in an african child an unexpected diagnosis" }

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"MEBENDAZOLE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "STRONGYLOIDIASIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MEBENDAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALBENDAZOLE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "STRONGYLOIDIASIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALBENDAZOLE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "IMATINIB MESYLATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "204644", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG, QD, APPROXIMATELY 133 MG/M2/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYELOFIBROSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMATINIB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARVEDILOL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARVEDILOL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG/KG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYELOFIBROSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "IMATINIB MESYLATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "204644", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "54 MILLIGRAM/SQ. METER, QD (100 MG ON ALTERNATE DAYS)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "54", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMATINIB." } ], "patientagegroup": null, "patientonsetage": "5", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Intentional product misuse", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Aspartate aminotransferase increased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatic enzyme increased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Alanine aminotransferase increased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BOTA S, ALVES P, CONSTANTINO C, MAIA R.. HYPEREOSINOPHILIA AND SEVERE BONE DISEASE IN AN AFRICAN CHILD: AN UNEXPECTED DIAGNOSIS. BMJ CASE REPORTS. 2019?12:1-3", "literaturereference_normalized": "hypereosinophilia and severe bone disease in an african child an unexpected diagnosis", "qualification": "3", "reportercountry": "PT" }, "primarysourcecountry": "PT", "receiptdate": "20200102", "receivedate": "20191105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16994451, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" } ]

{ "abstract": "As part of a synthesis of evidence regarding the abuse and addiction liability of dextromethorphan (DM), an over-the-counter cough medicine available in over 140 preparations, an uncommonly published case of dextromethorphan dependence (addiction) is described, with specific, rarely published complications. The individual was interviewed and several medical databases were also reviewed (Medline, 1966-present; PubMed) for all content relating to the Keywords: dextromethorphan, abuse, dependence, cough medicine, addiction, withdrawal, psychosis. The patient evidenced history suggesting substance dependence, substance-induced psychosis and substance withdrawal in relation to DM. A literature review revealed that DM has specific serotonergic and sigma-1 opioidergic properties. Dextrorphan (DOR), the active metabolite of DM, has similar properties; however, DOR is a weaker sigma opioid receptor agonist, and a stronger NMDA receptor antagonist. DM and DOR display specific biological features of addiction, and are capable of inducing specific psychiatric sequelae. A specific, reproducible toxidrome with significant psychiatric effects occurred, when DM was abused at greater than indicated doses, with more profound and potentially life-threatening effects at even higher doses. DM withdrawal appears evident. DM's active metabolite, DOR, has pharmacodynamic properties and intoxication effects similar to dissociatives, and may be more responsible for the dissociative effect that this DM abuser sought. However, it is this same metabolite that may be fraught with the potentially life-threatening psychoses and dissociative-induced accidents, as well as addiction. While DM has been hypothesized as the most commonly abused dissociative, health-care providers seem largely unaware of its toxidrome and addiction liability.", "affiliations": "Addiction Services, Veterans Administration Medical Center and Associate Professor, Department of Psychiatry, Wright State University School of Medicine, Dayton, OH 45428, USA. shannon.miller2@med.va.gov", "authors": "Miller|Shannon C|SC|", "chemical_list": "D000701:Analgesics, Opioid; D000996:Antitussive Agents; D004366:Nonprescription Drugs; D017480:Receptors, sigma; D003917:Dextrorphan; D003915:Dextromethorphan", "country": "United States", "delete": false, "doi": "10.1080/13556210500352410", "fulltext": null, "fulltext_license": null, "issn_linking": "1355-6215", "issue": "10(4)", "journal": "Addiction biology", "keywords": null, "medline_ta": "Addict Biol", "mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D000996:Antitussive Agents; D003702:Delusions; D003915:Dextromethorphan; D003917:Dextrorphan; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005260:Female; D006212:Hallucinations; D006801:Humans; D004366:Nonprescription Drugs; D011605:Psychoses, Substance-Induced; D017480:Receptors, sigma; D012008:Recurrence; D013375:Substance Withdrawal Syndrome; D019966:Substance-Related Disorders", "nlm_unique_id": "9604935", "other_id": null, "pages": "325-7", "pmc": null, "pmid": "16318953", "pubdate": "2005-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Dextromethorphan psychosis, dependence and physical withdrawal.", "title_normalized": "dextromethorphan psychosis dependence and physical withdrawal" }

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"drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (POWDER)", "drugenddate": null, "drugenddateformat": null, "drugindication": "COUGH", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXTROMETHORPHAN [DEXTROMETHORPHAN HYDROBROMIDE]" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXTROMETHORPHAN HYDROBROMIDE\\GUAIFENESIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SYRUP", "drugdosagetext": "UNK (CONSUMED ABOUT 3 OUNCES, ON TWO SEPARATE OCCASIONS)", "drugenddate": null, "drugenddateformat": null, "drugindication": "NASOPHARYNGITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TUSSIN DM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXTROMETHORPHAN HYDROBROMIDE\\GUAIFENESIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SYRUP", "drugdosagetext": "UNK (FIVE TIMES PER DAY, (ROUGHLY 40 OUNCES OF COUGH SYRUP) (SINGLE DAY USE)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TUSSIN DM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GUAIFENESIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SYRUP", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "COUGH", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ROBITUSSIN (GUAIFENESIN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXTROMETHORPHAN HYDROBROMIDE\\GUAIFENESIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SYRUP", "drugdosagetext": "UNK, DAILY (PROGRESSED TO DAILY USE)", "drugenddate": null, "drugenddateformat": null, "drugindication": "COUGH", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TUSSIN DM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXTROMETHORPHAN HYDROBROMIDE\\GUAIFENESIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SYRUP", "drugdosagetext": "UNK, 3X/DAY (8 OUNCES OF LIQUID COUGH SYRUP THREE TIMES PER DAY (24 OUNCES PER DAY)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TUSSIN DM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXTROMETHORPHAN HYDROBROMIDE\\GUAIFENESIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SYRUP", "drugdosagetext": "UNK (THEN SEVERAL TIMES PER DAY-NEEDING TO USE MORE)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TUSSIN DM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "GUAIFENESIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "GEL", "drugdosagetext": "UNK (GEL TABS)", "drugenddate": null, "drugenddateformat": null, "drugindication": "COUGH", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ROBITUSSIN (GUAIFENESIN)" }, { "actiondrug": null, "activesubstance": null, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SYRUP", "drugdosagetext": "UNK (REGULAR DM SYRUP)", "drugenddate": null, "drugenddateformat": null, "drugindication": "COUGH", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXTROMETHORPHAN [DEXTROMETHORPHAN HYDROBROMIDE]" } ], "patientagegroup": null, "patientonsetage": "33", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MILLER, S.. DEXTROMETHORPHAN PSYCHOSIS, DEPENDENCE AND PHYSICAL WITHDRAWAL. ADDICTION BIOLOGY. 2005?10 (4):325-327", "literaturereference_normalized": "dextromethorphan psychosis dependence and physical withdrawal", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190416", "receivedate": "20190416", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16204544, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "US-PFIZER INC-2019140176", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "GUAIFENESIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SYRUP", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "COUGH", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ROBITUSSIN (GUAIFENESIN)" }, { "actiondrug": null, "activesubstance": null, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (POWDER)", "drugenddate": null, "drugenddateformat": null, "drugindication": "COUGH", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXTROMETHORPHAN [DEXTROMETHORPHAN HYDROBROMIDE]" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DEXTROMETHORPHAN HYDROBROMIDE\\GUAIFENESIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SYRUP", "drugdosagetext": "UNK (CONSUMED ABOUT 3 OUNCES, ON TWO SEPARATE OCCASIONS)", "drugenddate": null, "drugenddateformat": null, "drugindication": "NASOPHARYNGITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TUSSIN DM" }, { "actiondrug": null, "activesubstance": null, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SYRUP", "drugdosagetext": "UNK (REGULAR DM SYRUP)", "drugenddate": null, "drugenddateformat": null, "drugindication": "COUGH", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXTROMETHORPHAN [DEXTROMETHORPHAN HYDROBROMIDE]" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CAFFEINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MG, DAILY (ADDING TO HER DM)", "drugenddate": null, "drugenddateformat": null, "drugindication": "COUGH", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NODOZ" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DEXTROMETHORPHAN HYDROBROMIDE\\GUAIFENESIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SYRUP", "drugdosagetext": "UNK UNK, 3X/DAY (CONSUMING 8 OUNCES OF LIQUID COUGH SYRUP THREE TIMES PER DAY (24 OUNCES PER DAY)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TUSSIN DM" }, { 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{ "abstract": "BACKGROUND\nOpportunistic invasive fungal infections are increasingly frequent in intensive care patients. Their clinical spectrum goes beyond the patients with malignancies, and for example invasive pulmonary aspergillosis has recently been described in critically ill patients without such condition. Liver failure has been suspected to be a risk factor for aspergillosis.\n\n\nMETHODS\nWe describe three cases of adult respiratory distress syndrome with sepsis, shock and multiple organ failure in patients with severe liver failure among whom two had positive Aspergillus antigenemia and one had a positive Aspergillus serology. In all cases bronchoalveolar lavage fluid was positive for Aspergillus fumigatus. Outcome was fatal in all cases despite treatment with voriconazole and aggressive symptomatic treatment.\n\n\nCONCLUSIONS\nInvasive aspergillosis should be among rapidly raised hypothesis in cirrhotic patients developing acute respiratory symptoms and alveolar opacities.", "affiliations": "Assistance Publique--Hôpitaux de Paris, Service de Pneumologie et Réanimation, Groupe Hospitalier Pitié-Salpêtrière, Paris, France. helene.prodanovic@psl.ap-hop-paris.fr <helene.prodanovic@psl.ap-hop-paris.fr>", "authors": "Prodanovic|Hélène|H|;Cracco|Christophe|C|;Massard|Julien|J|;Barrault|Camille|C|;Thabut|Dominique|D|;Duguet|Alexandre|A|;Datry|Annick|A|;Derenne|Jean-Philippe|JP|;Poynard|Thierry|T|;Similowski|Thomas|T|", "chemical_list": "D000935:Antifungal Agents", "country": "England", "delete": false, "doi": "10.1186/1471-230X-7-2", "fulltext": "\n==== Front\nBMC GastroenterolBMC Gastroenterology1471-230XBioMed Central London 1471-230X-7-21726674710.1186/1471-230X-7-2Case ReportInvasive pulmonary aspergillosis in patients with decompensated cirrhosis: case series Prodanovic Hélène 1helene.prodanovic@psl.ap-hop-paris.frCracco Christophe 1hristophe.cracco@psl.ap-hop-paris.frMassard Julien 2julien.massard@hge.aphp.frBarrault Camille 3camille.barrault@hmn.aphp.frThabut Dominique 2dominique.thabut@psl.aphp.frDuguet Alexandre 1alexandre.duguet@psl.ap-hop-paris.frDatry Annick 4annik.datry@psl.ap-hop-paris.frDerenne Jean-Philippe 1jpd@lppr.orgPoynard Thierry 2poynard@teaser.frSimilowski Thomas 1thomas.similowski@psl.ap-hop-paris.fr1 Assistance Publique – Hôpitaux de Paris, Service de Pneumologie et Réanimation, Groupe Hospitalier Pitié-Salpêtrière, Paris, France2 Assistance Publique – Hôpitaux de Paris, Service d'Hépato-Gastroentérologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France3 Assistance Publique – Hôpitaux de Paris, Service d'Hépato-Gastroentérologie, Hopital Henri-Mondor, Créteil, France4 Assistance Publique – Hôpitaux de Paris, Laboratoire de Parasitologie-Mycologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France2007 31 1 2007 7 2 2 2 5 2006 31 1 2007 Copyright © 2007 Prodanovic et al; licensee BioMed Central Ltd.2007Prodanovic et al; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\n\nBackground\nOpportunistic invasive fungal infections are increasingly frequent in intensive care patients. Their clinical spectrum goes beyond the patients with malignancies, and for example invasive pulmonary aspergillosis has recently been described in critically ill patients without such condition. Liver failure has been suspected to be a risk factor for aspergillosis.\n\nCase presentation\nWe describe three cases of adult respiratory distress syndrome with sepsis, shock and multiple organ failure in patients with severe liver failure among whom two had positive Aspergillus antigenemia and one had a positive Aspergillus serology. In all cases bronchoalveolar lavage fluid was positive for Aspergillus fumigatus. Outcome was fatal in all cases despite treatment with voriconazole and agressive symptomatic treatment.\n\nConclusion\nInvasive aspergillosis should be among rapidly raised hypothesis in cirrhotic patients developing acute respiratory symptoms and alveolar opacities.\n==== Body\nBackground\nInvasive pulmonary aspergillosis is a severe and often lethal infection. It mainly occurs in patients with malignancy who experience deep and prolonged neutropenia, but there are other established risk factors (e.g. high-dose long-term corticosteroid therapy or advanced forms of AIDS) [1]. Invasive pulmonary aspergillosis has recently been described in critically ill patients without malignancy [2-4], and Aspergilluss is increasingly considered as an emerging pathogen in non-hematological patients. Among the non-hematological patients diagnosed with invasive pulmonary aspergillosis in the critical care setting were patients with Child C liver cirrhosis [3]. This condition has thus be considered as a possible risk factor for invasive pulmonary aspergillosis, all the more so that acute liver failure is known to promote fungal infection [5]. In support of this contention and to raise the awareness of clinicians managing patients with decompensated cirrhosis, we report invasive pulmonary aspergillosis in three such patients.\n\nCase presentations\nThe three cases were diagnosed over a 18 months period, in two different hospitals.\n\nCase 1\nA 54-year-old man was admitted for ascites and acute renal failure revealing Child-Pugh stage C13 alcoholic cirrhosis. A liver biopsy showed severe acute alcoholic hepatitis and treatment with prednisolone 1 mg/kg a day was started. Human immunodeficiency virus (HIV) serology was negative, as were viral hepatitis B (HBV) and viral hepatitis C (HCV) tests. Over the following 21 days, four episodes of hemorrhagic shock from grade II esophageal varices occurred. A transjugular intrahepatic portosystemic shunt was placed on day 21. On day 22, severe sepsis developed with middle lobe alveolar consolidation on the chest x-ray. Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) was performed before initiating empirical antibiotic therapy with piperacillin-tazobactam and ofloxacin. Microbiological examination of the BAL fluid evidenced the presence of mycelia, hence the addition of fluconazole to the treatment. On day 23, the patient deteriorated and was admitted to the ICU (Simplified Acute Physiology Score II -SAPS2-61, Organ dysfunction and/or Infection -ODIN 4/7). The chest x-ray radiograph showed bilateral diffuse alveolar opacities. The patient was mechanically ventilated (PaO2/FiO2158 mmHg). The total neutrophil count was 21,000/mm3 (lymphocytes 219/mm3). Blood and urine samples, pleural and peritoneal fluids, and all catheters yielded negative cultures. Microbiological examination of repeated BAL fluid (performed on day 24) was negative, but the aspergillosis latex antigen agglutination test was positive at 1/256 (Platelia Aspergillus EIA for immunoenzymatic detection of galactomannan antigen of Aspergillus in serum; Bio-Rad, Marnes la Coquette, France). Aspergillus serology was negative (Protide Immunoelectrophoresis Aspergillus FSK1-MICROGEN, Beckman-Coulter, Fullerton, USA). Blood aspergillosis antigen tests (Platelia Aspergillus EIA for immunoenzymatic detection of galactomannan antigen of Aspergillus in serum; Bio-Rad, Marnes la Coquette, France) were positive on two occasions (possible false positive in the first instance because of the administration of piperacillin-tazobactam [6,7]). Fluconazole was switched to intravenous voriconazole (loading dose 400 mg two times on day 1, maintenance dose 200 mg twice daily) on day 27. The patient died on day 29. The family refused necropsy.\n\nCase 2\nA 55-year-old man was first admitted for severe pneumonia with rhabdomyolysis, acute renal failure and encephalopathy, revealing Child-Pugh stage C12 alcoholic cirrhosis. Empirical antibiotic therapy with piperacillin-tazobactam and ofloxacin was started. The serology tests for HIV, HBV and HCV were negative. On day 2, septic shock developed and the patient was transferred to the ICU (SAPS2 92; ODIN 5/7). He was mechanically ventilated (PaO2/FiO2 104 mmHg), placed under continuous hemodiafiltration, and received hemodynamic support plus intravenous hydrocortisone hemisuccinate (50 mg every 6 hours, 6 days). Upon the results of initial blood cultures idenfying Streptococcus pneumoniae as the likely cause of the pneumonia, antibiotic therapy was switched to high dose amoxycillin (6 g daily). The patient improved. He could be weaned from mechanical ventilation after two weeks, and from continuous hemodiafiltration after three weeks. Mechanical ventilation was resumed two weeks later because of a catheter-related Staphylococcus infection causing septic shock. After one additional week, new bilateral pulmonary infiltrates appeared. Microbiological examination of BAL fluid was negative for bacteria, while the histopathological examination yielded signs of alveolar damage with alveolar hemosiderosis (Golde score 38). At this time, the total leucocyte count was 8,600/mm3 (258 lymphocytes). BAL fluid and plugged telescopic catheter specimen grew Aspergillus fumigatus (five colonies). Two serum aspergillosis antigen tests were positive at a four days interval, both at 6.3 ng/ml (Platelia Aspergillus EIA for immunoenzymatic detection of galactomannan antigen of Aspergillus in serum; Bio-Rad, Marnes la Coquette, France). Aspergillus serology was negative (Protide Immunoelectrophoresis Aspergillus FSK1-MICROGEN, Beckman-Coulter, Fullerton, USA). Intravenous voriconazole was prescribed (loading dose 400 mg two times on day 1, maintenance dose 200 mg twice daily) but the patient developed multiple organ failure and died on the second day of this treatment. The family refused necropsy.\n\nCase 3\nA 64-year-old woman with a C14 alcoholic cirrhosis (Child Pugh score) and a histologically proven alcoholic hepatitis was admitted after one month of oral corticosteroid therapy, with a diagnosis of hepatic encephalopathy, in the context of a Klebsiella urinary tract infection. Amoxicillin/clavulanic acid was prescribed. The serology tests for HIV, HBV and HCV were negative. Over the week following admission, the patient developed acute respiratory failure, with bilateral pulmonary infiltrates and severe hypoxemia (PaO2 57 mmHg with oxygen 10 L/min). There was fever (38.5°C) and a total leucocyte count of 10,100/mm3 (300 lymphocytes). The patient was transferred to the ICU (SAPS2 39, ODIN 3/7) and fiberoptic bronchoscopy was performed. Microbiological examination of BAL fluid and bronchial aspiration showed hyphae, and both types of sample grew Aspergillus fumigatus. No other infectious agents were identified. Aspergillosis antigen tests were negative (Platelia Aspergillus EIA for immunoenzymatic detection of galactomannan antigen of Aspergillus in serum; Bio-Rad, Marnes la Coquette, France). The Aspergillus agglutination test was positive with one arch and a titer of 1/320 (Protide Immunoelectrophoresis Aspergillus FSK1-MICROGEN, Beckman-Coulter, Fullerton, USA). Intravenous voriconazole was prescribed (loading dose 400 mg two times on day 1, maintenance dose 200 mg twice daily). The patient developed multiple organ failure with severe hepatic dysfunction and died 2 weeks after admission (third day of voriconazole treatment). The family refused necropsy.\n\nConclusion\nAlthough they did not meet the host-related criteria of the European Organisation for Research and Treatment of Cancer (EORTC), the first two of our cases fulfilled the definition of \"probable\" invasive pulmonary aspergillosis [1]. The third case fulfilled one host-related criteria (prolonged administration of systemic corticosteroids in the previous 60 days) and also qualified as \"probable\" on the EORTC grid [1]. Because there was no Aspergillus culture from a normally sterile site, no tissue biopsy and no necropsy, none of the cases can be classified as \"proven\". We however believe that these three patients who rapidly developed bilateral pulmonary infiltrates indeed suffered from invasive aspergillosis. Indeed, in the three cases, elements suggestive of the presence of Aspergillus were present concomittantly in respiratory samples and in the blood, whereas the non-mycologic microbiological workup was consistently negative. Of note, CT scans could not be performed, so we do not know whether the halo sign, considered of high diagnostic value in cancer patients, was present or not. The value of this sign is yet to be ascertained in critically ill patients. Similarly, our patients did not exhibit wheezes or hemoptysis, which are important clinical signs of invasive pulmonary aspergillosis.\n\nOur patients presented several possible risk factors for invasive pulmonary aspergillosis. Steroid exposure was noted in the three cases, even though the EORTC host-related criteria were met in only one case. In one case, steroid exposure only consisted in the short duration stress dose of hydrocortisone that is currently routinely used in septic shock, but is has been shown shown that hydrocortisone promotes the growth of aspergillus in vitro [8]. In addition, it could be speculated that in critically ill patients, the threshold dose of corticosteroid that increases the risk of invasive aspergillosis is lower than in other patients because of the possible state of immunoparalysis associated with critical illness [9]. Corticosteroids are also known to promote aspergillosis in patients with underlying lung lesions [10]. These elements strengthen the notion that corticosteroids should be used with caution in critically ill patients. They suggest that in the presence of Aspergillus infection, stopping or tapering such treatments should at least be the matter of discussion. Of note, previous lung disease and lung structural damage due to pneumonia or acute respiratory distress syndrome were present in the three cases, and could have intrinsically promoted invasive aspergillosis [11]. Importantly, the three patients exhibited severe hepatic dysfunction. This condition deteriorates the host defense capacity. Cirrhosis is strongly associated with an increased risk of sepsis and acute respiratory failure [12]. Opportunistic infections usually associated with profound immunosuppression have been reported in cirrhotic patients otherwise free of immunosuppressive conditions or treatments [13]. T-lymphocyte count is inversely related to the severity of cirrhosis [14]. In addition, as mentioned in the introduction, acute liver failure promotes fungal infections [5]. Therefore, the occurrence of invasive pulmonary aspergillosis in patients with severe liver failure is not really surprising. It has been described in solid organ transplant recipients [15] including liver transplant recipients [16]. In the three patients described here, the overall leukocyte counts were normal but the the lymphocyte counts were very low at the time of diagnosis, and always dramatically lower than upon admission. We therefore consider these three patients as severely immunocompromised. This may contribute to explain why Aspergillus serology was negative in the first two patients and only weakly positive in the third one, a common finding in the presence of immunosuppression [17].\n\nFinally, it must be noted that the fatal outcome in the three cases that we describe is not suprising in view of the very high mortality expected from the SAPS values at the outset and of the dismal prognosis of severe sepsis and multiple organ failure in patients with advanced liver failure.\n\nThis case series fuels the hypothesis that severe, decompensated liver cirrhosis may be considered as a host risk factor for the development of invasive aspergillosis [3]. However, this assumption should be put into perspective, since in all cases other risk factors for opportunistic infection were present, such as steroid exposure, antibiotic use and severe critical illness. In patients with advanced or decompensated liver cirrhosis and pneumonia, a primary or secondary fungal origin should be considered, if infiltrates progress in spite of adequate antibiotic therapy and respiratory insufficiency develops. Further diagnostic exploration is mandatory, including bronchoscopy and lavage, mycological sampling, and serology for Aspergillus antigen. Medical imaging may be contributive, but is less pathognomonic than in neutropenic patients. Early pre-emptive treatment with antifungals is warranted.\n\nCompeting interests\nThe author(s) declare that they have no competing interests.\n\nAuthors' contributions\nHP, CC, JM, CB, DT and ADu all contributed to the collection of clinical data, literature review, and drafting the manuscript. ADa carried out the microbiological and serological diagnostic of aspergillosis. JPD and TP reviewed the patients' files critically, and reviewed the manuscript for intellectual content. TS supervised the whole process and provided major input to the manuscript in its final form. All the authors gave final approval of the submitted manuscript.\n\nPre-publication history\nThe pre-publication history for this paper can be accessed here:\n\n\n\nAcknowledgements\nWritten consent to publish the observations anonimously was obtained from the patients' relatives.\n\nThis work did not involve any funding body.\n\nThe authors thank Ms Marilyn Amouyal-Jones for her help with English style and grammar.\n==== Refs\nAscioglu S Rex JH de Pauw B Bennett JE Bille J Crokaert F Denning DW Donnelly JP Edwards JE Erjavec Z Fiere D Lortholary O Maertens J Meis JF Patterson TF Ritter J Selleslag D Shah PM Stevens DA Walsh TJ Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus Clin Infect Dis 2002 34 7 14 11731939 10.1086/323335 \nMeersseman W Vandecasteele SJ Wilmer A Verbeken E Peetermans WE Van Wijngaerden E Invasive aspergillosis in critically ill patients without malignancy Am J Respir Crit Care Med 2004 170 621 625 15229094 10.1164/rccm.200401-093OC \nRolando N Harvey F Brahm J Philpott-Howard J Alexander G Casewell M Fagan E Williams R Fungal infection: a common, unrecognised complication of acute liver failure J Hepatol 1991 12 1 9 2007764 10.1016/0168-8278(91)90900-V \nLionakis MS Kontoyiannis DP Glucocorticoids and invasive fungal infections Lancet 2003 362 1828 1838 14654323 10.1016/S0140-6736(03)14904-5 \nHartemink KJ Paul MA Spijkstra JJ Girbes AR Polderman KH Immunoparalysis as a cause for invasive aspergillosis? Intensive Care Med 2003 29 2068 2071 12768234 10.1007/s00134-003-1778-z \nPalmer LB Greenberg HE Schiff MJ Corticosteroid treatment as a risk factor for invasive aspergillosis in patients with lung disease Thorax 1991 46 15 20 1871691 \nAder F Nseir S Guery B Tillie-Leblond I [Acute invasive pulmonary aspergillosis in chronic lung disease--a review ][published in French under: Aspergillose pulmonaire aigue invasive et pathologies pulmonaires chroniques] Rev Mal Respir 2006 23 6S11 6S20 16820744 \nForeman MG Mannino DM Moss M Cirrhosis as a risk factor for sepsis and death: analysis of the National Hospital Discharge Survey Chest 2003 124 1016 1020 12970032 10.1378/chest.124.3.1016 \nIkawa H Hayashi Y Ohbayashi C Tankawa H Itoh H Autopsy case of alcoholic hepatitis and cirrhosis treated with corticosteroids and affected by Pneumocystis carinii and cytomegalovirus pneumonia Pathol Int 2001 51 629 632 11564218 10.1046/j.1440-1827.2001.01249.x \nLombardo L Capaldi A Poccardi G Vineis P Peripheral blood CD3 and CD4 T-lymphocyte reduction correlates with severity of liver cirrhosis Int J Clin Lab Res 1995 25 153 156 8562979 \nMinari A Husni R Avery RK Longworth DL DeCamp M Bertin M Schilz R Smedira N Haug MT Mehta A Gordon SM The incidence of invasive aspergillosis among solid organ transplant recipients and implications for prophylaxis in lung transplants Transpl Infect Dis 2002 4 195 200 12535262 \nFortun J Martin-Davila P Moreno S Barcena R de Vicente E Honrubia A Garcia M Nuno J Candela A Uriarte M Pintado V Prevention of invasive fungal infections in liver transplant recipients: the role of prophylaxis with lipid formulations of amphotericin B in high-risk patients J Antimicrob Chemother 2003 52 813 819 14563893 10.1093/jac/dkg450 \nIkawa H Hayashi Y Ohbayash C Tankawa H Itoh H Autopsy case of alcoholic hepatitis and cirrhosis treated with corticosteroids and affected by Pneumocystis carinii and cytomegalovirus pneumonia Pathol Int 2001 51 629 632 11564218 10.1046/j.1440-1827.2001.01249.x \nLombardo L Capaldi A Poccardi G Vineis P Peripheral blood CD3 and CD4 T-lymphocyte reduction correlates with severity of liver cirrhosis Int J Clin Lab Res 1995 25 153 156 8562979 \nMinari A Husni R Avery RK Longworth DL DeCamp M Bertin M Schilz R Smedira N Haug MT Mehta A Gordon SM The incidence of invasive aspergillosis among solid organ transplant recipients and implications for prophylaxis in lung transplants Transpl Infect Dis 2002 4 195 200 12535262 \nFortun J Martin-Davila P Moreno S Barcena R de Vicente E Honrubia A Garcia M Nuno J Candela A Uriarte M Pintado V Prevention of invasive fungal infections in liver transplant recipients: the role of prophylaxis with lipid formulations of amphotericin B in high-risk patients J Antimicrob Chemother 2003 52 813 819 14563893 10.1093/jac/dkg450 \nHerbrecht R Letscher-Bru V Oprea C Lioure B Waller J Campos F Villard O Liu KL Natarajan-Ame S Lutz P Aspergillus galactomannan detection in the diagnosis of invasive aspergillosis in cancer patients J Clin Oncol 2002 20 1898 1906 11919250 10.1200/JCO.2002.07.004\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-230X", "issue": "7()", "journal": "BMC gastroenterology", "keywords": null, "medline_ta": "BMC Gastroenterol", "mesh_terms": "D000935:Antifungal Agents; D001228:Aspergillosis; D001232:Aspergillus fumigatus; D001707:Biopsy, Needle; D018450:Disease Progression; D017809:Fatal Outcome; D005260:Female; D005440:Fluid Therapy; D016469:Fungemia; D006801:Humans; D008104:Liver Cirrhosis, Alcoholic; D017093:Liver Failure; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure; D012128:Respiratory Distress Syndrome; D012720:Severity of Illness Index", "nlm_unique_id": "100968547", "other_id": null, "pages": "2", "pmc": null, "pmid": "17266747", "pubdate": "2007-01-31", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "11564218;11731939;11919250;12535262;12970032;14563893;16820744;14654323;15229094;2007764;1871691;8562979;12768234", "title": "Invasive pulmonary aspergillosis in patients with decompensated cirrhosis: case series.", "title_normalized": "invasive pulmonary aspergillosis in patients with decompensated cirrhosis case series" }

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Invasive pulmonary aspergillosis in patients with decompensated cirrhosis: case series. 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Invasive pulmonary aspergillosis in patients with decompensated cirrhosis: case series. 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"Prodanovic, H.. Invasive pulmonary aspergillosis in patients with decompensated cirrhosis: case series. BMC Gastroenterology. 2007;7:2:10.1186/1471-230X-7-2", "literaturereference_normalized": "invasive pulmonary aspergillosis in patients with decompensated cirrhosis case series", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20220310", "receivedate": "20220201", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20410561, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220423" } ]

{ "abstract": "The combination of 5-flourouracil (5-FU) and leukovorin is widely used as adjuvant chemotherapy for metastatic colorectal carcinoma. The most common clinical side effects of 5-FU are related to its gastrointestinal toxicity, chiefly stomatitis and diarrhea. The latter may be severe in up to 30% and occasionally is life-threatening. We describe a case of therapy-induced enteritis presenting as acute abdominal pain and present the computed tomographic (CT) findings. In light of the prevalence of this regimen, the potential morbidity of this complication, and a paucity of CT examples in the radiologic literature, this case illustrates an important adverse effect of this medication. Early recognition and treatment should avoid significant morbidity and mortality.", "affiliations": "Department of Radiology, Louisiana State University Health Sciences Center, Shreveport, USA.", "authors": "Zamani|Ramin|R|;Heldmann|Maureen|M|", "chemical_list": "D000964:Antimetabolites, Antineoplastic; D002955:Leucovorin; D005472:Fluorouracil", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0024-6921", "issue": "156(3)", "journal": "The Journal of the Louisiana State Medical Society : official organ of the Louisiana State Medical Society", "keywords": null, "medline_ta": "J La State Med Soc", "mesh_terms": "D015746:Abdominal Pain; D000964:Antimetabolites, Antineoplastic; D017024:Chemotherapy, Adjuvant; D003110:Colonic Neoplasms; D004751:Enteritis; D005260:Female; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D008875:Middle Aged; D036542:Tomography, Spiral Computed", "nlm_unique_id": "7505618", "other_id": null, "pages": "143-4", "pmc": null, "pmid": "15233387", "pubdate": "2004", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Enteritis as a complication of adjuvant combination chemotherapy using 5-fluorouracil and leukovorin: clinical and helical computed tomographic features.", "title_normalized": "enteritis as a complication of adjuvant combination chemotherapy using 5 fluorouracil and leukovorin clinical and helical computed tomographic features" }

[ { "companynumb": "US-PFIZER INC-2016280077", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLON CANCER STAGE III", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "008107", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLON CANCER STAGE III", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN." } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Enteritis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ZAMANI, R.. ENTERITIS AS A COMPLICATION OF ADJUVANT COMBINATION CHEMOTHERAPY USING 5-FLUOROURACIL AND LEUKOVORIN: CLINICAL AND HELICAL COMPUTED TOMOGRAPHIC FEATURES. JOURNAL OF THE LOUISIANA STATE MEDICAL SOCIETY. 2004;156(3):143-144", "literaturereference_normalized": "enteritis as a complication of adjuvant combination chemotherapy using 5 fluorouracil and leukovorin clinical and helical computed tomographic features", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160608", "receivedate": "20160608", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12447819, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160815" } ]

{ "abstract": "Echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion occurs in approximately 5% of non-small cell lung cancer (NSCLC) cases. Variants 1 and 3a/b are the most common EML4-ALK variants. Emerging evidence indicates that patients with variant 1 and those with variant 3a/b exhibit differential therapeutic responses. However, the National Comprehensive Cancer Network guidelines have not included the EML4-ALK fusion subtype in treatment decision-making to date. Herein, we report the case of a non-smoking 36-year-old female patient who was diagnosed with right lung adenocarcinoma in 2005 (cT1N3M0, IIIB) and received definitive chemoradiotherapy. The patient achieved a partial response, and her disease remained under control for 8 years. However, in May 2013, the patient was diagnosed with brain metastasis and underwent subsequent surgical resection, followed by postoperative brain radiotherapy and chemotherapy. Postoperative pathology confirmed ALK gene rearrangement, and next-generation sequencing performed in 2020 identified the EML4-ALK variant as variant 1. After progression-free survival lasting 4 years, new metastatic lesions were found in the patient's right lung, and she was administered crizotinib for 20 months. Due to a suspicious recurrence in the intracranial surgical margin area, as well as an unbearable gastrointestinal reaction to crizotinib, alectinib was later adopted. At the 7-month follow-up, positron emission tomography/computed tomography revealed a clinical complete response. This case of an NSCLC patient with EML4-ALK fusion variant 1 who exhibited an exceptional response to chemoradiotherapy and ALK inhibitors might broaden horizons in efforts to reveal the molecular mechanism of radiosensitivity in ALK-positive NSCLC and provide reference for further research regarding the optimal radiotherapy delivery dose and tyrosine kinase inhibitor selection.", "affiliations": "Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.;Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.;Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.;Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.;Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.", "authors": "Xu|Xinyan|X|;Liu|Di|D|;Wen|Junmiao|J|;Chen|Jiayan|J|;Fan|Min|M|", "chemical_list": null, "country": "China", "delete": false, "doi": "10.21037/tlcr-20-1212", "fulltext": "\n==== Front\nTransl Lung Cancer Res\nTransl Lung Cancer Res\nTLCR\nTranslational Lung Cancer Research\n2218-6751\n2226-4477\nAME Publishing Company\n\n33489810\ntlcr-09-06-2500\n10.21037/tlcr-20-1212\nCase Report\nA case report of exceptional clinical response to chemoradiotherapy and tyrosine kinase inhibitors in a patient with EML4-ALK fusion variant 1 non-small cell lung cancer\nXu Xinyan 1 2 #\nLiu Di 1 2 #\nWen Junmiao 1 2\nChen Jiayan 1 2\nFan Min 1 2\n1 Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China;\n2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China\n# These authors contributed equally to this work.\n\nCorrespondence to: Jiayan Chen, MD; Min Fan, MD, PhD. Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China. Email: chenjiayan2008@126.com; fanmin_fuscc@aliyun.com.\n12 2020\n12 2020\n9 6 25002507\n21 10 2020\n04 12 2020\n2020 Translational Lung Cancer Research. All rights reserved.\n2020\nTranslational Lung Cancer Research.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0.\nEchinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion occurs in approximately 5% of non-small cell lung cancer (NSCLC) cases. Variants 1 and 3a/b are the most common EML4-ALK variants. Emerging evidence indicates that patients with variant 1 and those with variant 3a/b exhibit differential therapeutic responses. However, the National Comprehensive Cancer Network guidelines have not included the EML4-ALK fusion subtype in treatment decision-making to date. Herein, we report the case of a non-smoking 36-year-old female patient who was diagnosed with right lung adenocarcinoma in 2005 (cT1N3M0, IIIB) and received definitive chemoradiotherapy. The patient achieved a partial response, and her disease remained under control for 8 years. However, in May 2013, the patient was diagnosed with brain metastasis and underwent subsequent surgical resection, followed by postoperative brain radiotherapy and chemotherapy. Postoperative pathology confirmed ALK gene rearrangement, and next-generation sequencing performed in 2020 identified the EML4-ALK variant as variant 1. After progression-free survival lasting 4 years, new metastatic lesions were found in the patient’s right lung, and she was administered crizotinib for 20 months. Due to a suspicious recurrence in the intracranial surgical margin area, as well as an unbearable gastrointestinal reaction to crizotinib, alectinib was later adopted. At the 7-month follow-up, positron emission tomography/computed tomography revealed a clinical complete response. This case of an NSCLC patient with EML4-ALK fusion variant 1 who exhibited an exceptional response to chemoradiotherapy and ALK inhibitors might broaden horizons in efforts to reveal the molecular mechanism of radiosensitivity in ALK-positive NSCLC and provide reference for further research regarding the optimal radiotherapy delivery dose and tyrosine kinase inhibitor selection.\n\nKeywords:\n\nLung cancer\nechinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK)\nvariant 1\ncase report\n==== Body\npmcIntroduction\n\nLung cancer is the leading cause of cancer-related death globally, and non-small cell lung cancer (NSCLC) accounts for more than 80% of lung cancer cases (1). Approximately 65% of NSCLC cases are initially diagnosed as locally advanced (stage IIIB) or advanced (stage IV) (2). Anaplastic lymphoma kinase (ALK) gene rearrangements occur in 3–7% of NSCLC. ALK rearrangements are more common in younger patients with a history of never or light smoking (3,4), and are associated with a high incidence of brain metastases (BM) (5). Specific molecular alterations contribute to tumor heterogeneity in locally advanced or advanced NSCLC, which results in variation in treatment efficacy. Herein, we present the case of a patient with ALK-positive variant 1 NSCLC who exhibited a favorable response to treatment with chemoradiotherapy and ALK inhibitors, indicating the inherent therapeutic sensitivity of this specific subtype of lung cancer. We present the following article in accordance with the CARE reporting checklist (available at http://dx.doi.org/10.21037/tlcr-20-1212).\n\nCase presentation\n\nA non-smoking 36-year-old female patient was diagnosed with lung cancer originating in the middle and lower lobes of the right lung in January 2005. The patient was staged as cT1N3M0 (overall stage IIIB) according to 6th Edition of American Joint Committee on Cancer (AJCC) TNM Staging System (2002), which was routinely applied in tumor staging at that time (Figure 1). Pathological examination of the right-sided supraclavicular nodes by percutaneous needle biopsy revealed a poorly differentiated adenocarcinoma. Subsequently, the patient underwent sequential definitive chemoradiotherapy. Chemotherapy was administered every 3 weeks for 5 cycles using vinorelbine (25 mg/m2, days 1 and 8) with cisplatin (30 mg/m2, days 1–3). A linear accelerator with 6 MV photons was used to deliver a total dose of 6527 cGy [actual mean dose of planning target volume (PTV)] in 31 fractions, with a conventional fractional dose of 2 Gy a day and 5 days a week, to a prescribed isodose of 95%, utilizing a seven-field intensity-modulated radiation therapy (IMRT) technique. The gross tumor volume (GTV) was defined as the primary tumor lesion plus the involved lymph nodes (1R, 2R, 4R). The clinical target volume (CTV) was defined as the GTV plus the mediastinal lymphatic drainage area. The PTV was defined as the CTV plus a 1-cm expansion (Figure 2A). The dose-volume histogram (DVH) showed that doses for organs at risk (OARs) were acceptable (Figure 2B). After completing chemoradiotherapy, the patient was observed to have achieved a partial response, and her disease remained under control for 8 years, during which time she was regularly followed up (Figure 1).\n\nFigure 1 Diagnosis and treatment procedure.\n\nFigure 2 Thoracic and intracranial radiotherapy plans. (A) Contouring of lesions and isodose curves in thoracic radiotherapy. (B) Dose-volume histogram (DVH) of the thoracic radiotherapy plan. (C) Hematoxylin and eosin (HE) staining of a surgically removed intracranial lesion, original magnification ×100. (D) Postoperative radiotherapy plan for brain metastasis. (E) DVH of the intracranial radiotherapy plan.\n\nIn May 2013, the patient began to experience headache and a decrease in grip strength of the right upper limb. Positron emission tomography/computed tomography (PET/CT) was performed and revealed a metastatic lesion, measuring 3.7×2.9 cm, in the left frontal/parietal lobe with a maximum standardized uptake value (SUVmax) of 12.6 (Figure 1). She underwent surgical resection, and postoperative pathology confirmed metastatic lung adenocarcinoma (Figure 2C). Fluorescence in situ hybridization (FISH) detected ALK gene rearrangement, while exon sequencing revealed no epidermal growth factor receptor mutation. The ALK variant was identified by FoundationOne next-generation sequencing (NGS) assays as variant 1 (V1) in post-hoc analysis (2020). Postoperative brain radiotherapy and chemotherapy was delivered in consideration of intracranial oligometastasis in this patient. For the radiotherapy, the GTV was defined as the tumor bed, the CTV was defined as the tumor bed plus the surrounding edema area, and the PTV was defined as the CTV plus a 1-cm expansion. A dose of 50 Gy was administered in 25 fractions (Figure 2D,E) and was accompanied by 4 cycles of pemetrexed (500 mg/m2, day 1) combined with cisplatin (75 mg/m2, days 1–3) every 3 weeks. After treatment, a marked improvement was observed in the patient’s primary intracranial symptoms, which was supported by no obvious recurrence or metastasis in brain magnetic resonance (MR) at regular follow-up examinations. However, 4 years later, in August 2017, the patient experienced anhelation and progressive emaciation, and PET/CT discovered new metastatic lesions in the right lung and right pleura, although no significant intracranial recurrence or metastasis was observed. CT-guided needle aspiration of the right pleural lesion confirmed metastatic lung adenocarcinoma (Figures 1,3). One cycle of chemotherapy of pemetrexed (500 mg/m2, d1) combined with carboplatin (AUC =5, day 1) was delivered, and the patient achieved a partial response.\n\nFigure 3 Pathologic findings of a thoracic metastatic biopsy lesion. (A) HE staining, original magnification ×200. (B) ALK rearrangement detected by immunohistochemistry (IHC), original magnification ×200. (C) Cell keratin 7 (CK7) expression detected by IHC, original magnification ×200. (D) Expression of thyroid transcription factor (TTF)-1 by IHC, original magnification ×200.\n\nFrom March 2018, the patient was prescribed crizotinib, starting with the standard dose of 250 mg bid. However, in response to this treatment, she developed unbearable stomachache and gastric distention accompanied by fatigue, resulting in a dose reduction to 250 mg qd. During treatment with crizotinib, the patient’s thoracic disease remained stable, except for a suspicious recurrence in the surgical margin area at the 15-month follow-up (Figure 1). Intracranial disease progression was detected by magnetic resonance imaging at another hospital 5 months later, and considering the patient’s persistent gastrointestinal side effects, the administration of crizotinib was discontinued. Since November 2019, the patient has been receiving the second-generation tyrosine kinase inhibitor (TKI) alectinib at dose of 600 mg bid. No adverse events of grade 3 or above have occurred so far. It is worth noting that the strengthening signal of the potential intracranial recurrent lesion was weakened after 1 month of treatment with alectinib and has remained stable since then. At the latest follow-up in July, 2020, PET/CT revealed no abnormal hypermetabolic region, indicating a clinical complete response (Figure 1).\n\nWritten informed consent was obtained from the patient for publication of this study and any accompanying images. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013).\n\nDiscussion\n\nRadical chemoradiotherapy has long been the cornerstone treatment for unresectable stage III NSCLC (6,7), with ≥60 Gy thoracic radiotherapy (8) and two to four cycles of cisplatin-based chemotherapy as the recommended regimen (9,10). The latest National Comprehensive Cancer Network (NCCN) guidelines recommend durvalumab as consolidation therapy only for patients with no disease progression after two or more cycles of definitive chemoradiotherapy (11). However, the general therapeutic effect for unresectable stage III NSCLC patients who receive chemoradiotherapy is unsatisfactory, with median overall survival (OS) of less than 30 months, median progression-free survival (PFS) of less than 12 months, and a 5-year overall survival rate of less than 30% (6-10). In the case described above, a patient, who was initially diagnosed as stage IIIB in 2005 and achieved PFS lasting 8 years, benefitted immensely from treatment with definitive chemoradiotherapy, achieving an exceptional therapeutic response. For patients who develop symptomatic intracranial oligometastasis during follow-up, especially those with a large tumor burden, surgical resection followed by stereotactic radiosurgery or whole-brain radiotherapy is deemed an appropriate option by the NCCN guidelines (11). Combined data from the PROFILE 1005 and 1007 trials indicated that brain radiotherapy before crizotinib could prolong the intracranial time to progression from 7.0 to 13.2 months (12). Mak et al. (13) found that the receipt of targeted therapy after cranial irradiation was strongly connected with improved survival. Ni et al. (14) reported that upfront brain radiotherapy followed by crizotinib provided considerable clinical benefits for patients with baseline oligometastatic intracranial lesions. The treatment strategy for our patient after her diagnosis of intracranial oligometastasis was consistent with those in other studies and achieved moderately better PFS than that previously reported (12).\n\nSpecific oncogenic driver alterations may explain the favorable radiotherapeutic response in this case. The most frequent ALK gene translocation partner is echinoderm microtubule-associated protein-like 4 (EML4) (15). Among all variants, the most common are V1 (EML4 exon 13 fused to ALK exon 20, E13;A20) and V3a/b (EML4 exon 6a/b fused to ALK exon 20, E6a/b;A20) (15). Current evidence focusing on radiotherapeutic response in ALK-positive patients is mainly based on cranial radiotherapy in patients with BM. Johung et al. (15) and Arrieta et al. (16) demonstrated that in NSCLC patients with BM, those harboring EGFR mutations and ALK rearrangements have superior radiotherapeutic control rates compared to those with KARS mutations and wild-type (WT) NSCLC. Arrieta et al. also reported that ALK-positive NSCLC patients had longer intracranial PFS than those with WT NSCLC (18.4 vs. 8.7 months), which was comparable to that of patients with EGFR mutation (18.2 months) (16). Mak et al. (13) found that after adjustment for receipt of systemic therapy (TKI and chemotherapy) and baseline characteristics (including number of BM and presence of extracranial metastases) in patients with BM, those with ALK rearrangements displayed improved survival compared to those with mutations in EGFR or KRAS, or a WT genetic profile. The observations reported in our case are in line with those of previous studies demonstrating the promising response of ALK-positive NSCLC patients to intracranial radiotherapy in terms of long PFS (4 years in this case). To our knowledge, this is the first report of a case of EML4-ALK V1 NSCLC demonstrating an excellent response to primary thoracic radiotherapy, which was reflected in prolonged PFS of 8 years after definitive thoracic chemoradiotherapy. Of note, previous studies on the impact of ALK rearrangements on radiotherapeutic response were mostly based on small patient cohorts, and differential radiosensitivity among ALK variant subtypes has rarely been investigated. Currently, genetic profiles are not taken into consideration in radiotherapy-related decision-making (11,17). This case, in which a patient with EML4-ALK fusion V1 exhibited a favorable response to radiotherapy, could potentially serve as a reference for future dose optimization research for such patients.\n\nCrizotinib is a first-generation TKI that targets ALK gene rearrangements and presents significant benefits in regard to survival and intracranial disease control (3,18). The brain remains the most common site of progression in patients with or without BM at initial diagnosis(12). In this case, the patient also experienced suspicious intracranial progression after 15 months of treatment with crizotinib. Alectinib, a second-generation ALK inhibitor that has demonstrated effective central nervous system (CNS) penetration, was notably reported to delay CNS progression versus crizotinib, irrespective of prior CNS disease or brain radiotherapy (19). Mok et al. observed the OS benefit of alectinib in patients with [HR 0.58 (95% CI, 0.34–1.00)] and without [HR 0.76 (95% CI, 0.45–1.26)] baseline CNS metastases (20). Of note, alectinib is now recommended as the preferred first-line strategy (11) for patients with ALK-positive advanced NSCLC, based on its outstanding performance in the ALEX study, in which it achieved a median PFS of 34.8 months in untreated ALK-positive patients with advanced NSCLC (20). Moreover, the incidence of adverse events, including gastrointestinal adverse events, was reported to be markedly lower with alectinib than with crizotinib (21,22). In the case of our patient, alectinib considerably relieved severe gastrointestinal side effects associated with crizotinib, and complete response was obtained after 7 months of alectinib treatment. Nonetheless, second-generation TKIs are associated with a higher incidence of developing resistant mutations than first-generation TKIs (23), which diminishes therapeutic options after the failure of second-generation TKI therapy. Hence, investigation of genetic alteration subtypes is critical to deepening our understanding of therapeutic efficacy and improving alternative treatment options.\n\nPatients with V1 have been reported to achieve longer PFS in response to crizotinib than non-V1 patients (24), while non-V3 patients display a longer PFS than those with V3 (25). The patient in the case described above obtained a PFS of at least 15 months after first-line treatment with crizotinib, even with a dose reduction due to side events. This PFS is superior to the average median PFS of 10.9 months (3,26), and is consistent with the results of a previous study in which patients with V1 achieved better efficacy of crizotinib than non-V1 (24). Lin et al. (23) reported that patients with V3 were more likely to harbor resistance mutations than those with V1 (57% vs. 30%, P=0.023). In particular, they found that those with V3 were more prone than those with V1 to develop G1202R mutation (32% vs. 0%, P<0.001), which is more common in patients resistant to second-generation TKIs and only showed a response to the third-generation TKI lorlatinib (27). It has been indicated that among patients receiving second-generation ALK inhibitors after crizotinib, those with V1 have a longer PFS than those with V3, which to some degree explains the excellent performance of alectinib in the case of our patient. However, with the administration of lorlatinib after first- and second-generation TKI therapy, patients with V3 tended to outperform those with V1 in terms of PFS (23). Although prospective phase III data from the ALEX study (26) did not show a significant difference in therapeutic efficacy between V1 and V3a/b with crizotinib or alectinib in the first-line setting, there is still potential to incorporate ALK variants into efficacy prediction and TKI treatment decision-making. To the best of our knowledge, the ALK rearrangement subtype of V1 may have contributed to the favorable response to TKIs in this case, leaving next-step treatment alternatives to be discussed when this patient eventually acquires resistance to alectinib.\n\nConclusions\n\nHere, we have presented the case of a NSCLC patient with EML4-ALK fusion V1 who exhibited a favorable response to chemoradiotherapy as well as ALK inhibitors. Variant subtypes of EML4-ALK may be potential research targets for further studies regarding differentiated responses to radiotherapy in such patients, leaving deepened mechanism researches to be conducted in the future. Up to now, the NCCN guidelines have not included the EML4-ALK fusion subtype into treatment decision-making, neither in relation to radiotherapy nor TKIs (11). This case might broaden horizons in uncovering the differentiated radiosensitivity of NSCLC with different EML4-ALK variants, paving the way for further retrospective and prospective studies regarding optimized radiotherapy delivery dose and TKI selection in the future.\n\nSupplementary\n\nThe article’s supplementary files as\n\n10.21037/tlcr-20-1212 10.21037/tlcr-20-1212\n\nAcknowledgments\n\nFunding: Clinical Research Plan of SHDC (SHDC2020CR3025B), CSCO-Leading Cancer Research Fund (Y-2019AZZD-0561), CSCO-MSD Cancer Research Fund (Y-MSD2020-0336), Lian Yun Gang Shi Hui Lan Public Foundation (HL-HS2020-66).\n\nEthical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Written informed consent was obtained from the patient for publication of this study and any accompanying images. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013).\n\nReporting Checklist: The authors have completed the CARE reporting checklist. Available at http://dx.doi.org/10.21037/tlcr-20-1212\n\nConflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-20-1212). The authors have no conflicts of interest to declare.\n\n(English Language Editor: J. Reynolds)\n==== Refs\nReferences\n\n1 Siegel RL Miller KD Jemal A . Cancer statistics, 2018. CA Cancer J Clin 2018;68 :7-30. 10.3322/caac.21442 29313949\n2 William WN Jr Lin HY Lee JJ Revisiting stage IIIB and IV non-small cell lung cancer: analysis of the surveillance, epidemiology, and end results data. 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J Clin Oncol 2010;28 :2181-90. 10.1200/JCO.2009.26.2543 20351327\n8 Bradley JD Paulus R Komaki R Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol 2015;16 :187-99. 10.1016/S1470-2045(14)71207-0 25601342\n9 Senan S Brade A Wang LH PROCLAIM: Randomized Phase III Trial of Pemetrexed-Cisplatin or Etoposide-Cisplatin Plus Thoracic Radiation Therapy Followed by Consolidation Chemotherapy in Locally Advanced Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol 2016;34 :953-62. 10.1200/JCO.2015.64.8824 26811519\n10 Liang J Bi N Wu S Etoposide and cisplatin versus paclitaxel and carboplatin with concurrent thoracic radiotherapy in unresectable stage III non-small cell lung cancer: a multicenter randomized phase III trial. Ann Oncol 2017;28 :777-83. 10.1093/annonc/mdx009 28137739\n11 National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer Version 3.2020. Available online: https://www.nccn.org/professionals/physician_gls/default.aspx#nscl. Accessed August 12, 2020.\n12 Costa DB Shaw AT Ou SH Clinical Experience With Crizotinib in Patients With Advanced ALK-Rearranged Non-Small-Cell Lung Cancer and Brain Metastases. J Clin Oncol 2015;33 :1881-8. 10.1200/JCO.2014.59.0539 25624436\n13 Mak KS Gainor JF Niemierko A Significance of targeted therapy and genetic alterations in EGFR, ALK, or KRAS on survival in patients with non-small cell lung cancer treated with radiotherapy for brain metastases. Neuro Oncol 2015;17 :296-302. 10.1093/neuonc/nou146 25053852\n14 Ni J Li G Yang X Optimal timing and clinical value of radiotherapy in advanced ALK-rearranged non-small cell lung cancer with or without baseline brain metastases: implications from pattern of failure analyses. Radiat Oncol 2019;14 :44. 10.1186/s13014-019-1240-1 30866974\n15 Johung KL Yao X Li F A clinical model for identifying radiosensitive tumor genotypes in non-small cell lung cancer. Clin Cancer Res 2013;19 :5523-32. 10.1158/1078-0432.CCR-13-0836 23897899\n16 Arrieta O Ramirez-Tirado LA Caballe-Perez E Response rate of patients with baseline brain metastases from recently diagnosed non-small cell lung cancer receiving radiotherapy according to EGFR, ALK and KRAS mutation status. Thorac Cancer 2020;11 :1026-37. 10.1111/1759-7714.13359 32072746\n17 Cassidy RJ Zhang X Patel PR Next-generation sequencing and clinical outcomes of patients with lung adenocarcinoma treated with stereotactic body radiotherapy. Cancer 2017;123 :3681-90. 10.1002/cncr.30794 28608966\n18 Solomon BJ Cappuzzo F Felip E Intracranial Efficacy of Crizotinib Versus Chemotherapy in Patients With Advanced ALK-Positive Non-Small-Cell Lung Cancer: Results From PROFILE 1014. J Clin Oncol 2016;34 :2858-65. 10.1200/JCO.2015.63.5888 27022118\n19 Gadgeel S Peters S Mok T Alectinib versus crizotinib in treatment-naive anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer: CNS efficacy results from the ALEX study. Ann Oncol 2018;29 :2214-22. 10.1093/annonc/mdy405 30215676\n20 Mok T Camidge DR Gadgeel SM Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study. Ann Oncol 2020;31 :1056-64. 10.1016/j.annonc.2020.04.478 32418886\n21 Cho BC Obermannova R Bearz A Efficacy and Safety of Ceritinib (450 mg/d or 600 mg/d) With Food Versus 750-mg/d Fasted in Patients With ALK Receptor Tyrosine Kinase (ALK)-Positive NSCLC: Primary Efficacy Results From the ASCEND-8 Study. J Thorac Oncol 2019;14 :1255-65. 10.1016/j.jtho.2019.03.002 30851442\n22 Peters S Camidge DR Shaw AT Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2017;377 :829-38. 10.1056/NEJMoa1704795 28586279\n23 Lin JJ Zhu VW Yoda S Impact of EML4-ALK Variant on Resistance Mechanisms and Clinical Outcomes in ALK-Positive Lung Cancer. J Clin Oncol 2018;36 :1199-06. 10.1200/JCO.2017.76.2294 29373100\n24 Yoshida T Oya Y Tanaka K Differential Crizotinib Response Duration Among ALK Fusion Variants in ALK-Positive Non-Small-Cell Lung Cancer. J Clin Oncol 2016;34 :3383-9. 10.1200/JCO.2015.65.8732 27354483\n25 Woo CG Seo S Kim SW : Differential Protein Stability and Clinical Responses of EML4-ALK Fusion Variants to Various ALK Inhibitors in Advanced ALK-rearranged Non-small Cell Lung Cancer. Ann Oncol 2017;28 :791-7. 10.1093/annonc/mdw693 28039177\n26 Camidge DR Dziadziuszko R Peters S Updated Efficacy and Safety Data and Impact of the EML4-ALK Fusion Variant on the Efficacy of Alectinib in Untreated ALK-Positive Advanced Non-Small Cell Lung Cancer in the Global Phase III ALEX Study. J Thorac Oncol 2019;14 :1233-43. 10.1016/j.jtho.2019.03.007 30902613\n27 Gainor JF Dardaei L Yoda S Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer. Cancer Discov 2016;6 :1118-33. 10.1158/2159-8290.CD-16-0596 27432227\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2218-6751", "issue": "9(6)", "journal": "Translational lung cancer research", "keywords": "Lung cancer; case report; echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK); variant 1", "medline_ta": "Transl Lung Cancer Res", "mesh_terms": null, "nlm_unique_id": "101646875", "other_id": null, "pages": "2500-2507", "pmc": null, "pmid": "33489810", "pubdate": "2020-12", "publication_types": "D002363:Case Reports", "references": "32038920;30866974;21903745;32072746;25470694;28586279;25624436;29373100;27432227;28137739;26438117;32418886;30215676;26811519;19318668;23897899;29313949;27354483;30851442;28039177;30902613;20351327;27022118;25053852;28608966;25601342", "title": "A case report of exceptional clinical response to chemoradiotherapy and tyrosine kinase inhibitors in a patient with EML4-ALK fusion variant 1 non-small cell lung cancer.", "title_normalized": "a case report of exceptional clinical response to chemoradiotherapy and tyrosine kinase inhibitors in a patient with eml4 alk fusion variant 1 non small cell lung cancer" }

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{ "abstract": "Stopping immunosuppression in a transplant patient with donor-derived malignancy offers the theoretical benefit that reconstitution of the patient's immune system will allow \"rejection\" of the malignancy, as the malignancy also originates from allogeneic tissue. However, this option exists with the caveat that the patient's allograft(s) will likely be rejected too. In simultaneous pancreas-kidney (SPK) recipients, the normal continued functioning and possible absence of malignancy in either the unaffected kidney or pancreas further complicate this decision.\nThe charts of 3 patients with donor-derived metastatic malignancies after SPK were retrospectively reviewed in detail. We provide treatment and management recommendations based on successful outcomes and a review of the existing literature.\nConsistent with a broad review of the literature, in all 3 cases, complete immunosuppression cessation, removal of both grafts, and in 1 case treatment with an immune checkpoint inhibitor to augment the immune response was successful. One patient is doing well 1 year after successfully undergoing kidney retransplantation, while a second patient is active on the waitlist for SPK retransplantation after no evidence of metastatic disease for 2 years.\nThe successful management of metastatic donor-derived malignancies requires allograft removal, immunosuppression cessation, and adjuvant therapy that includes occasional use of checkpoint inhibitors to augment the immune response.", "affiliations": "School of Medicine, University of California, San Francisco, San Francisco, CA.;Department of Surgery, University of California, San Francisco, San Francisco, CA.;Department of Surgery, University of California, San Francisco, San Francisco, CA.;Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.;Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.;Department of Surgery, University of California, San Francisco, San Francisco, CA.;Department of Surgery, University of California, San Francisco, San Francisco, CA.;Department of Surgery, University of California, San Francisco, San Francisco, CA.;Department of Surgery, University of California, San Francisco, San Francisco, CA.", "authors": "Amara|Dominic|D|;Wisel|Steven A|SA|;Braun|Hillary J|HJ|;Collisson|Eric A|EA|;Friedlander|Terence|T|;Worner|Giulia|G|;Roll|Garret R|GR|;Hirose|Ryutaro|R|;Stock|Peter G|PG|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1097/TXD.0000000000001090", "fulltext": "\n==== Front\nTransplant Direct\nTransplant Direct\nTXD\nTransplantation Direct\n2373-8731 Lippincott Williams & Wilkins Hagerstown, MD \n\n33324741\n00002\n10.1097/TXD.0000000000001090\n022\nPancreas and Islet Transplantation\nMetastatic Donor-derived Malignancies Following Simultaneous Pancreas-kidney Transplant: Three Case Reports and Management Strategies\nAmara Dominic BA1 Wisel Steven A. MD2 Braun Hillary J. MD2 Collisson Eric A. MD3 Friedlander Terence MD3 Worner Giulia NP2 Roll Garret R. MD2 Hirose Ryutaro MD2 Stock Peter G. MD, PhD2 1 School of Medicine, University of California, San Francisco, San Francisco, CA.\n2 Department of Surgery, University of California, San Francisco, San Francisco, CA.\n3 Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.\nCorrespondence: Peter G. Stock, MD, PhD, Division of Transplant Surgery, University of California, San Francisco, 505 Parnassus Ave, M-884, San Francisco, CA 94143. (Peter.Stock@ucsf.edu).\n08 12 2020 \n1 2021 \n7 1 e63618 9 2020 06 10 2020 Copyright © 2020 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.2020This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.Background.\nStopping immunosuppression in a transplant patient with donor-derived malignancy offers the theoretical benefit that reconstitution of the patient’s immune system will allow “rejection” of the malignancy, as the malignancy also originates from allogeneic tissue. However, this option exists with the caveat that the patient’s allograft(s) will likely be rejected too. In simultaneous pancreas-kidney (SPK) recipients, the normal continued functioning and possible absence of malignancy in either the unaffected kidney or pancreas further complicate this decision.\n\nMethods.\nThe charts of 3 patients with donor-derived metastatic malignancies after SPK were retrospectively reviewed in detail. We provide treatment and management recommendations based on successful outcomes and a review of the existing literature.\n\nResults.\nConsistent with a broad review of the literature, in all 3 cases, complete immunosuppression cessation, removal of both grafts, and in 1 case treatment with an immune checkpoint inhibitor to augment the immune response was successful. One patient is doing well 1 year after successfully undergoing kidney retransplantation, while a second patient is active on the waitlist for SPK retransplantation after no evidence of metastatic disease for 2 years.\n\nConclusion.\nThe successful management of metastatic donor-derived malignancies requires allograft removal, immunosuppression cessation, and adjuvant therapy that includes occasional use of checkpoint inhibitors to augment the immune response.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\nSimultaneous pancreas-kidney (SPK) recipients require aggressive immunosuppression to temporize the alloimmune response and the recurrence of autoimmunity. SPK programs generally use lymphocyte-depleting induction regimens, followed by a relatively significant burden of maintenance immunosuppression compared with regimens typically used after solitary kidney transplant.1 Consequently, immunosuppression modification when recipients develop a new malignancy is challenging. For donor-derived malignancies, the option of reducing or stopping immunosuppression to “reject” the tumor presents a unique therapeutic option with the caveat that the allograft will likely be rejected.2 This approach’s theoretical basis is that the host immune system’s reconstitution will trigger an alloimmune response against the malignancy, as the malignancy originates from donor tissue. However, an algorithm for stopping immunosuppression, allograft removal, and implementing medical measures such as chemotherapy is not well defined. Decision-making can be challenging in the setting of a well-functioning kidney or pancreas allograft, which may be uninvolved in the metastatic cancer, as allograft removal needs to be strongly considered to allow immunosuppression withdrawal. Given the paucity of literature on this subject and accompanying decisions, the purpose of this study is to present 3 cases of donor-derived metastatic malignancies after SPK and provide management recommendations based on successful outcomes and a review of the existing literature.\n\nMATERIALS AND METHODS\nThree charts of SPK recipients with donor-derived malignancy were retrospectively reviewed. Our institution does not require IRB review for clinical case study reports on up to 3 clinical experiences identified during clinical care. For privacy, all Health Insurance Portability and Accountability Act identifiers have been removed. All 3 patients underwent donor pancreas implantation into the right iliac vessels (systemic endocrine drainage) with enteric exocrine drainage (donor duodenum to recipient ileum) and donor kidney implantation into the left iliac vessels with a ureteroneocystostomy.\n\nCASE SUMMARIES\nCase No. 1: Donor-transmitted Pancreatic Adenocarcinoma Detected 6 Months Post SPK\nClinical History\nAt the time of her SPK, patient 1 was a 42-year-old woman with a history of end-stage renal disease (ESRD) secondary to type 1 diabetes (DM1) with a calculated panel reactive antibodies (cPRA) of 91. She underwent thymoglobulin induction and transitioned to a maintenance immunosuppression of tacrolimus (trough goal 5–15 µg/L), everolimus (trough goal 5–7 µg/L), mycophenolate 540 mg BID, and prednisone 5 mg daily. In the 6 months following transplant, she was seen >10 times at multiple hospitals for recurrent abdominal pain. She received steroids and thymoglobulin for possible rejection. Two months post SPK, a computerized tomography (CT) abdomen-pelvis showed stranding around the pancreas allograft suggestive of possible pancreatitis but with normal lipase. At 6-month posttransplant, it became known that the patient’s donor had transmitted an adenocarcinoma to 3 other recipients who received organs from the same donor. At that time, a positron emission tomography (PET) scan revealed diffuse nodal uptake within the left supraclavicular, mediastinal, mesenteric, and right external iliac nodal regions.\n\nManagement and Outcome\nThree days after the PET scan, given the concern for donor-derived malignancy, the patient underwent removal of both grafts, followed by immunosuppression cessation. Based on the concern for metastatic disease and the confirmed transmission of aggressive malignancy to the other recipients of organs from the same donor, no preoperative biopsy was attempted as the transplants were going to be removed regardless of any biopsy findings. The PET-avid lymph nodes were also not biopsied at the time of surgery. Explant pathology confirmed widespread adenocarcinoma in the pancreas most consistent with a pancreatic primary with extensive lymphovascular invasion and periovarian and fallopian tube involvement. Tumor genotyping identified mutations that would potentially allow serial monitoring via cell-free DNA (cf-DNA) testing. By 6 months following the allograft removals, the previously seen PET-avid lesions had resolved. The patient continued to have no evidence of cancer for the following year and a half, by both cross-sectional imaging and cf-DNA testing. When being considered for repeat kidney transplant, she was noted to have several new donor-specific antibodies (DSA). Two years after her graft removals, given the substantial time period without evidence of malignancy, the patient underwent a second kidney transplant and restarted immunosuppression. The patient was also listed for a pancreas transplant but received a kidney-only offer, which was accepted given lower immunosuppression requirements and concern over an extended delay with waiting for a compatible pancreas as she had a cPRA of 100% at the time. Six months later, she underwent treatment for an antibody-mediated rejection episode, and 11 months after her second kidney transplant had a PET scan that found no evidence of cancer. The patient is now 3½ years from her original SPK, 3 years from her graft removals, and 1 year from her kidney retransplant. She has been considered for pancreas transplant but is not currently thought to be a candidate due to her recent rejection treatment and a continued cPRA of 100%.\n\nCase No. 2: Donor-derived Pancreatic Adenocarcinoma Detected ≥10 Years Post SPK\nClinical History\nAt the time of her SPK, patient 2 was a 28-year-old woman with a history of DM1 and ESRD since age 12 with a cPRA of 0%. She underwent thymoglobulin induction and was transitioned to a maintenance regimen of tacrolimus (trough goal 5–15 µg/L), mycophenolate 540 mg BID, and everolimus (trough goal 2–3 µg/L). She had an uneventful course with excellent function of both grafts for 10 years, when she developed chronic abdominal pain. Initial imaging and endoscopies did not identify an etiology for the pain. Twelve years after her SPK, the patient was treated with thymoglobulin for suspected rejection due to an elevated lipase, but no biopsy was done at that time. The lipase returned to normal, but imaging showed fullness in the donor duodenum wall. A subsequent fine-needle aspiration showed adenocarcinoma (Figure 1). The patient underwent PET-CT scan, which showed mediastinal, left supraclavicular, and retroperitoneal lymphadenopathy in addition to marked hypermetabolism of the transplanted pancreas’s head and duodenal cuff.\n\nFIGURE 1. Images of the lesion associated with the allograft pancreas in the right lower quadrant in case 2. A, Coronal CT scan. B, Axial CT scan. C, Successful ultrasound-guided fine-needle aspiration of the lesion in the transplanted duodenum associated with the allograft pancreas. CT, computed tomography.\n\nManagement and Outcome\nThe patient had her tacrolimus trough goal lowered to 3–5 µg/L, mycophenolate lowered to 180 mg BID, and everolimus continued with troughs of 2–3 µg/L. The plan was made to discontinue immunosuppression entirely if the cancer was confirmed to be donor-derived. Short-tandem repeat-based identity mapping was performed on the tumor, which confirmed donor-derived malignancy. After this result, the patient underwent removal of both grafts so that immunosuppression could be discontinued to treat the metastatic donor-derived pancreatic adenocarcinoma. Final pathology confirmed a 6.5 -cm poorly differentiated adenocarcinoma involving the pancreatic head with invasion into the duodenum, ampulla, and peripancreatic soft tissue and metastatic adenocarcinoma in 5 of 16 lymph nodes. Three months after her graft removals, repeat PET scan showed no hypermetabolic lesions to suggest malignancy, and her CA 19-9 decreased from elevated at 85 before her graft removals to within the normal range. PET scans in the 11 months after pancreatectomy and nephrectomy continued to display no evidence of cancer, and her CA 19-9 has remained normal. Her cPRA is currently 99%, and she was also noted to have a new HLA class 1 DSA. The patient is now 14 years from her original SPK, 2 years from her graft pancreatectomy and nephrectomy, and is now listed for another SPK. The oncology service will continue to monitor her on the waitlist with PET scans and serum CA-19-9.\n\nCase No. 3: Donor-derived Renal Cell Carcinoma Detected 13 Years Post SPK\nClinical History\nAt the time of her SPK, patient 3 was a 33-year-old woman with a history of DM1 and ESRD with a cPRA of 24%. She underwent thymoglobulin induction and transitioned to an immunosuppression regimen of tacrolimus (trough goal 5–15 µg/L), mycophenolate 360 mg BID, and prednisone 5 mg daily. She had excellent graft function and an uncomplicated course for 7 years. She developed biopsy-proven chronic allograft nephropathy 7 years after transplant and returned to dialysis but remained insulin independent. Thirteen years after her SPK, a CT scan performed to evaluate nondescript abdominal pain showed a new 3 -cm mass in the transplant kidney. Ultrasound surveillance imaging done 6 months later described this lesion as a vascular lesion in the transplant kidney’s superior pole, which had grown to 4.7 cm. Previously anuric, over the next month, the patient developed hematuria with increasing abdominal pain. A PET/CT scan done revealed a hypermetabolic lesion in the transplant kidney without evidence of metastatic disease.\n\nManagement and Outcome\nGiven the concern for donor-derived malignancy in the transplanted kidney, 2 days after the PET scan, the patient underwent transplant nephrectomy. Final pathology revealed a 5.8 -cm, stage T1b renal cell carcinoma (RCC) of unclassified subtype. Given this diagnosis, the patient’s immunosuppression regimen was reduced to a tacrolimus trough goal of 3–5 µg/L but otherwise maintained to preserve allograft pancreas function. Over the subsequent 6 months, surveillance CT scans showed no evidence of metastatic disease. However, 11 months following the transplant nephrectomy, a CT scan identified a 7-mm soft tissue nodule in the left lower quadrant deemed to be low likelihood for recurrence given the RCC’s low stage. Serial imaging identified the lesion’s slow growth to 1.6 cm. She was referred to oncology, who elected to treat this lesion as local recurrence with stereotactic radiation therapy. The lesion showed slight interval growth over the subsequent 9 months without metastatic spread despite radiation therapy.\n\nTwo years after transplant nephrectomy, she was found to have new retroperitoneal, pulmonary, and hepatic nodules suspicious for metastatic disease. She was still insulin independent. Over the course of several multidisciplinary discussions, immunosuppression cessation was recommended, as was tyrosine kinase inhibition. She deferred these recommendations due to the dramatic improvement in quality of life her pancreas transplant had provided and challenges with blindness and insulin administration. Two months later, she was admitted with severe pain and was found to have a malignant pleural effusion and hepatic metastases. She then agreed to discontinue immunosuppression and initiate the checkpoint inhibitor nivolumab. She was still resistant to graft pancreatectomy, opting to wait to see if she might remain insulin independent. Four weeks after nivolumab initiation, she developed severe right lower quadrant pain with fever. CT scan showed dramatic improvement in hepatic and retroperitoneal metastatic disease burden, but her transplant pancreas was necrotic appearing. The patient underwent immediate transplant pancreatectomy, which was challenging due to profound local inflammation. A bovine pericardial patch was required to reconstruct the iliac vein. On the first day after pancreatectomy, the iliac vein thrombosed, necessitating thrombectomy and placement of a bare-metal stent across the narrowing. She was subsequently discharged with continued CT scan surveillance showing resolution of her retroperitoneal lymphadenopathy and decrease in the size of her liver metastases (Figure 2). The patient is now 16 years from her original SPK, 2½ years from her transplant nephrectomy, and 3 months from her transplant pancreatectomy. For her donor-derived RCC, she will continue on monthly nivolumab for 1 year with regular follow-up with oncology.\n\nFIGURE 2. The left-sided panels show the metastatic liver lesions in case 3 before explantation of the allograft pancreas and cycle 2 of nivolumab. Multiple liver lesions can be seen measuring 2.2, 0.6, and 2.3 cm in the left-top, left-middle, and left-bottom panels, respectively. The right-sided panels show the liver after explanation of the allograft pancreas and multiple cycles of nivolumab. The liver lesion in the top panels has reduced from 2.2 to 1.0 cm in size, while the liver lesion in bottom panels has reduced from 2.3 to 0.85 cm in size. The liver lesion in the middle panel was resolved and was not seen on subsequent scans. Lesions are all indicated by white arrows.\n\nDISCUSSION\nThis series reports the successful initial treatment of 3 SPK recipients with donor-derived metastatic malignancies. The literature on the treatment of metastatic donor-derived malignancy is limited overall and particularly limited in SPK recipients. In the larger kidney transplant literature, several systematic reviews have investigated the management of donor transmitted malignancy. In 2013, Xiao et al identified 104 donor-transmitted cases and showed that 67% of patients underwent graft nephrectomy and withdrawal of immunosuppression, representing the most common approach pursued. The use of adjuvant chemotherapy, radiotherapy, and immunotherapy was highly variable ranging from 0% to 80% use depending on tumor tissue of origin.3 In 2020, Eccher et al presented a similar analysis of 234 recipients with cancer of donor origin and noted that metastatic disease marked the most significant predictor of death even in this population. Because of the option of return to dialysis, most kidney recipients were treated maximally with immunosuppression cessation, graft removal regardless of tumor tissue of origin, grade, or subtype. However, adjuvant medical treatments were pursued and individualized based on tumor tissue of origin, grade, and subtype.4 For instance, 2 recent case reports have described the successful treatment of metastatic melanoma in a kidney-only recipients through immunosuppression cessation, allograft explantation, and based on the relative success in general metastatic melanoma, adjuvant immune checkpoint therapy.5,6\n\nThe literature in pancreas transplants alone (PTA) is limited to single case reports. The first donor-transmitted malignancy in a PTA was reported by Perosa et al in 2010. The malignancy was limited to the pancreas and treated successfully with graft pancreatectomy and immunosuppression cessation.7 Nagaraju et al reported a case of a soft tissue sarcoma arising in a pancreas allograft, which was not tested for donor origin but nevertheless successfully treated with graft pancreatectomy and immunosuppression cessation.8\n\nFocusing on SPK patients, Roza et al reported the first donor-derived malignancy in a transplanted pancreas in an SPK recipient in 2001. However, this patient died of malignancy after transplant pancreatectomy, immunosuppression cessation, and 2 chemotherapy courses.9 In 2020, Meier et al reported the successful treatment of a widely metastatic BK virus-associated renal carcinoma in an SPK patient with graft nephrectomy and IL-2 immunotherapy. In their case, rejection of the pancreas resulted in a spontaneous rupture of a pseudoaneurysm of the pancreas arterial anastomosis requiring emergent surgery.10 To our knowledge, there is no other literature on the successful treatment of metastatic donor-derived malignancy in SPK recipients.\n\nOur series adds to this literature by describing the successful initial treatment of 3 SPK patients with donor-derived metastatic malignancy. Patient 1 had donor-transmitted malignancy, meaning the malignancy was present in the donor at the time of donation, while patients 2 and 3 had malignancy that likely originated from donor tissue years after transplantation. Although the timing of the development of these donor-derived malignancies was disparate, in all 3 cases, the malignancy expanded under the surveillance of recipient immune systems that were suppressed to prevent rejection. The common strategy used in all 3 cases forms the basis for the algorithm outlined in Figure 3. The strategies and proposed algorithm are based on our experience and a comprehensive literature review, which demonstrate that successful treatment of metastatic malignancies in transplant recipients is dependent on early allograft removal once donor-derived malignancy is identified, which allows immune reconstitution via immunosuppression cessation. These steps also permit the additional option of treatment with a checkpoint inhibitor, which can cause vigorous rejection if a transplanted organ remains in place.\n\nFIGURE 3. Algorithm outlining management strategy of metastatic donor-derived malignancy in SPK patients. aMalignancy not squamous, skin or lymphoma and <24 mo from transplant, or current/previous lesion noted in transplanted organ. bTesting options include FISH, HLA typing, and nucleic acid–based testing. cRecommendation to remove remaining graft arguably stronger for a remaining pancreas than a remaining kidney, due to a higher risk of rejection and complications with the pancreas in particular. dExperimental directions for assessing response to therapy may include cPRA retesting as a potential biomarker for “rejection” of donor antigens. Cell-free DNA may experimentally be used to comment on tumor burden and response. eAdjuvant chemo- or targeted-therapy may also be indicated based on the malignancy’s tissue of origin, subtype, and grade. Immunotherapy may be preferred on a theoretical basis. However, most adjuvant recommendations are based on the general oncology literature as there are no standard of care recommendations for adjuvant treatment of donor-derived malignancy. fRemoval of remaining grafts before initiation of immunotherapy due to the high risk of rejection and complications with immunotherapy. SPK, simultaneous pancreas-kidney; PET-CT, positron emission tomography-computerized tomography scan; NED, no evidence of disease.\n\nIn the cases above, the methods for distinguishing donor from recipient tumor origin included analysis for differences in microsatellites, that is, short-tandem repeats or checking for a panel of specific gene mutations. These genomic techniques represent just a few options in a larger arsenal of techniques that can be applied to distinguish between donor and recipient tissue. These approaches also include HLA-typing or using fluorescence in situ hybridization for karyotyping.11-15 Using genomic techniques allowed us to apply cell-free-DNA testing as an adjunct to support our determination of no tumor recurrence in case 1. Cell free-DNA testing for malignancy has been described as potentially useful in determining cancer recurrence. However, it remains an evolving, experimental diagnostic tool.16\n\nFocusing on the management approach to each case, case 1 was clearly a tumor that was transmitted with the donor pancreas, as the heart and liver recipients had metastatic pancreatic adenocarcinoma with similar histopathology. In contrast to SPK cases, stopping immunosuppression or removing the transplants in the cases of the heart and liver recipients would have been fatal. As a result, the heart and liver recipient ultimately died from metastatic pancreatic adenocarcinoma. In our case, the kidney and pancreas could be immediately removed due to the options for dialysis and insulin, respectively. At the time of allograft pancreatectomy and nephrectomy (6 mo after transplant), the tumor had metastasized to the adjacent fallopian tube. Although there was no evidence of tumor in the explanted kidney, a PET scan at the time of pancreatectomy and nephrectomy revealed diffuse nodal uptake within the left supraclavicular, mediastinal, mesenteric, and right external iliac regions. Despite the tumor’s locally aggressive nature with lymphovascular invasion, stopping all immunosuppression resulted in normalization of the PET scan within 6 months and no evidence of metastatic disease. In this case, simply restoring the immune response allowed “rejection” of the donor-derived tumor. It is difficult to determine how much of the tumor control is related to restoring immune-mediated tumor surveillance by stopping immunosuppression versus alloimmune rejection of tumor-bearing donor HLA. The fact that the alloimmune response likely provided a substantial contribution to eliminating the tumor is reflected by the dramatic increase in anti-HLA antibodies to a cPRA of 100%. Despite her high panel reactive antibodies, she received a 0-mismatched kidney transplant approximately 2 years after her explant and continues to do well with no evidence of tumor recurrence.\n\nThe malignancy in case 2 occurred in the transplanted pancreas of an SPK recipient 10 years after transplant. Following the confirmation of the tumor’s donor origin, both the pancreas and kidney were explanted, and immunosuppression was stopped. Like case 1, removal of both organs allowed complete immunosuppression cessation and resulted in resolution of the systemic lymphadenopathy and hypermetabolism at the site of the pancreas transplant observed with sequential PET scans. The decision to remove the normally functioning kidney transplant with no evidence of disease was difficult, but since the tumor was donor-derived, we were concerned about occult disease. We also wanted to be prepared to use checkpoint inhibitors to augment the immune response if immunosuppression withdrawal was insufficient to clear the tumor cells. In case 2, like case 1, immunosuppression withdrawal was also associated with an increase of donor specific HLA antibody and a cPRA of nearly 100%, suggesting that the alloimmune response contributed to the control of the tumor. There has been no evidence of recurrence 2 years following the explants, and the patient is active for both kidney and pancreas retransplantation.\n\nCase 3 is different than the others in that the donor-derived malignancy occurred in a nonfunctioning kidney allograft 13 years following SPK, and the pancreas transplant was functioning normally. At the time of nephrectomy, there was no evidence of metastatic disease, so immunosuppression was lowered but not stopped based on the pancreas’s ongoing excellent function. Transplant pancreatectomy would have allowed immunosuppression cessation and would have been in line with the literature in single organ transplants where graft removal and immunosuppression cessation are the standard approaches. However, the treatment of SPK patients remains more complex than the treatment of kidney or PTA transplants as providers must weigh the risks of removing a normally functioning transplant that may be tumor-free. Thus, this decision involved a risk-benefit assessment by the transplant team and a conversation with the patient regarding preferences. The recipient ultimately did not want to abandon immunosuppression and felt having a functioning pancreas’s benefits outweighed the disease recurrence risks. When metastatic disease became apparent (pulmonary effusion, liver lesions), immunosuppression was stopped. She continued to have normal pancreas function but developed severe pain at the local recurrence site and required a chest tube for drainage of the malignant effusion. At this point, checkpoint inhibitors were initiated, but due to her frail condition and normal function (at the time), the pancreas allograft was not removed. However, within weeks of starting checkpoint inhibitors, her increasing insulin requirements and severe pain over the pancreas allograft prompted emergent transplant pancreatectomy. The checkpoint inhibitor therapy’s potency was remarkable, and the aggressive rejection induced was almost immediate. In retrospect, pancreatectomy should have been performed before checkpoint inhibitor initiation, as removal of the markedly inflamed and vascular allograft was challenging. The complications of higher blood loss and postexplant deep venous thrombosis might have been avoided. Therefore, removing the pancreas before the massive inflammatory response checkpoint inhibitors can induce may be safest. Despite the negative aspects of the rejection induced by checkpoint inhibitor therapy, the aggressive immune response was also associated with her metastatic disease’s rapid improvement. Within 3 months of immunotherapy initiation, the pulmonary, liver, and lymph lesions have improved substantially based on imaging studies.\n\nWe elected to reactivate the patients for either kidney alone or SPK in cases 1 and 2 following 2 years of being cancer free. Although the decision to proceed with transplantation for all potential recipients with a history of treated cancers is dependent on disease-free survival estimates for each malignancy, these data are not available for the scenarios described here. We are optimistic that the immune memory for the donor HLA will be able to maintain adequate control of the original donor-derived tumor, but rigorous follow-up will be necessary to ensure that immunosuppression reinitiation has not compromised immune-mediated control of the tumor. The ongoing presence of DSA would suggest ongoing antitumor activity and could be monitored for future study purposes.\n\nIn summary, the finding of metastatic donor-derived malignancy following SPK should prompt immediate removal of the allograft with the primary lesion, immunosuppression cessation, and strong consideration for removal of the second allograft too. If the natural immune surveillance associated with stopping immunosuppression fails to control the metastatic disease, checkpoint inhibition can augment the natural immune response and successfully control aggressive metastatic disease. This algorithm is only possible for kidney or SPK recipients since these patients have alternative medical therapies following allograft removal, unlike heart, lung, or liver recipients. This strategy is consistent with a broad literature review, demonstrating that successful management of metastatic donor-derived malignancies requires allograft removal, immunosuppression cessation, and adjuvant therapy dictated by tumor tissue of origin that can include occasional immunotherapy use to augment the immune response.\n\nACKNOWLEDGMENTS\nThe content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.\n\nPublished online 8 December, 2020.\n\nD.A. and P.G.S. did conception and design. D.A., S.W., and G.W. did acquisition of data. D.A., E.A.C., T.F., G.R.R., R.H., and P.G.S. did analysis and interpretation of data. D.A. and P.G.S. drafted the article. S.W., H.J.B., E.A.C., T.F., G.R.R., R.H., and P.G.S. critically revised the article.\n\nH.J.B. was funded by the National Institutes of Health Grant Number T32AI125222.\n\nThe authors declare no conflicts of interest.\n==== Refs\nREFERENCES\n1. Redfield RR Scalea JR Odorico JS \nSimultaneous pancreas and kidney transplantation: current trends and future directions.\n\nCurr Opin Organ Transplant . 2015 ; 20 :94 –102\n25565444 \n2. Strauss DC Thomas JM \nTransmission of donor melanoma by organ transplantation.\n\nLancet Oncol . 2010 ; 11 :790 –796\n20451456 \n3. Xiao D Craig JC Chapman JR \nDonor cancer transmission in kidney transplantation: a systematic review.\n\nAm J Transplant . 2013 ; 13 :2645 –2652\n24034231 \n4. Eccher A Girolami I Motter JD \nDonor-transmitted cancer in kidney transplant recipients: a systematic review.\n\nJ Nephrol . 2020 \n5. Boyle SM Ali N Olszanski AJ \nDonor-derived metastatic melanoma and checkpoint inhibition.\n\nTransplant Proc . 2017 ; 49 :1551 –1554\n28838438 \n6. Singh P Pandey D Rovin B \nSuccessful treatment and five years of disease-free survival in a donor transmitted metastatic melanoma with ipilimumab therapy.\n\nCureus . 2019 ; 11 :e4658 31328051 \n7. Perosa M Crescentini F Antunes I \nDonor-derived malignancy in a pancreas graft.\n\nTranspl Int . 2010 ; 23 :e5 –e6\n19895378 \n8. Nagaraju S Grethlein SJ Vaishnav S \nCase report: primary de novo sarcoma in transplant pancreas allograft.\n\nTransplant Proc . 2017 ; 49 :2352 –2354\n29198676 \n9. Roza AM Johnson C Juckett M \nAdenocarcinoma arising in a transplanted pancreas.\n\nTransplantation . 2001 ; 72 :1156 –1157\n11579317 \n10. Meier RPH Müller YD Dietrich P-Y \nImmunologic clearance of a BK virus-associated metastatic renal allograft carcinoma.\n\nTransplantation . 2020 \n11. Schmitt C Ciré K Schattenkirchner S \nHighly sensitive DNA typing for detecting tumors transmitted by transplantation.\n\nTranspl Int . 1998 ; 11 :382 –386\n9787416 \n12. Robin AJ Cohen EP Chongkrairatanakul T \nA single center’s approach to discriminating donor versus host origin of renal neoplasia in the allograft kidney.\n\nAnn Diagn Pathol . 2016 ; 23 :32 –34\n27402221 \n13. Milton CA Barbara J Cooper J \nThe transmission of donor-derived malignant melanoma to a renal allograft recipient.\n\nClin Transplant . 2006 ; 20 :547 –550\n16968479 \n14. Palanisamy A Persad P Koty PP \nDonor-derived myeloid sarcoma in two kidney transplant recipients from a single donor.\n\nCase Rep Nephrol . 2015 ; 2015 :821346 25977825 \n15. Kim JK Carmody IC Cohen AJ \nDonor transmission of malignant melanoma to a liver graft recipient: case report and literature review.\n\nClin Transplant . 2009 ; 23 :571 –574\n19681978 \n16. Corcoran RB Chabner BA \nApplication of Cell-free DNA Analysis to Cancer Treatment.\n\nN Engl J Med . 2018 ; 379 :1754 –1765\n30380390\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2373-8731", "issue": "7(1)", "journal": "Transplantation direct", "keywords": null, "medline_ta": "Transplant Direct", "mesh_terms": null, "nlm_unique_id": "101651609", "other_id": null, "pages": "e636", "pmc": null, "pmid": "33324741", "pubdate": "2021-01", "publication_types": "D016428:Journal Article", "references": "32091486;11579317;9787416;30380390;27402221;28838438;25977825;19681978;19895378;25565444;31328051;32535833;29198676;24034231;16968479;20451456", "title": "Metastatic Donor-derived Malignancies Following Simultaneous Pancreas-kidney Transplant: Three Case Reports and Management Strategies.", "title_normalized": "metastatic donor derived malignancies following simultaneous pancreas kidney transplant three case reports and management strategies" }

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{ "abstract": "BACKGROUND\nMyasthenia gravis (MG) can be aggravated by several classes of drugs, including antibiotics. Penicillins are considered safe drugs for the management of infectious disease in patients with MG. However, a few cases of MG exacerbations after penicillin treatment have been reported in literature.\n\n\nMETHODS\nWe report six patients with MG developing acute worsening of symptoms after amoxicillin or amoxicillin/clavulanate treatment. In most of the cases, symptoms started in a few days after antibiotic administration. In all cases, we observed a worsening of the Myasthenia Gravis Foundation of America (MGFA) clinical classification. Most patients required a therapeutic intervention with dosage increase of the previous therapy or the introduction of new drugs for MG. All patients had a full recovery to baseline neurological conditions within 1-2 months.\n\n\nCONCLUSIONS\nWe concluded that patients receiving amoxicillin should be closely monitored for possible acute relapse.", "affiliations": "Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy. veriavacchiano@gmail.com.;Department of Thoracic Surgery, Maggiore Teaching Hospital, Bologna, Italy.;Neurology Unit, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.;Department of General and Thoracic Surgery, University Hospital of Chieti, Chieti, Italy.;Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.;Neurology Unit, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.", "authors": "Vacchiano|Veria|V|;Solli|Piergiorgio|P|;Bartolomei|Ilaria|I|;Lai|Giulia|G|;Liguori|Rocco|R|;Salvi|Fabrizio|F|", "chemical_list": "D000900:Anti-Bacterial Agents; D000658:Amoxicillin", "country": "Italy", "delete": false, "doi": "10.1007/s10072-020-04387-5", "fulltext": null, "fulltext_license": null, "issn_linking": "1590-1874", "issue": "41(8)", "journal": "Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology", "keywords": "Amoxicillin; Drugs; Myasthenia gravis; Penicillin", "medline_ta": "Neurol Sci", "mesh_terms": "D000658:Amoxicillin; D000900:Anti-Bacterial Agents; D002908:Chronic Disease; D006801:Humans; D009157:Myasthenia Gravis; D009364:Neoplasm Recurrence, Local", "nlm_unique_id": "100959175", "other_id": null, "pages": "2255-2257", "pmc": null, "pmid": "32296986", "pubdate": "2020-08", "publication_types": "D016428:Journal Article", "references": null, "title": "Exacerbation of myasthenia gravis after amoxicillin therapy: a case series.", "title_normalized": "exacerbation of myasthenia gravis after amoxicillin therapy a case series" }

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EXACERBATION OF MYASTHENIA GRAVIS AFTER AMOXICILLIN THERAPY: A CASE SERIES. 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EXACERBATION OF MYASTHENIA GRAVIS AFTER AMOXICILLIN THERAPY: A CASE SERIES. 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EXACERBATION OF MYASTHENIA GRAVIS AFTER AMOXICILLIN THERAPY: A CASE SERIES. 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EXACERBATION OF MYASTHENIA GRAVIS AFTER AMOXICILLIN THERAPY: A CASE SERIES. 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EXACERBATION OF MYASTHENIA GRAVIS AFTER AMOXICILLIN THERAPY: A CASE SERIES. 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EXACERBATION OF MYASTHENIA GRAVIS AFTER AMOXICILLIN THERAPY: A CASE SERIES. 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EXACERBATION OF MYASTHENIA GRAVIS AFTER AMOXICILLIN THERAPY: A CASE SERIES. 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EXACERBATION OF MYASTHENIA GRAVIS AFTER AMOXICILLIN THERAPY: A CASE SERIES. 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{ "abstract": "Drug-coated balloons are used widely as a form of endovascular treatment for peripheral arterial disease, to improve patency by reducing neointimal hyperplasia and restenosis. We present a rare case of acute coronary syndrome secondary to anaphylaxis after inflation of a paclitaxel-coated balloon used to treat a recurrent superficial femoral artery stenosis.", "affiliations": "Department of Surgery, Prince of Wales Hospital, Sydney, New South Wales, Australia. Electronic address: harry.narroway@health.nsw.gov.au.;Department of Surgery, Prince of Wales Hospital, Sydney, New South Wales, Australia.;Department of Surgery, Prince of Wales Hospital, Sydney, New South Wales, Australia.;Department of Surgery, Prince of Wales Hospital, Sydney, New South Wales, Australia; Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia; The Vascular Institute, Prince of Wales Hospital, Sydney, New South Wales, Australia.;Department of Surgery, Prince of Wales Hospital, Sydney, New South Wales, Australia; Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia; The Vascular Institute, Prince of Wales Hospital, Sydney, New South Wales, Australia.", "authors": "Narroway|Harry G|HG|;Katib|Nedal|N|;Gomes|Miguel L|ML|;Varcoe|Ramon L|RL|;Thomas|Shannon D|SD|", "chemical_list": "D002317:Cardiovascular Agents; D017239:Paclitaxel", "country": "Netherlands", "delete": false, "doi": "10.1016/j.avsg.2020.06.010", "fulltext": null, "fulltext_license": null, "issn_linking": "0890-5096", "issue": "69()", "journal": "Annals of vascular surgery", "keywords": null, "medline_ta": "Ann Vasc Surg", "mesh_terms": "D000368:Aged; D000707:Anaphylaxis; D000800:Angioplasty, Balloon; D002317:Cardiovascular Agents; D003251:Constriction, Pathologic; D004342:Drug Hypersensitivity; D005260:Female; D005263:Femoral Artery; D006801:Humans; D000074962:Kounis Syndrome; D017239:Paclitaxel; D058729:Peripheral Arterial Disease; D016896:Treatment Outcome; D062666:Vascular Access Devices", "nlm_unique_id": "8703941", "other_id": null, "pages": "450.e17-450.e22", "pmc": null, "pmid": "32561243", "pubdate": "2020-11", "publication_types": "D002363:Case Reports", "references": null, "title": "Kounis Syndrome after Angioplasty of the Superficial Femoral Artery with Paclitaxel-Coated Balloon.", "title_normalized": "kounis syndrome after angioplasty of the superficial femoral artery with paclitaxel coated balloon" }

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"drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCHLOROTHIAZIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "IRBESARTAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IRBESARTAN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETYLSALICYLIC ACID" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "076131", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 MG/M2 (COATED BALLOONS)", "drugenddate": null, "drugenddateformat": null, "drugindication": "PERIPHERAL ARTERY STENOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." } ], "patientagegroup": null, "patientonsetage": "79", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Kounis syndrome", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Bronchospasm", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Anaphylactic reaction", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "NARROWAY, H.. KOUNIS SYNDROME AFTER ANGIOPLASTY OF THE SUPERFICIAL FEMORAL ARTERY WITH PACLITAXEL?COATED BALLOON. ANNALS OF VASCULAR SURGERY. 2020?1.E1?1.E6", "literaturereference_normalized": "kounis syndrome after angioplasty of the superficial femoral artery with paclitaxel coated balloon", "qualification": "1", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20200902", "receivedate": "20200826", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18197243, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20201103" } ]

{ "abstract": "Penile squamous cell carcinoma (PeSCC) is a rare tumor and advanced PeSCC is associated with poor survival due to the aggressiveness of the disease and lack of effective systemic therapies. We describe for the first time a case with advanced chemoradiation refractory PeSCC who had documented response to active immunotherapy with the immune checkpoint inhibitor, anti-programmed death-1 monoclonal antibody Nivolumab. The patient suffered from a poor prognosis human papillomavirus-negative PeSCC, with a somatic inactivation mutation of cyclin-dependent kinase inhibitor 2A (CDKN2A) gene in tumor cells, and treatment with Nivolumab resulted in a partial response to therapy and significant tumor shrinkage. Histology transitions and alterations in tumor-infiltrating cytotoxic CD8 T-cell lymphocytes, programmed death ligand-1 expression on tumor cells and immune cells in tumor lesion biopsies pretreatment and posttreatment with Nivolumab were observed and described. In conclusion, in patients with metastatic PeSCC active immunotherapy combinations with an anti-programmed death-1/programmed death ligand-1 agent may be beneficial and further relative clinical studies are required.", "affiliations": "Department of Pharmacology, Unit of Clinical Pharmacology and Therapeutic Oncology, Medical School, National and Kapodistrian University of Athens.;Department of Pharmacology, Unit of Clinical Pharmacology and Therapeutic Oncology, Medical School, National and Kapodistrian University of Athens.;Urology, \"Henry Dunant\" Hospital Center.;Department of Radiation Therapy-Oncology, 401 General Military Hospital of Athens.;Department of Radiology, General Hospital of Athens \"Laikon\", Athens, Greece.;OncoDNA SA, Gosselies, Belgium.", "authors": "Trafalis|Dimitrios T|DT|;Alifieris|Constantinos E|CE|;Kalantzis|Anastasios|A|;Verigos|Kosmas E|KE|;Vergadis|Chrysovalantis|C|;Sauvage|Sébastien|S|", "chemical_list": "D000970:Antineoplastic Agents; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab", "country": "United States", "delete": false, "doi": "10.1097/CJI.0000000000000221", "fulltext": null, "fulltext_license": null, "issn_linking": "1524-9557", "issue": "41(6)", "journal": "Journal of immunotherapy (Hagerstown, Md. : 1997)", "keywords": null, "medline_ta": "J Immunother", "mesh_terms": "D000970:Antineoplastic Agents; D002294:Carcinoma, Squamous Cell; D059248:Chemoradiotherapy; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019008:Drug Resistance, Neoplasm; D017809:Fatal Outcome; D006801:Humans; D007167:Immunotherapy; D016246:Lymphocytes, Tumor-Infiltrating; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D000077594:Nivolumab; D010412:Penile Neoplasms; D061026:Programmed Cell Death 1 Receptor; D013602:T-Lymphocytes, Cytotoxic; D047368:Tumor Burden", "nlm_unique_id": "9706083", "other_id": null, "pages": "300-305", "pmc": null, "pmid": "29642086", "pubdate": "2018", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Evidence for Efficacy of Treatment With the Anti-PD-1 Mab Nivolumab in Radiation and Multichemorefractory Advanced Penile Squamous Cell Carcinoma.", "title_normalized": "evidence for efficacy of treatment with the anti pd 1 mab nivolumab in radiation and multichemorefractory advanced penile squamous cell carcinoma" }

[ { "companynumb": "GR-TEVA-2018-GR-946887", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "77269", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PENILE SQUAMOUS CELL CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINORELBINE\\VINORELBINE TARTRATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PENILE SQUAMOUS CELL CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINORELBINE" } ], "patientagegroup": null, "patientonsetage": "47", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Malignant neoplasm progression", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201604" } }, "primarysource": { "literaturereference": "TRAFALIS D. EVIDENCE FOR EFFICACY OF TREATMENT WITH THE ANTI?PD?1 MAB NIVOLUMAB IN RADIATION AND MULTICHEMOREFRACTORY ADVANCED PENILE SQUAMOUS CELL CARCINOMA.. J IMMUNOTHER. 2018?41:.", "literaturereference_normalized": "evidence for efficacy of treatment with the anti pd 1 mab nivolumab in radiation and multichemorefractory advanced penile squamous cell carcinoma", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20180823", "receivedate": "20180823", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15310888, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" } ]

{ "abstract": "To explore the activity of pazopanib (P) + sirolimus (S) in patients who progressed after previous clinical benefit on pazopanib.\n\n\n\nEight patients with progressing metastatic high grade soft tissue sarcoma (STS) whose disease advanced on P following a response duration of at least 4 months were offered re-challenge of P supplemented by off-label S and a single patient with progressing metastatic chondrosarcoma was offered the combination as compassionate treatment. Patients were treated in two centers: Hadassah Medical Center and Tel Aviv Medical Center. Patients received oral P 200-600 mg once a day supplemented by S 3-4 mg taken separately, 12 h after the P dose.\n\n\n\nPatients received treatment from December 2012 to February 2016. Four progressed on the combination and their treatment was terminated. Two patients were undergoing treatment when data was summarized. Best Response Evaluation Criteria in Solid Tumour (RECIST) responses were: one partial response (PR), four stable disease (SD), and four progressive disease (PD), corresponding to five PR and four PD on the Choi criteria. Median progression free survival was 5.5 months (range 4-17).\n\n\n\nOur series showed that the combination of P + S has activity in STS patients selected by previous response to P and in a patient with chondrosarcoma, suggesting this can serve as a mechanism to reverse resistance to P and extend the chemotherapy-free window.", "affiliations": "Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. danielakatz@hadassah.org.il.;Department of Radiology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.;Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.;Boston University School of Medicine, Boston, USA.;Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.;The Unit of Bone and Soft Tissue Oncology, Division of Oncology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.", "authors": "Katz|D|D|0000-0002-8776-7815;Azraq|Y|Y|;Eleyan|F|F|;Gill|S|S|;Peretz|T|T|;Merimsky|O|O|", "chemical_list": "D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib; D020123:Sirolimus", "country": "England", "delete": false, "doi": "10.1186/s12885-016-2618-1", "fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 261810.1186/s12885-016-2618-1Research ArticlePazolimus: pazopanib plus sirolimus following progression on pazopanib, a retrospective case series analysis http://orcid.org/0000-0002-8776-7815Katz D. +972-2-6778919danielakatz@hadassah.org.il 1Azraq Y. yusef@hadassah.org.il 2Eleyan F. faras@hadassah.org.il 1Gill S. sukhmani@bu.edu 3Peretz T. tamary@hadassah.org.il 1Merimsky O. oferm@tlvmc.gov.il 451 Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel 2 Department of Radiology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel 3 Boston University School of Medicine, Boston, USA 4 The Unit of Bone and Soft Tissue Oncology, Division of Oncology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel 5 Affiliated with Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel 8 8 2016 8 8 2016 2016 16 61629 4 2016 26 7 2016 © The Author(s). 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nTo explore the activity of pazopanib (P) + sirolimus (S) in patients who progressed after previous clinical benefit on pazopanib.\n\nMethods\nEight patients with progressing metastatic high grade soft tissue sarcoma (STS) whose disease advanced on P following a response duration of at least 4 months were offered re-challenge of P supplemented by off-label S and a single patient with progressing metastatic chondrosarcoma was offered the combination as compassionate treatment. Patients were treated in two centers: Hadassah Medical Center and Tel Aviv Medical Center. Patients received oral P 200–600 mg once a day supplemented by S 3–4 mg taken separately, 12 h after the P dose.\n\nResults\nPatients received treatment from December 2012 to February 2016. Four progressed on the combination and their treatment was terminated. Two patients were undergoing treatment when data was summarized. Best Response Evaluation Criteria in Solid Tumour (RECIST) responses were: one partial response (PR), four stable disease (SD), and four progressive disease (PD), corresponding to five PR and four PD on the Choi criteria. Median progression free survival was 5.5 months (range 4–17).\n\nConclusions\nOur series showed that the combination of P + S has activity in STS patients selected by previous response to P and in a patient with chondrosarcoma, suggesting this can serve as a mechanism to reverse resistance to P and extend the chemotherapy-free window.\n\nKeywords\nSarcomaSolitary fibrous tumorChondrosarcomaPazopanibSirolimusVEGFmTORTyrosine kinase inhibitorResistanceissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nSoft tissue sarcoma (STS) treatment arsenal included until 2012 only chemotherapies given as single agents or in combination [1]. Many of these chemotherapy protocols produce serious, intolerable toxicities such as pancytopenia, alopecia and nephrotoxicity. Pazopanib (P), a vascular endothelial growth factor (VEGF) receptor inhibitor was granted approval by the FDA and EMA for the treatment of STS patients in second line and beyond. According to the registration trial, the PALLETE trial, P increased mean progression free survival (PFS) by 3 months compared to placebo with a manageable toxicity profile comprised mainly of fatigue, diarrhea, hypertension and hair hypopigmentation that differs significantly from that of chemotherapy [2].\n\nOther classes of targeted drugs were evaluated in STS but none possessed convincing clinical benefit. One of these classes consists of mammalian target of rapamycin (mTOR) inhibitors, a class of drugs with anti-proliferative effects supporting their role as anti-cancer agents [3]. Sirolimus (S) was the first drug in the class to be evaluated as an anti-cancer agent and remains the most convenient because of its low price and favorable toxicity profile [4]. S has been tried in a sample of sarcoma patients alone and in combination with chemotherapeutic agents such as cyclophosphamide and gemcitabine with intriguing results [5–9].\n\nHowever, much of the recent research has been performed using newer patented agents within this family, such as ridaforolimus and everolimus. Ridaforolimus, a new mTOR inhibitor analogue, was the only compound to be evaluated as a maintenance agent in metastatic STS. The study demonstrated a PFS increase of 3.1 weeks [10]. Although this study exhibited tumor growth control, it lacked the clinical significance to allow approval for use by any drug legislation agency. Everolimus was studied in combination with sorafenib, a VEGF receptor inhibitor among others, in patients with unresectable osteosarcoma which showed a 45 % PFS but fell short of the target endpoint 50 % 6-month PFS and was therefore considered negative [11].\n\nAs responses to pazopanib are rarely durable and resistance develops in the absence of additional evidence based target therapies, chemotherapy is recommended. However, reversal of resistance may as well be sought, especially in those cases where pazopanib has been well tolerated offering advantageous quality of life over chemotherapy [12–14]. Emerging preclinical and clinical data for multikinase and mTOR inhibitors relies on the mechanistic hypothesis that the combination blocks angiogenesis at two different points in the signaling pathway and suggests that their concomitant administration after progression on pazopanib has the potential to offer further disease stabilization and prolong the chemotherapy-free window [15, 16].\n\nHere we report on a retrospective series of eight unresectable metastatic advanced STS patients and one chondrosarcoma patient treated with P + S.\n\nMethods\nPatients with progressing metastatic unresectable high grade STS, whose disease advanced on P following a response duration of at least 4 months were offered re-challenge of P supplemented by off-label S in two medical centers; Hadassah Medical Center and Tel Aviv Medical Center. A single patient with progressing unresectable metastatic chondrosarcoma resistant to chemotherapy was offered the combination as compassionate treatment. All patients were in good performance status with an ECOG 0–1. Patient data collection was initiated following local IRB approval.\n\nTreatment schedule and evaluation\nPatients received oral P 200–600 mg once a day supplemented by S 3–4 mg taken separately, 12 h after the P dose. In those cases in which serum S levels were measured 7–14d after treatment was started, S dose was adjusted for a serum level of 15–20 ng/ml. Drug dosage was reduced according to toxicity. Prior to the initiation of the combination therapy, chest, abdomen and pelvis contrast CT or PET-CT were done and repeated at 6–8 w intervals and after 6 months at 12 w intervals. Patients with response or stable disease (SD) continued treatment until disease progression (PD). Blood tests were repeated bi-weekly in the first month and monthly thereafter. Toxicity was recorded at each clinic visit and summarized in Table 1.Table 1 Patient characteristics and clinical and molecular findings\n\nPatient #\tPathology\tPrimary site/Recurrence\tDFI from surgery to relapse (mos)\tNumber of lines before P\tDuration of P treatment (mos)\tDuration of P + S treatment (mos)\tBest RECIST response\tBest Choi response\tP dose (mg)\tS dose (mg)\tProcedures while on P + S\tToxicity\tStatus\tGenomic profile by FoundationOne\t\n1\tSFT\tLung/Lung + heart\t10\t0\t4\t2\tPD\tPD\t400\t4\t\t\tAWD\t\t\n2\tSFT\tPleura/Duadenum + Spleen + liver\t13\t0\t8\t2\tPD\tPD\t600\t4\t\tLethargy\tDead\tNAB2-STAT6 fusion\t\n\t\t\t\t\t\t\t\t\t\t\t\t\t\tTP53 P278S\t\n\t\t\t\t\t\t\t\t\t\t\t\t\t\tAXIN1 A740T\t\n\t\t\t\t\t\t\t\t\t\t\t\t\t\tBRD4 truncation exon 8\t\n3\tUPS\tLimb/Lung\t24\t3\t22\t2\tPD\tPD\t800\t3\t\t\tDead\t\t\n4\tUPS\tGluteus/Lung + pleura\t41\t3\t6\t5\tPR\tPR\t200\t4\t\tGlucose intolerance-metformin\tDead\t\t\n5\tULMS\tUterus/Lung\t13\t2\t8\t16 on going\tSD\tPR\t400\t3\tMetastasectomy and SBRT\tSub-febrile fever, glu intolerance-metformin\tAWD\tALK IGFGP5-ALK fusion\t\n\t\t\t\t\t\t\t\t\t\t\t\t\t\tTSC2 splice site*\t\n\t\t\t\t\t\t\t\t\t\t\t\t\t\tCDKN2A loss\t\n\t\t\t\t\t\t\t\t\t\t\t\t\t\tTP53 L330P\t\n6\tLMS\tLimb/Lung\t14\t1\t28\t5\tSD\tPR\t400\t3\t\tBowel perforation\tAWD\t\t\n7\tDSRCT\tRetroperitoneum\t0\t3\t12\t11\tSD\tPR\t200\t3\t\tProteinuria\tDead\t\t\n8\tUUS\tUterus/Lung + retroperitoneum\t3\t1\t4\t1\tPD\tPD\t400\t4\t\t\tDead\t\t\n9\tChondrosarcoma grade II\tLimb/Lung\t47\t1\t0\t3 on going\tSD\tPR\t400\t4\t\t\tAWD\tCKS1B amplification\t\n\t\t\t\t\t\t\t\t\t\t\t\t\t\tMEF2C amplification\t\n*see Fig. 3\n\n\n\n\nOutcome evaluation\nResponse was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1) and Choi criteria. According to Choi criteria, response is based on both a minimum of a 10 % reduction in size and a 15 % reduction in density. Progression was defined as new lesions, an increase in ≥10 % in tumor size without meeting any criteria for a PR according to tumor density/contrast enhancement, or an increase ≥15 % in tumor density/contrast enhancement. PFS was calculated from the first date of treatment to the date of documented progression according to RECIST. Overall survival was computed from first date of treatment to the date of death or last date of follow up.\n\nResults\nBetween December 2012 to February 2016, nine patients received P + S in combination. Four patients progressed on the combination and their treatment was terminated. Two patients were undergoing treatment when we summarized the data.\n\nEight patients (five females); 2 solitary fibrous tumor (SFT), 2 undifferentiated pleomorphic sarcoma (UPS), 1 uterine leiomyosarcoma (ULMS), 1 leiomyosarcoma (LMS), 1 desmoplastic small round cell tumor (DSRCT), 1 undifferentiated uterine sarcoma (UUS) between the ages of 36–74 received P + S in combination, following escape from response to P of at least 4 months and one patient with grade II metastatic chondrosarcoma received the combination without initial P (Table 1). Patients ages ranged between 20 and 74 years old.\n\nFive patients (5/8) benefited from the combination. Best RECIST responses were one PR (patient #4 with UPS), four SD and four PD. Median PFS was 5.5 m (range 4–17). Two patients are still on treatment (patients 5 and 9). Four patients are alive. Patient #5 underwent two consecutive resections of three lung metastases (right middle lobe, subpleural and left lower lobe) after completing 6 m of P + S (P 200 mg + S 4 mg) with SD as best response according to RECIST and PR according to Choi (see Fig. 1). Prior to treatment initiation, she was rapidly progressing on P single agent. Baseline CT demonstrated a new right lung lesion compared with CT 6 weeks prior. On Pathology the RML lesion was completely fibrotic, the left sub-pleural lesion consisted of extensive necrosis with scarce residual sarcoma cells and the left lower lobe lesion was composed mainly of viable sarcoma tissue. The patient’s treatment was discontinued following the oligo-metastasectomy. Three months later, chest CT demonstrated a new RML lesion and treatment with P + S was resumed (P 200 mg + S 4 mg). Following 7.5 months of stable disease, stereotactic body radiotherapy (SBRT) was administrated to the single right middle lobe lesion while the patient’s treatment continued.Fig. 1 Response to P + S combination therapy. Computed tomography (CT) scan (arterial phase after contrast medium) of the chest. (a) Baseline (b) Six months after starting P + S combination therapy. Arrows indicate the response observed in the intrathoracic lesion, marked by decrease in tumor density\n\n\n\nThere was one serious adverse event of small bowel perforation after 5 months on treatment, which was surgically treated with complete recovery. On pathology, a necrotic metastasis was present on the wall of the small bowel at the site of perforation. Additionally, two patients developed hyperglycemia compliant to metformin, one patient complained of lethargy. Overall, treatment was very well tolerated without added side effects.\n\nDiscussion\nWe assessed the efficacy of the combination P + S in a series of eight patients with unresectable metastatic high grade STS and one patient with grade II chondrosarcoma. Currently, there are no evidence-based molecular predictive markers for response to tyrosine kinase inhibitors [17]. In order to optimize the chance of response, we enriched the treatment group with patients who had already shown benefit from P alone and escaped response, with the hope that this strategy would reverse resistance and delay the use of cytotoxic compounds. This study was not designed to delineate efficacy by STS subtype, but rather serve as a proof of concept that P + S is an effective way to combat resistance to P and prolong PFS. Out of the nine patients, four had S levels measured 7–14d after treatment was started and S dose was adjusted for a serum level of 15–20 ng/ml. However, since three patients responded despite not having their levels adjusted, we cannot determine that there is a correlation between blood level and response.\n\nAfter the addition of S, we noticed additional limited toxicity. Only one patient developed a serious adverse event (SAE) (small bowel perforation) necessitating hospitalization and surgery with complete recovery. Of mention, the toxicity observed in this patient was related to the efficacy of the combination on the tumor, which was located on the wall of the small bowel. Less serious side effects developed in three patients; two patients developed hyperglycemia controlled by metformin and one patient developed a drug fever, which resolved over time. Overall, most patients tolerated the addition of S well. With the exception of the SAE above, there were no additional hospital admissions due to side effects from therapy. In terms of activity, 56 % (5/9) of the patients had a PFS of at least 5 months from the initiation of combination therapy. Following progression on the combination therapy, all STS patients received an additional line of chemotherapy.\n\nWe proposed supplementing P with S for various reasons. S has a favorable toxicity profile, its levels can be monitored, and preclinical and clinical data suggests that the combination with a VEGF receptor tyrosine kinase inhibitor (TKI) may potentially reverse resistance [8, 11, 15, 16, 18]. Pazopanib is a multikinase inhibitor that blocks the VEGF and PDGF receptors. However, acquired resistance to P eventually develops [12, 13, 19]. There are several potential mechanisms for the development of resistance; the most relevant being a compensatory increase in VEGF levels. As P blocks the VEGF receptor, hypoxia develops secondary to the negative effects of the receptor blockade on angiogenesis, leading to regression of blood vessels and an increase in HIF-1a levels via the mTOR pathway [18]. HIF-1a upregulates production of target genes including VEGF in the tumor microenvironment (Fig. 2). mTOR inhibition offsets the production of VEGF through complementary inhibition of the PTEN-AKT-mTOR pathway [20].Fig. 2 Compensatory VEGF overexpression. Initiation of pazopanib leads to a decrease in angiogenesis and development of hypoxia. Hypoxia causes an increase in HIF-1a levels, leading to increased production of target genes including VEGF. mTOR inhibition may stop this compensatory increase\n\n\n\nAnother important adaptive mechanism of resistance to P is upregulation of fibroblast growth factor 2 (FGF2) [21]. FGF activates the FGF receptor inducing angiogenesis through the mTOR signaling pathway, along with several other pathways. Abrogating the mTOR pathway ameliorates angiogenesis induced by FGF2 [22]. On a different note, platelet derived growth factor receptor a (PDGFRa) was found to be activated by mTOR inhibition [22]. Therefore, combining S with an PDGFR inhibitor such as P may overcome potential resistance [23]. Furthermore, in the phase III SUCCEED trial designed to assess efficacy of single agent oral ridaforolimus on patients with STS, there was proof of tumor growth control, albeit clinically insignificant. The results of this trial support the use of combination therapy with other signaling inhibitors to overcome the activation of possible intracellular compensatory signaling pathways [10].\n\nThe rationale for adding mTOR inhibition to reverse resistance is not novel. The mTOR inhibitor everolimus was combined with an aromatase inhibitor exemestane in breast cancer patients who progressed while receiving an aromatase inhibitor. The results showed that adding everolimus increased PFS by 4.1 months [24]. In breast cancer, resistance to endocrine therapy is mediated through mTOR-induced phosphorylation of estrogen receptors and the addition of everolimus disrupts this phosphorylation and resulting resistance [25, 26]. An additional study evaluated the effect of the multikinase inhibitor, sorafenib, and the mTOR inhibitor, everolimus, in patients with metastatic osteosarcoma. The clinical benefit rate (CBR) at 6 months was 45 % with combination therapy, while another phase II study in a similar population showed a CBR of 29 % at 6 months for sorafenib alone [11, 15]. The study suggests that in osteosarcoma, resistance to sorafenib is mediated, at least partly, through the mTOR pathway. Sorafenib suppresses the mTORC1 pathway but simultaneously activates mTORC2 which promotes tumor progression. Adding the mTOR inhibitor everolimus overcomes this resistance. Regardless of the type of cancer, mTOR is a universal mediator of protein synthesis affecting angiogenesis and proliferation and mechanistically its inhibition may circumvent resistance [27].\n\nPatient #5 exhibited an “exceptional” response to P + S treatment. This patient underwent next generation sequencing (NGS) using the Foundation One test which showed a mutation in TSC2 splice site 2545. TSC2 is part of the TSC1-TSC2 complex, which inhibits mTORC1 through its Rheb-GAP activity. When the complex is active, the levels of Rheb-GTP decrease, inactivating mTORC1 and blocking its cell growth promotion (see Fig. 3). A mutation in TSC1 or TSC2 can lead to loss of function and constant activation of the mTORC complex [28]. This patient had a specific TSC2 mutation that had not been described in malignant tissue in COSMIC as of February 2016. However, it is known that TSC2 splice site alteration affects exon 22 and causes protein truncation [29]. This leads to inactivation of the GTPase domain of the TSC1-2 complex, leading to constant downstream activation of mTORC1 and cell growth.Fig. 3 TSC1-2 complex activation and effect on mTOR pathway. TSC1-2 forms a complex with the GTPase domain of Rheb, converting it to its inactive, Rheb-GDP form. A loss of function mutation in TSC1-2 leads to increased levels and unopposed action of Rheb-GTP on mTORC1, leading to constant cell growth. Additionally, loss of function of TSC1-2 hinders mTORC2 activation\n\n\n\nWe included one patient with a paratracheal unresectable grade II chondrosarcoma (#9) who had failed docetaxel in combination with gemcitabine. The P + S was offered as compassionate therapy given the lack of additional treatment options. The patient exhibited a rapid clinical response to the combination with resolution of chest pain, shortness of breath, and no re-accumulation of a pleural effusion that had previously been tapped. CT findings three months later confirmed the clinical improvement showing liquidification of the tumor with stabilization of disease (see Fig. 4). The patient’s P + S treatment is ongoing.Fig. 4 Response to P + S combination therapy in grade II paratracheal chondrosarcoma. Computed tomography (CT) scan. Three months after starting P + S combination therapy a response was observed in the form of tumor liquidification and stabilization of disease\n\n\n\nAs previously mentioned, this study was not intended to evaluate efficacy by sarcoma subtype. However, two patients with metastatic SFT progressed on the combination therapy. In a study that evaluated P efficacy in SFT, a lower level activity was reported for P compared to sumitinib and bevacizumab plus temozolomide. This lower level of response was supported by preclinical data. Therefore, it is possible that progression on the combination seen in our study suggests real resistance within this subtype [19].\n\nAs seen with P alone, disease stabilization as defined by RECIST is the most frequent response in this series. However, Choi criteria assesses a change in density as well as size of the target lesions and therefore appears to be a better predictor of clinical response [30]. In our sample, all of the patients with SD by RECIST were confirmed to exhibit PR according to Choi.\n\nOur clinical data, even if retrospective and on a small heterogenic group of patients, confirms that P + S was active in more than half of the patients. However, a potential limitation of this study is that response to single agent S following resistance to P was not tested. It is possible the patients in this study who benefited from P + S could have also benefited from S alone. However, combination P + S did not add significant additional toxicity, with its only downside being the additional cost. A future randomized control trial comparing P + S to S alone following resistance to P may further elucidate whether combination therapy is necessary. Because the arsenal of treatments in sarcoma is limited, any benefit observed by this combination therapy should be further investigated.\n\nConclusion\nOur series showed that the combination of P + S has activity in STS and chondrosarcoma patients selected by previous response to P. The goal of therapy for patients with metastatic sarcoma is to prolong life and palliate symptoms. Thus the favored approach remains to use less toxic drugs. P is currently the only approved targeted small molecule in second-line and beyond treatment in STS with a favorable toxicity profile which differs greatly from that of chemotherapy. Resistance to P eventually develops and the addition of S serves to prolong the chemotherapy-free window. This retrospective series proposes to enhance the therapeutic landscape of STS patients. We suggest that the current results serve as proof of concept for the use of combination P + S after escape from P and should be explored prospectively in a large randomized control trial to evaluate the efficacy of combination therapy in different sarcoma subtypes.\n\nAbbreviations\nCBR, clinical benefit rate; DSRCT, desmoplastic small round cell tumor; FGF2, fibroblast growth factor 2; LMS, Leiomyosarcoma; mTOR, mammalian target of rapamycin; NGS, next generation sequencing; P, pazolimus; PD, progressive disease; PDGFRa, platelet derived growth factor receptor a; PFS, progression free survival; PR, partial response; RECIST, best response evaluation criteria in solid tumour; S, sirolimus; SAE, serious adverse event; SBRT, stereotactic body radiotherapy; SD, stable disease; SFT, solitary fibrous tumor; STS, soft tissue sarcoma; TKI, tyrosine kinase inhibitor; ULM, uterine leiomyosarcoma; UPS, undifferentiated pleomorphic sarcoma; UUS, undifferentiated uterine sarcoma; VEGF, vascular endothelial growth factor\n\nAcknowledgements\nAll those contributing towards the article meet criteria for authorship.\n\nFunding\nThere were no sources of support in the form of grants, equipment, or drugs.\n\nAvailability of data and materials\nAll data generated and analyzed during this study are included in this published article.\n\nAuthors’ contribution\nAcquisition of data was performed by authors DK, YA, FA, OM. All authors made a substantial contribution to the conception, design, analysis and interpretation of data; All authors were involved in drafting and revising the manuscript; All authors take public responsibility for appropriate portions of the content and agreed to be accountable for all aspects of the work. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nAll patients included in the article gave their consent for information about their case to be published.\n\nEthics approval and consent to participate\nThe Hadassah Medical Organization (HMO) ethics committee granted an exempt from requiring ethics approval to this study (0116-116 HMO).\n\nAdditional data and material\nAll data supporting the findings and conclusions of this manuscript are presented within the manuscript.\n==== Refs\nReferences\n1. 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Merimsky O Gorzalczany Y Sagi-Eisenberg R Molecular impacts of rapamycin-based drug combinations: combining rapamycin with gemcitabine or imatinib mesylate (Gleevec) in a human leiomyosarcoma model Int J Oncol 2007 31 225 232 17549426 \n6. Merimsky O Targeting metastatic leiomyosarcoma by rapamycin plus gemcitabine: an intriguing clinical observation Int J Mol Med 2004 14 931 935 15492868 \n7. Bernstein-Molho R Kollender Y Issakov J Bickels J Dadia S Flusser G Clinical activity of mTOR inhibition in combination with cyclophosphamide in the treatment of recurrent unresectable chondrosarcomas Cancer Chemother Pharmacol 2012 70 855 860 10.1007/s00280-012-1968-x 23053256 \n8. Stacchiotti S Marrari A Tamborini E Palassini E Virdis E Messina A Response to imatinib plus sirolimus in advanced chordoma Ann Oncol 2009 20 1886 1894 10.1093/annonc/mdp210 19570961 \n9. 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Benjamin RS Choi H Macapinlac HA Burgess MA Patel SR Chen LL We should desist using RECIST, at least in GIST J Clin Oncol 2007 25 1760 1764 10.1200/JCO.2006.07.3411 17470866\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2407", "issue": "16()", "journal": "BMC cancer", "keywords": "Chondrosarcoma; Pazopanib; Resistance; Sarcoma; Sirolimus; Solitary fibrous tumor; Tyrosine kinase inhibitor; VEGF; mTOR", "medline_ta": "BMC Cancer", "mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002813:Chondrosarcoma; D018450:Disease Progression; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007191:Indazoles; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011743:Pyrimidines; D012189:Retrospective Studies; D012509:Sarcoma; D020123:Sirolimus; D013449:Sulfonamides; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult", "nlm_unique_id": "100967800", "other_id": null, "pages": "616", "pmc": null, "pmid": "27501793", "pubdate": "2016-08-08", "publication_types": "D016428:Journal Article", "references": "21527590;19112174;22149876;15492868;22595799;23715582;17264755;18411301;15340059;19570961;26635184;18650835;25902899;24982384;25498219;19925796;24491407;25664166;17549426;15578919;25089183;17766661;18827568;18987047;16033851;17470866;23053256;12039858;27267837;25269954", "title": "Pazolimus: pazopanib plus sirolimus following progression on pazopanib, a retrospective case series analysis.", "title_normalized": "pazolimus pazopanib plus sirolimus following progression on pazopanib a retrospective case series analysis" }

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{ "abstract": "OBJECTIVE\nTopiramate (TPM) is a sulfa-derivative monosaccharide that is used mainly for treating epilepsy and preventing migraine. Within the gamut of side effects attributable to this drug, ophthalmologic manifestations are of crucial importance. In this study, for the first time, the aim was to provide a systematic literature review regarding this issue.\n\n\nMETHODS\nFor the time period 1996-2011, a PubMed search was made for the studies concerning the adverse/beneficial effects of TPM on vision. Overall, 404 citations out of a total of 2756 TPM-related studies were examined for relevance.\n\n\nRESULTS\nA total of 74 relevant studies were reviewed, 65 of which comprise small observational studies describing the ophthalmic side effects of TPM in 84 patients. Of these patients, 66 were affected by ciliochoroidal effusion syndrome as the cardinal ocular side effect of TPM (17 cases of myopic shift and 49 cases of angle closure glaucoma). A comprehensive statistical analysis is provided on these 66 subjects. Other rare side effects of TPM on the vision were also reviewed, including massive choroidal effusion, ocular inflammatory reactions, visual field defects, probable effects on retina, cornea, and sclera, and neuroophthalmologic complications. In addition, a framework is provided to classify these results.\n\n\nCONCLUSIONS\nDue to the expanding spectrum of indications for the administration of TPM, neurologists and psychiatrists should be aware of its diverse ocular side effects. In conclusion, ocular complications following this drug should be taken seriously and be subjected to ophthalmic counseling.", "affiliations": "Medical School, Isfahan University of Medical Sciences, Isfahan, Iran.", "authors": "Abtahi|Mohammad-Ali|MA|;Abtahi|Seyed-Hossein|SH|;Fazel|Farhad|F|;Roomizadeh|Peyman|P|;Etemadifar|Masoud|M|;Jenab|Keivan|K|;Akbari|Mojtaba|M|", "chemical_list": null, "country": "New Zealand", "delete": false, "doi": "10.2147/OPTH.S27695", "fulltext": null, "fulltext_license": null, "issn_linking": "1177-5467", "issue": "6()", "journal": "Clinical ophthalmology (Auckland, N.Z.)", "keywords": "eye; ophthalmology; review; side effect; topiramate; vision", "medline_ta": "Clin Ophthalmol", "mesh_terms": null, "nlm_unique_id": "101321512", "other_id": null, "pages": "117-31", "pmc": null, "pmid": "22275816", "pubdate": "2012", "publication_types": "D016428:Journal Article", "references": "21800704;16188011;12823570;21414526;18245982;12005284;18182113;18451209;21941501;12850232;21058272;11438067;14700673;19439868;20005660;11476137;19173373;17668412;17583873;12390655;16643588;21034312;11483094;19347133;18443614;9578038;17505734;12690373;18462502;20050121;9264038;16092949;21278619;12942938;16804780;18632523;12714417;16921218;16767213;16765687;20952855;17111186;20571045;19407835;17568334;19365189;18382180;20606870;20434235;12583802;21269432;19412496;17912565;16528143;18071999;14711721;17922725;17641720;18201514;16534176;19491971;19171058;14998699;20482511;19133528;19008799;19001233;19829963;21103879;19150415;20413935;16797716;11346412;21772653;12650986;17927286;12187555;16021148;11709030;21279186;12149075;18604026;19788679;16705522;20842587;19109208;19478906;18688152;18537527;18091300;16236051;12470170;21174597;14610152;19514879;11591899;15805668;18091456;17880860", "title": "Topiramate and the vision: a systematic review.", "title_normalized": "topiramate and the vision a systematic review" }

[ { "companynumb": "FR-UNICHEM PHARMACEUTICALS (USA) INC-UCM201804-000093", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PROPRANOLOL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPRANOLOL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "INDORAMIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MIGRAINE PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INDORAMIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "090162", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." } ], "patientagegroup": null, "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Ciliary body disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Choroidal detachment", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Angle closure glaucoma", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ABTAHI M,ABTAHI S,FAZEL F,ROOMIZADEH P,ETEMADIFAR M,JENAB K. TOPIRAMATE AND THE VISION: A SYSTEMATIC REVIEW. CLINICAL OPHTHALMOLOGY 2012 JAN?.", "literaturereference_normalized": "topiramate and the vision a systematic review", "qualification": "3", "reportercountry": "IR" }, "primarysourcecountry": "FR", "receiptdate": "20180410", "receivedate": "20180410", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14738992, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180711" }, { "companynumb": "IR-UNICHEM PHARMACEUTICALS (USA) INC-UCM201803-000080", "fulfillexpeditecriteria": "1", "occurcountry": "IR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "090162", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MIGRAINE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." } ], "patientagegroup": null, "patientonsetage": "40", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypopyon", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Iris adhesions", "reactionmeddraversionpt": "21.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Angle closure glaucoma", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Iridocyclitis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ABTAHI M,ABTAHI S,FAZEL F,ROOMIZADEH P,ETEMADIFAR M,JENAB K. TOPIRAMATE AND THE VISION: A SYSTEMATIC REVIEW. CLINICAL OPHTHALMOLOGY 2012 JAN 11?.", "literaturereference_normalized": "topiramate and the vision a systematic review", "qualification": "3", "reportercountry": "IR" }, "primarysourcecountry": "IR", "receiptdate": "20180328", "receivedate": "20180328", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14687435, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" }, { "companynumb": "IR-CIPLA LTD.-2016CH18682", "fulfillexpeditecriteria": "1", "occurcountry": "CH", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "79162", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "BIPOLAR DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Blood brain barrier defect", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Vitritis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Myopia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Conjunctivitis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Iris atrophy", "reactionmeddraversionpt": "19.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Angle closure glaucoma", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2004" } }, "primarysource": { "literaturereference": "ABTAHI MA, ABTAHI SH, FAZEL F, ROOMIZADEH P, ETEMADIFAR M, JENAB K, ET.AL,. TOPIRAMATE AND THE VISION: A SYSTEMATIC REVIEW. CLINICAL OPHTHALMOLOGY. 2012;6:117 TO 131", "literaturereference_normalized": "topiramate and the vision a systematic review", "qualification": "3", "reportercountry": "CH" }, "primarysourcecountry": "CH", "receiptdate": "20161018", "receivedate": "20160926", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12778591, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" } ]

{ "abstract": "BACKGROUND\nPseudomyxoma peritonei is a disease caused by the widespread distribution of mucinous tumor into the peritoneal space from a perforated appendiceal neoplasm.\n\n\nMETHODS\nAll patients in this study had cytoreductive surgery with total gastrectomy plus perioperative intraperitoneal chemotherapy. A high diverting jejunostomy was used on all patients. Patient characteristics, adverse events, and survival were accumulated prospectively.\n\n\nRESULTS\nFifty-eight patients were available for long-term follow-up. In the univariate analysis, features associated with a less favorable outcome included female gender (p = 0.0127), intestinal obstruction before treatment (p = 0.00791), and prior surgical score (PSS) (p = 0.0054). In the multivariate analysis, the two significant variables were grade (p = 0.0458) and PSS (p = 0.0041). Median survival was 12 years with a 5-, 10-, and 20-year survival of 76%, 58%, and 37%, respectively. There were two postoperative deaths (3.4%) and Grades 3 and 4 adverse events in 20 (34.5%) patients.\n\n\nCONCLUSIONS\nA 10-year survival after cytoreductive surgery, total gastrectomy with temporary high diverting jejunostomy, and perioperative chemotherapy occurred in 58% of these patients with advanced pseudomyxoma peritonei. High-grade disease and extensive prior surgery with a high PSS were associated with reduced benefit.", "affiliations": "Center for Gastrointestinal Malignancies, MedStar Washington Hospital Center, Washington, District Columbia, USA.;Westat, Rockville, Maryland, USA.", "authors": "Sugarbaker|Paul H|PH|http://orcid.org/0000-0002-2431-7366;Chang|David|D|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1002/jso.26506", "fulltext": null, "fulltext_license": null, "issn_linking": "0022-4790", "issue": "124(3)", "journal": "Journal of surgical oncology", "keywords": "EPIC; HIPEC; doxorubicin; mitomycin C; peritonectomy; visceral resections", "medline_ta": "J Surg Oncol", "mesh_terms": "D002288:Adenocarcinoma, Mucinous; D000328:Adult; D000368:Aged; D001063:Appendiceal Neoplasms; D065426:Cytoreduction Surgical Procedures; D005260:Female; D005743:Gastrectomy; D006801:Humans; D007582:Jejunostomy; D008297:Male; D008875:Middle Aged; D019990:Perioperative Care; D011553:Pseudomyxoma Peritonei; D012189:Retrospective Studies; D015996:Survival Rate", "nlm_unique_id": "0222643", "other_id": null, "pages": "378-389", "pmc": null, "pmid": "33914912", "pubdate": "2021-09", "publication_types": "D016428:Journal Article", "references": null, "title": "Treatment of advanced pseudomyxoma peritonei using cytoreductive surgery including total gastrectomy and perioperative chemotherapy.", "title_normalized": "treatment of advanced pseudomyxoma peritonei using cytoreductive surgery including total gastrectomy and perioperative chemotherapy" }

[ { "companynumb": "US-MYLANLABS-2021M1073824", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "200170", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "15 MILLIGRAM/SQ. METER", "drugenddate": null, "drugenddateformat": null, "drugindication": "Adenocarcinoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MILLIGRAM/SQ. METER", "drugenddate": null, "drugenddateformat": null, "drugindication": "Adenocarcinoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXTROSE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Solution", "drugdosagetext": "DOSE: 1.5 L/M2", "drugenddate": null, "drugenddateformat": null, "drugindication": "Adenocarcinoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXTROSE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MITOMYCIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "15 MILLIGRAM/SQ. METER", "drugenddate": null, "drugenddateformat": null, "drugindication": "Adenocarcinoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MITOMYCIN" } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pancreatitis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Sugarbaker PH, Chang D. Treatment of advanced pseudomyxoma peritonei using cytoreductive surgery including total gastrectomy and perioperative chemotherapy. J-Surg-Oncol 2021;124(3):378-389.", "literaturereference_normalized": "treatment of advanced pseudomyxoma peritonei using cytoreductive surgery including total gastrectomy and perioperative chemotherapy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211019", "receivedate": "20211019", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19968737, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220303" }, { "companynumb": "US-AMGEN-USASP2021124254", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MILLIGRAM/SQ. 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TREATMENT OF ADVANCED PSEUDOMYXOMA PERITONEI USING CYTOREDUCTIVE SURGERY INCLUDING TOTAL GASTRECTOMY AND PERIOPERATIVE CHEMOTHERAPY. JOURNAL OF SURGICAL ONCOLOGY. 2021?124:378?389", "literaturereference_normalized": "treatment of advanced pseudomyxoma peritonei using cytoreductive surgery including total gastrectomy and perioperative chemotherapy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210818", "receivedate": "20210818", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19718537, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "US-FRESENIUS KABI-FK202111321", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "063277", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Unknown", "drugdosagetext": "15 MG/M2 IN (1.5 PERCENT) GLUCOSE, HIPEC", "drugenddate": null, "drugenddateformat": null, "drugindication": "Pseudomyxoma peritonei", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "040278", "drugbatchnumb": "UNKNOWN,UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Unknown", "drugdosagetext": "(5-FLUOROURACIL)?400 MG/M2, EPIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "Pseudomyxoma peritonei", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MITOMYCIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN,UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Unknown", "drugdosagetext": "15 MG/M2, HIPEC", "drugenddate": null, "drugenddateformat": null, "drugindication": "Pseudomyxoma peritonei", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MITOMYCIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXTROSE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN,UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Unknown", "drugdosagetext": "1.5 L/M2 PERITONEAL DIALYSIS SOLUTION", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXTROSE" } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pancreatitis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Sugarbaker P, Chang D. Treatment of advanced pseudomyxoma peritonei using cytoreductive surgery including total gastrectomy and perioperative chemotherapy.. 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Treatment of advanced pseudomyxoma peritonei using cytoreductive surgery including total gastrectomy and perioperative chemotherapy. J Surg Oncol. 2021;124:378-389", "literaturereference_normalized": "treatment of advanced pseudomyxoma peritonei using cytoreductive surgery including total gastrectomy and perioperative chemotherapy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211103", "receivedate": "20211103", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20027876, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" }, { "companynumb": "US-MYLANLABS-2021M1073822", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "200170", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "15 MILLIGRAM/SQ. 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J-Surg-Oncol 2021;124(3):378-389.", "literaturereference_normalized": "treatment of advanced pseudomyxoma peritonei using cytoreductive surgery including total gastrectomy and perioperative chemotherapy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211019", "receivedate": "20211019", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19968736, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" }, { "companynumb": "US-DRREDDYS-LIT/USA/21/0142716", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXORUBICIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "208657", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Cytoreductive surgery", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN HYDROCHLORIDE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MITOMYCIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Cytoreductive surgery", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MITOMYCIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXTROSE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.5 L/M2", "drugenddate": null, "drugenddateformat": null, "drugindication": "Cytoreductive surgery", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXTROSE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Cytoreductive surgery", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL" } ], "patientagegroup": "5", "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pancreatitis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Sugarbaker P, Chang D. Treatment of advanced pseudomyxoma peritonei using cytoreductive surgery including total gastrectomy and perioperative chemotherapy. 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Treatment of advanced pseudomyxoma peritonei using cytoreductive surgery including total gastrectomy and perioperative chemotherapy.. Journal of Surgical Oncology. 2021 SEP;124(3):378-389.", "literaturereference_normalized": "treatment of advanced pseudomyxoma peritonei using cytoreductive surgery including total gastrectomy and perioperative chemotherapy", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211020", "receivedate": "20211020", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19974345, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20220304" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-316321", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "91418", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "15 MG/M.SQ", "drugenddate": null, "drugenddateformat": null, "drugindication": "Chemotherapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MITOMYCIN" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "15 MG/M.SQ", "drugenddate": null, "drugenddateformat": null, "drugindication": "Chemotherapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MITOMYCIN C" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Chemotherapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL" } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pancreatitis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Failure to anastomose", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Hepatorenal syndrome", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "Sugarbaker PH, Chang D. Treatment of advanced pseudomyxoma peritonei using cytoreductive surgery including total gastrectomy and perioperative chemotherapy. J Surg Oncol. 2021;124(3):378-389", "literaturereference_normalized": "treatment of advanced pseudomyxoma peritonei using cytoreductive surgery including total gastrectomy and perioperative chemotherapy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211103", "receivedate": "20211103", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20028095, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220303" }, { "companynumb": "US-PFIZER INC-2021550642", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXORUBICIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "050467", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "15 MG/M2, IN 1.5% DEXTROSE PERITONEAL DIALYSIS SOLUTION AT A VOLUME OF 1.5 L/M2", "drugenddate": null, "drugenddateformat": null, "drugindication": "PSEUDOMYXOMA PERITONEI", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN HCL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MITOMYCIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "15 MG/M2 IN 1.5% DEXTROSE PERITONEAL DIALYSIS SOLUTION AT A VOLUME OF 1.5 L/M2.", "drugenddate": null, "drugenddateformat": null, "drugindication": "PSEUDOMYXOMA PERITONEI", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MITOMYCIN C" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUOROURACIL SODIUM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG/M2", "drugenddate": null, "drugenddateformat": null, "drugindication": "PSEUDOMYXOMA PERITONEI", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "5?FLUOROURACIL [FLUOROURACIL SODIUM]" } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pancreatitis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SUGARBAKER, P.. TREATMENT OF ADVANCED PSEUDOMYXOMA PERITONEI USING CYTOREDUCTIVE SURGERY INCLUDING TOTAL GASTRECTOMY AND PERIOPERATIVE CHEMOTHERAPY. JOURNAL OF SURGICAL ONCOLOGY. 2021?124 (3):378?389", "literaturereference_normalized": "treatment of advanced pseudomyxoma peritonei using cytoreductive surgery including total gastrectomy and perioperative chemotherapy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210823", "receivedate": "20210519", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19274425, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "US-PFIZER INC-2021539989", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXORUBICIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "050467", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "15 MG/M2, IN 1.5% DEXTROSE PERITONEAL DIALYSIS SOLUTION AT A VOLUME OF 1.5 L/M2", "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN HCL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUOROURACIL SODIUM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MG/M2", "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "5?FLUOROURACIL [FLUOROURACIL SODIUM]" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MITOMYCIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "15 MG/M2 IN 1.5% DEXTROSE PERITONEAL DIALYSIS SOLUTION AT A VOLUME OF 1.5 L/M2", "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MITOMYCIN C" } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pancreatitis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SUGARBAKER, P.. TREATMENT OF ADVANCED PSEUDOMYXOMA PERITONEI USING CYTOREDUCTIVE SURGERY INCLUDING TOTAL GASTRECTOMY AND PERIOPERATIVE CHEMOTHERAPY. JOURNAL OF SURGICAL ONCOLOGY. 2021?124 (3):378?389", "literaturereference_normalized": "treatment of advanced pseudomyxoma peritonei using cytoreductive surgery including total gastrectomy and perioperative chemotherapy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210823", "receivedate": "20210519", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19274423, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" } ]

{ "abstract": "Background: Abiraterone acetate was approved by FDA and EMA in April and September 2011, respectively for treatment of patients with casteration resistant prostate cancer and those previously treated with docetaxel. It is a selective inhibitor of androgen biosynthesis which potentially and irreversibly blocks CYP17, a crucial enzyme in oestrogen and testosterone synthesis. Materials and Methods: This retrospective study was conducted to evaluate the safety and efficacy of abiraterone acetate in the treatment of castration resistant prostate cancer patients. Twenty-two male patients diagnosed with CRPC and experienced treatment failure with one or more lines of treatment (hormonal manipulation or chemotherapy) were selected and administered abiraterone acetate (1,000 mg daily) along with prednisone (5 mg twice daily). Results: Out of 22 patients, 32% had a good response in reduction of PSA values, while 22% had progression in disease and 45% had a stable disease. Potassium, Haemoglobin, and serum sreatinine levels were not affected by the drug. Due to severe GI intolerance, the drug had to be stopped for one patient. The results of this study showed that abiraterone acetate significantly lowered the PSA values and prolonged progression- free survival in metastatic castration resistant prostate cancer patients who had progressed after first-line or second-line treatment. The overall average median survival and the median duration of drug exposure for CRPC who received AA was found to be 11.1 months [range 3-18]. Since AA plus prednisolone are available as oral dosage forms, they can be given in outpatient setting. Conclusion: Abiraterone acetate is a drug of choice for CRPC and also for those who had previously received one or two chemotherapy regimens. Since it is a new therapeutic regimen, this study included small sample size, but there are a few studies indicating the therapeutic efficacy of AA among patients with castration-resistant prostate cancer.", "affiliations": "Department of Pharmacy Practice, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, Kochi, India.;Department of Pharmacy Practice, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, Kochi, India.;Department of Pharmacy Practice, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, Kochi, India.;Department of Medical Oncology and Hematology, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, India.", "authors": "James|Aloysius|A|;Vincent|Bini|B|;Sivadas|Akhila|A|;Pavithran|K|K|", "chemical_list": null, "country": "Iran", "delete": false, "doi": null, "fulltext": "\n==== Front\nInt J Hematol Oncol Stem Cell ResInt J Hematol Oncol Stem Cell ResIJHOSCRInternational Journal of Hematology-Oncology and Stem Cell Research2008-30092008-2207Tehran University of Medical Sciences, Hematology-Oncology and Stem Cell Transplantation Research Center Tehran, Iran IJHOSCR-12-4Original ArticleA Study on the Clinical Outcome of Abiraterone Acetate in Castration Resistant Prostate Cancer Patients James Aloysius 1Vincent Bini 1Sivadas Akhila 1Pavithran K. 2\n1 Department of Pharmacy Practice, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, Kochi, India\n2 Department of Medical Oncology and Hematology, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, IndiaCorresponding Author: K. Pavithran, Department of Medical Oncology and Hematology, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, India. Tel: +91 7012874725E-mail: pavithrank@aims.amrita.edu1 1 2018 12 1 4 7 13 6 2017 19 8 2017 \nCopyright : © International Journal of Hematology-Oncology and Stem Cell Research & Tehran University of Medical Sciences\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution License, (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground: Abiraterone acetate was approved by FDA and EMA in April and September 2011, respectively for treatment of patients with casteration resistant prostate cancer and those previously treated with docetaxel. It is a selective inhibitor of androgen biosynthesis which potentially and irreversibly blocks CYP17, a crucial enzyme in oestrogen and testosterone synthesis. \n\n\nMaterials and Methods: This retrospective study was conducted to evaluate the safety and efficacy of abiraterone acetate in the treatment of castration resistant prostate cancer patients. Twenty-two male patients diagnosed with CRPC and experienced treatment failure with one or more lines of treatment (hormonal manipulation or chemotherapy) were selected and administered abiraterone acetate (1,000 mg daily) along with prednisone (5 mg twice daily).\n\n\nResults: Out of 22 patients, 32% had a good response in reduction of PSA values, while 22% had progression in disease and 45% had a stable disease. Potassium, Haemoglobin, and serum sreatinine levels were not affected by the drug. Due to severe GI intolerance, the drug had to be stopped for one patient. The results of this study showed that abiraterone acetate significantly lowered the PSA values and prolonged progression- free survival in metastatic castration resistant prostate cancer patients who had progressed after first-line or second-line treatment. The overall average median survival and the median duration of drug exposure for CRPC who received AA was found to be 11.1 months [range 3−18]. Since AA plus prednisolone are available as oral dosage forms, they can be given in outpatient setting. \n\n\nConclusion: Abiraterone acetate is a drug of choice for CRPC and also for those who had previously received one or two chemotherapy regimens. Since it is a new therapeutic regimen, this study included small sample size, but there are a few studies indicating the therapeutic efficacy of AA among patients with castration-resistant prostate cancer.\n\nKey Words\nProstate-specific antigen (PSA)Abiraterone acetate (AA)Castration resistant prostate cancer (CRPCS)\n==== Body\nIntroduction\n Prostate cancer is mostly found in male population in western countries, second to skin cancer1. The main treatment option is hormonal therapy which allows long lasting and effective control of advanced stage cancer symptoms. Hormonal therapy provides long lasting and effective control of cancer-related symptoms; however, in most patients with metastatic prostate cancer the disease will progress when it becomes resistant to androgen synthesis. The introduction of docetaxel for the treatment of CRPC turns a turning point resulting in increased response rate and biochemical control by decreasing the PSA (Prostate Specific Antigen) levels. Although the combination of docetaxel and prednisolone increases the survival time by decreasing the PSA value, there are only few other alternatives when progression occurs after the treatment with docetaxel2. Abiraterone acetate (AA), a selective inhibitor of androgen biosynthesis, is a prodrug of abiraterone that potently and irreversibly blocks CYP450C17. It is a crucial enzyme in testosterone and oestrogen synthesis, resulting in virtually undetectable serum and intratumoral androgens3. It works well along with prednisolone for metastatic castration resistant prostate cancer (mCRPC). AA plus prednisolone prolong overall survival rate in patients compared to other regimens4. The efficacy of treatment is measured using prostate specific antigen (PSA), a reliable sensitive and easy to measure biomarker. The most common adverse effects were associated with increased concentrations of mineralocorticoids resulting in hypokalemia, fluid retention, and hypertension5. Concomitant administration with corticosteroids reduces the incidence and severity of these reactions. This study attempted to evaluate the clinical outcome of abiraterone acetate in CRPC patients by measuring their PSA value and analyze the ADR profile of abiraterone acetate in lab parameters (Serum Creatinine, Potassium, CBC) in patients.\n\nMATERIALS AND METHODS\n\nData collection\n\n\nThis retrospective study was conducted in Medical Oncology Department in a Tertiary-care hospital. Data were reviewed from the electronic medical records and clinical details of those patients treated with AA between 2013 and 2015 were collected. Since it was a retrospective study, written informed consent was waived. \n\n\nPatients and treatment\n\n\nMale patients with mCRPC who had disease progression after two or more regimens met the study inclusion criteria. Before administering AA, the patient was assessed for potassium level(less than 3.5mmol/L). AA was given as 4 tablets of 250mg per day one hour before or two hours after meal along with oral prednisolone 5mg twice a day. During the data collection period, 22 patients were treated with abiraterone acetate.\n\n\nOutcome measures\n\n\nThe clinical and biological follow-up were scheduled every 15 days within the first three months of treatment and monthly afterwards until treatment discontinuation. All pertinent data including patients’ characteristics, disease progression at diagnosis, Gleason score, tumour classification, and sites of metastases were collected from medical records before chemotherapy and AA administration.\n\nResults\nTable 1 Baseline characteristics\n\n\nCharacteristics\n\t\nNumber\n\t\nMedian(range)\n\t\nAge\t60-88\t70\t\nInitial Gleason Score\t\n5\t2\t 9%\t\n7\t6\t 27%\t\n8\t10\t 45%\t\n9\t4\t 18%\t\nSites Of Metastasis before CT\t\nBone only\t17\t77%\t\nMultiple\t2\t 10%\t\nNo Mets\t3\t 14%\t\nPSA before CT\t0 - 3208\t30.5\t\nPSA after progression from Chemotherapy \t0.52 - 612\t19.3\t\nPSA before AA\t0.02 - 413\t23.75\t\nPSA after progression from AA\t10.781 - 864\t40\t\nLines of CT before AA\t1\t1\t\n2\t10\t\n3\t6\t\n4\t4\t\nAdverse Drug Reactions\t\nSerum Creatinine\t Before\t0.58 - 3.55\t1.3\t\nAfter\t0.56 - 6.77\t1.12\t\nPotassium\t Before\t3.4 - 5.1\t4.1\t\nAfter\t3.5 - 5.9\t4\t\nHaemoglobin\t Before\t2.35 - 11.3\t11.5\t\nAfter\t2.34 - 12.9\t10.5\t\nTable 2 Treatment duration of Abiraterone Acetate\n\n\nMonths\n\t\nNo.\n\t\nPercentage (%)\n\t\n≤3months\t5\t23\t\n3-6 months\t10\t45\t\n>6months\t7\t32\t\nFor the effective analysis, survival time was calculated in two different manners: from the beginning of chemotherapy, defined as the time interval, between the start of first-line chemotherapy and before starting AA. Meanwhile, the effect of AA was also evaluated and the date of death was recorded. \n\nDiscussion\n Since abiraterone acetate was only used for the treatment of castration -resistant prostate cancer, this study included small sample size. \n\nThe introduction of docetaxel for the treatment of CRPC was a turning point since it resulted in an increased response rate by decreasing the PSA levels. Thus, the combination of docetaxel and prednisolone increased the survival time by decreasing the PSA value. There was no good alternative after progression from docetaxel6. In this study, we evaluated the effect of AA on castration- resistant prostate cancer and those patients who had progressed after one or two chemotherapy regimens. Frequent side effects related to the mineralocorticoid excess were potassium, haemoglobin, and serum creatinine levels. Abiraterone acetate was discontinued in only one patient due to an increase in creatinine level (6.6mg/dl), and no other major adverse drug reactions occurred. These results were in contrast to the results obtained in the study conducted by Joan Carles et al7. Initial Gleason score was found to \n\nbe above 8 (63%) in most patients; these results were similar to the study done by N Masahiko et al7. 77% of patients had bone metastasis, and 3 patients had no metastasis. Out of 22 patients, 16 had 2 - 3 previous chemotherapy regimens before starting abiraterone. \n\nMedian PSA value before chemotherapy was found to be 30.5 ng/ml [0 - 3208] and before abiraterone acetate was reported 23.75ng/ml. Median PSA value just before progression after starting abiraterone acetate was 19.3ng/ml [0.02 - 413]. This result shows that there is a significant decrease in the maximum value (3208 ng/ml to 413 ng/ml). Also, the overall survival rate after starting abiraterone acetate was significantly higher. 45 % of patients had 3 - 6 months of overall survival rate, 32 % had more than 6 months of survival rate without progression, and 23 % had progression after starting the drug. The overall average median survival and the median duration of drug exposure for CRPC who received AA was found to be 11.1 months [range 3−18]. Since AA plus prednisolone are available as oral dosage forms, they can be given in outpatient setting. \n\nCONCLUSION\n Abiraterone acetate is a drug of choice for CRPC and also for those who had previously received one or two chemotherapy regimens. Since it is a new therapeutic regimen, this study included small sample size, but there are few studies indicating the therapeutic efficacy of AA among patients with castration-resistant and newly diagnosed patients with metastatic prostate cancer. \n\nCONFLICTS OF INTEREST\n The authors declare that there is no conflict of interest.\n==== Refs\nReferences\n1 Jemal A Bray F Center MM Global cancer statistics CA Cancer J Clin 2011 61 2 69 90 21296855 \n2 Harshman LC Taplin ME Abiraterone Acetate: Targeting Persistent Androgen Dependence in Castration-Resistant Prostate Cancer Adv Ther. 2013 30 8 727 47 23979793 \n3 Barrie SE Potter GA Goddard PM Pharmacology of novel steroidal inhibitors of cytochrome P450 (17) alpha (17 alpha-hydroxylase/C17-20 lyase) J Steroid Biochem Mol Biol. 1994 50 5–6 267 73 7918112 \n4 De Bono JS Logothetis CJ Molina A Abiraterone and increased survival in metastatic prostate cancer N Engl J Med. 2011 364 21 1995 2005 21612468 \n5 Ryan CJ Smith MR de Bono JS Abiraterone in metastatic prostate cancer without previous chemotherapy N Engl J Med. 2013 368 138 48 \n6 Carles J Castellano D Climent MÁ Castration-resistant metastatic prostate cancer: current status and treatment possibilities Clin Transl Oncol. 2012 14 3 169 76 22374419 \n7 Nakayama Masahiko Kobayashi Hisanori Takahara Tomihiro Association of early PSA decline and time to PSA progression in abiraterone acetate- treated metastatic castration-resistant prostate cancer; a post-hoc analysis of Japanese phase 2 trials BMC Urol. 2016 16 1 27 27278777\n\n", "fulltext_license": "CC BY", "issn_linking": "2008-2207", "issue": "12(1)", "journal": "International journal of hematology-oncology and stem cell research", "keywords": "Abiraterone acetate (AA); Castration resistant prostate cancer (CRPCS); Prostate-specific antigen (PSA)", "medline_ta": "Int J Hematol Oncol Stem Cell Res", "mesh_terms": null, "nlm_unique_id": "101511150", "other_id": null, "pages": "4-7", "pmc": null, "pmid": "29951171", "pubdate": "2018-01-01", "publication_types": "D016428:Journal Article", "references": "23979793;27278777;22374419;21612468;7918112;23228172;21296855", "title": "A Study on the Clinical Outcome of Abiraterone Acetate in Castration Resistant Prostate Cancer Patients.", "title_normalized": "a study on the clinical outcome of abiraterone acetate in castration resistant prostate cancer patients" }

[ { "companynumb": "IN-JNJFOC-20180300282", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ABIRATERONE ACETATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "202379", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HORMONE-REFRACTORY PROSTATE CANCER", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ABIRATERONE ACETATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HORMONE-REFRACTORY PROSTATE CANCER", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Gastrointestinal disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood creatinine increased", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood potassium increased", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemoglobin decreased", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "JAMES A, VINCENT B, SIVADAS A, PAVITHRAN K. A STUDY ON THE CLINICAL OUTCOME OF ABIRATERONE ACETATE IN CASTRATION RESISTANT PROSTATE CANCER PATIENTS. INTERNATIONAL JOURNAL OF HEMATOLOGY-ONCOLOGY AND STEM CELL RESEARCH 01-JAN-2018?12 (1):4-7.", "literaturereference_normalized": "a study on the clinical outcome of abiraterone acetate in castration resistant prostate cancer patients", "qualification": "3", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20180308", "receivedate": "20180308", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14613269, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" } ]

{ "abstract": "OBJECTIVE\nTo describe the use of enoxaparin to treat suspected thrombosis in a preterm neonate.\n\n\nMETHODS\nA 29-week-gestation white infant with a family history of protein S deficiency lost color and blood flow to the right hand several hours after removal of the umbilical artery catheter. Although normal color returned to all except the distal first, second, and third fingers after warming, Doppler flow showed a radial artery defect, indicating a lack of blood flow. Enoxaparin 1 mg/kg intravenously every eight hours was then started. Heparin concentrations measured via anti-Xa assay drawn four and eight hours after a dose were 0.78 and 0.39 units/mL, respectively. Pharmacokinetic parameters calculated from these concentrations using a one-compartment model were elimination half-life four hours, volume of distribution 0.13 L/kg, and clearance 0.022 L/kg/h. No adverse effects were noted. Blood flow eventually returned, leaving only the third fingertip chronically injured.\n\n\nCONCLUSIONS\nDifferences between the neonatal and adult hemostatic systems contribute to an increased risk of thromboembolic events and an altered sensitivity to heparin anticoagulation in the neonate. Although heparin is currently the anticoagulant of choice, it may produce several adverse effects, such as hemorrhage and thrombocytopenia, which may be avoided by use of low-molecular-weight heparins (LMWHs). However, despite the efficacy and improved safety profile of LMWHs in adults, data regarding their use in children and neonates are scarce. This case demonstrates that enoxaparin can be used safely and effectively in a preterm infant through appropriate monitoring of heparin concentrations to adjust dosages. A larger volume of distribution of enoxaparin was noted in this neonate than in adults.\n\n\nCONCLUSIONS\nEnoxaparin 1 mg/kg intravenously every eight hours was used safely in this preterm infant with suspected thrombosis, suggesting that more than one dosing regimen may be appropriate in this population.", "affiliations": "Clincical Pharmacist, Women's Hospital of Greensboro, NC 27408-7079, USA. kim.dunaway@mosescone.com", "authors": "Dunaway|K K|KK|;Gal|P|P|;Ransom|J L|JL|", "chemical_list": "D000925:Anticoagulants; D017984:Enoxaparin", "country": "United States", "delete": false, "doi": "10.1345/aph.10110", "fulltext": null, "fulltext_license": null, "issn_linking": "1060-0280", "issue": "34(12)", "journal": "The Annals of pharmacotherapy", "keywords": null, "medline_ta": "Ann Pharmacother", "mesh_terms": "D000925:Anticoagulants; D017984:Enoxaparin; D006801:Humans; D007231:Infant, Newborn; D007235:Infant, Premature, Diseases; D013927:Thrombosis", "nlm_unique_id": "9203131", "other_id": null, "pages": "1410-3", "pmc": null, "pmid": "11144698", "pubdate": "2000-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Use of enoxaparin in a preterm infant.", "title_normalized": "use of enoxaparin in a preterm infant" }

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{ "abstract": "In immunocompromised patients, EBV may elicit B-cell transformation and proliferation. A 5-year-old microcephalic boy was admitted with fever and non-malignant polymorphic T-cell lymphoproliferative disease associated with EBV. A presumptive diagnosis of primary immunodeficiency with inability to control EBV was made and next-generation sequencing led to the identification of a novel ZBTB24 mutation (ICF2-syndrome). This case shows that susceptibility to EBV seems to be particular of ICF-2 as it has not been described in the other types of ICF. It is mandatory to raise the hypothesis of an underlying PID in case of severe EBV infection.", "affiliations": "Hospital de Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisbon, Portugal.;Departamento de Anatomia Patológica, Centro Hospitalar Universitário de Lisboa Central, Lisbon, Portugal.;Hospital de Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisbon, Portugal.;Centro de Genética Preditiva e Preventiva, Instituto de Biologia Molecular e Celular, Instituto de Investigação e Inovação em Saúde, Porto, Portugal.;CEDOC, Chronic Diseases Research Center, NOVA Medical School, Lisbon, Portugal.;Hospital de Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisbon, Portugal.", "authors": "Padeira|Gonçalo Luzes|GL|;Araújo|Catarina|C|;Cordeiro|Ana Isabel|AI|;Freixo|João|J|;Martins|Catarina Gregório|CG|;Neves|João Farela|JF|", "chemical_list": "D015415:Biomarkers", "country": "Switzerland", "delete": false, "doi": "10.3389/fimmu.2021.654167", "fulltext": "\n==== Front\nFront Immunol\nFront Immunol\nFront. Immunol.\nFrontiers in Immunology\n1664-3224\nFrontiers Media S.A.\n\n10.3389/fimmu.2021.654167\nImmunology\nCase Report\nCase Report: Primary Immunodeficiencies, Massive EBV+ T-Cell Lympoproliferation Leading to the Diagnosis of ICF2 Syndrome\nPadeira Gonçalo Luzes 1\n\nAraújo Catarina 2\n\nCordeiro Ana Isabel 1\n\nFreixo João 3\n\nMartins Catarina Gregório 4 5\n\nNeves João Farela 1 4 5 *\n\n1 Hospital de Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisbon, Portugal\n2 Departamento de Anatomia Patológica, Centro Hospitalar Universitário de Lisboa Central, Lisbon, Portugal\n3 Centro de Genética Preditiva e Preventiva, Instituto de Biologia Molecular e Celular, Instituto de Investigação e Inovação em Saúde, Porto, Portugal\n4 CEDOC, Chronic Diseases Research Center, NOVA Medical School, Lisbon, Portugal\n5 Comprehensive Health Research Centre (CHRC), NOVA Medical School, Nova University of Lisbon, Lisbon, Portugal\nEdited by: Sylvain Latour, Centre National de la Recherche Scientifique (CNRS), France\n\nReviewed by: Capucine Picard, Assistance Publique Hopitaux De Paris, France; Raz Somech, Sheba Medical Center, Israel\n\n*Correspondence: João Farela Neves, joao.farelaneves@chlc.min-saude.pt\nThis article was submitted to Primary Immunodeficiencies, a section of the journal Frontiers in Immunology\n\n28 4 2021\n2021\n12 65416715 1 2021\n08 4 2021\nCopyright © 2021 Padeira, Araújo, Cordeiro, Freixo, Martins and Neves\n2021\nPadeira, Araújo, Cordeiro, Freixo, Martins and Neves\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nIn immunocompromised patients, EBV may elicit B-cell transformation and proliferation. A 5-year-old microcephalic boy was admitted with fever and non-malignant polymorphic T-cell lymphoproliferative disease associated with EBV. A presumptive diagnosis of primary immunodeficiency with inability to control EBV was made and next-generation sequencing led to the identification of a novel ZBTB24 mutation (ICF2-syndrome). This case shows that susceptibility to EBV seems to be particular of ICF-2 as it has not been described in the other types of ICF. It is mandatory to raise the hypothesis of an underlying PID in case of severe EBV infection.\n\ncase report\nICF-2\nPrimary immune deficiencies\nEBV\nlymphoproliferation\n==== Body\nIntroduction\n\nEpstein-Barr virus (EBV) is one of eight human herpesviruses that establishes lifelong persistent infection in humans. More than 90% of adults have been infected with EBV, whose life cycle mimics the natural differentiation pathway of B cells, giving the virus access to its site of latent infection, the resting memory B cells (1).\n\nPrimary infection in early childhood is generally asymptomatic but later in life it usually causes infectious mononucleosis. In some patients, EBV can induce lymphoproliferation, lymphoma, and hemophagocytic lymphohistiocytosis (HLH) particularly in immunocompromised patients, reflecting the importance of continuous immune surveillance for the regulation of the virus (2). In healthy patients the propensity of EBV to induce B-cell proliferation seems to be counterbalanced by an immune system that maintains the overall number of EBV-infected B lymphocytes in a steady level (2).\n\nAfter infecting B-cells (and epithelial cells), the EBV replicative cycle that follows results in the expression of lytic proteins involved in immune evasion which interfere with antigen (Ag) processing and presentation to CD8+ T cells. Then, EBV switches to latent infection of B cells avoiding T-cell and NK-cell immunity, which is critical for colonization of the host. Although the exact mechanisms are still being discussed latency can take several forms (2), starting as a growth-transforming latent infection of B cells where expression of all latent proteins (EBV nuclear Ags (EBNA) 1, 2, 3A, 3B, 3C, and LP; latent membrane proteins (LMPs) 1 and 2) can be detected. In this state infected B cells expand rapidly in extrafollicular areas of oropharyngeal lymphoid tissues such as the tonsils, and large numbers of infected B cells can be found in the blood (latency III). Most of these infected cells are cleared by the immune system (2). Other latency forms consist of latency II which is a more restrict form of latency design to evade the immune system and where only EBNA1 and LMPs are expressed. Finally, only EBNA1 is expressed in latency I. In fact, viral persistence is achieved largely through silent infection of memory B cells where expression of viral Ags is extinguished (latency 0); in healthy carriers, EBV is exclusively found within this population in the blood (2).\n\nPrimary immunodeficiencies that present with EBV-driven LPDs are related to defects in the growth, differentiation and activities of B and/or T cells. Briefly, the host defense to EBV can be compromised by germline mutations in genes that encode proteins that are crucial for an adequate response (3): a) in the initial interaction between EBV-infected or antigen-presenting B cells and CD8+ T cells (CD27/CD70, 4-1BB/4-1BBL) and downstream signaling (requiring MAGT1, ITK, and RasGRP1) that will induce DNA synthesis by activation of CTPS1 and elicit proliferation of EBV-specific CD81 T cells; b) or following expansion of EBV-specific CD81 T cells by compromising cytotoxicity of CD8+ T and NK cells as seen in patients with mutations in the SAP pathway. SAP links SLAM-family receptors on hematopoietic cells with downstream intracellular signaling pathways to regulate T and NK cells. In the absence of SAP, cytotoxic functions of CD81 T and NK cells induced by engaging the SLAM-family receptors 2B4 (CD244) and NTB-A are abolished. These two pathways are required for the functioning of one-another as illustrated by the ASGRP1-dependent induction of CTPS1, the impaired NKG2D and 2B4 expression secondary to CD27/CD70 deficiency or by the impaired PLCγ1 activation due to ITK or MAGT1 deficiency (3).\n\nMoreover, in immunocompromised patients who present an impaired defense against EBV, the virus may elicit cell transformation and proliferation, leading to EBV-induced lymphoproliferative disorders (EBV-LPDs) (2). These are usually divided in reactive proliferations (including reactive lesions with no malignant potential like infectious mononucleosis and reactive lesions with varied malignant potential), B cell proliferations (including Hodgkin lymphoma and plasma cell neoplasms), T/natural killer (NK)-cell proliferations and immunodeficiency-related lymphoid proliferations. Combined T-cell and B-cell immunodeficiencies account for about two thirds of PIDs associated with EBV-driven lymphoproliferative disorders (4).\n\nThere are several primary immunodeficiencies in which EBV+ B-cell LPDs are an important feature, but very few germline mutations have been associated to documented EBV+ T/NK-cell LPD (4). We report the case of a boy with massive EBV+ T-cell LPD caused by a novel homozygous ZTBZ24 mutation.\n\nCase Report\n\nFive-year-old boy with no relevant family background but with personal history of epilepsy, severe psychomotor retardation, microcephaly, micrognathia, hypertelorism, low-set ears, epicanthal folds, and macroglossia ( Figure 1A ).\n\nFigure 1 (A) Microcephaly (B) Gastric biopsy: EBV-encoded small ribonucleic acid (EBER1) in situ hybridization shows positive nuclei EBER+ in the T cells lymphocytes. Double staining EBER-ISH (blue) and CD3-IHC (brown) (C) Thorax CT with mediastinal infiltration. (D) Clinical evolution, EBV load and therapeutics.\n\nAdmitted in the context of prolonged fever and generalized lymphadenopathies (cervical, abdominal, and mediastinal). He had no other complaints.\n\nAn extensive investigation was performed and an elevated EBV viral load (50,000 copies/ml) despite a negative EBV serology was found. Prior to receiving any immunosuppressive treatment, immunologic evaluation was performed and revealed normal serum levels of IgG, IgA and IgM, normal responses to diphteria and tetanus and a severe T and NK-cell lymphopenia, as well as B-cell lymphopenia, particularly low post-germinal class-switched memory B cells ( Table 1 ).\n\nTable 1 Investigation.\n\n\tReference\t\t\nInfectious\t\nEBV-VCA IgM/IgG\nEBV-EA IgG\nEBV-EBNA IgG\t–\tNegative/Negative\nNegative\nNegative\t\nCMV, HSV 1,HSV2, VZV, HHV6, HHV7 PCR\t–\tNegative\t\nCMV IgM/IgG\t–\tNegative/Positive\t\nEnterovirus PCR in stools; Multiplex PCR for respiratory virus\t–\tNegative\t\nParvovirus IgG/IgM\t–\tNegative\t\nHIV 1 and 2\t–\tNegative\t\nVHA IgM/IgG\t–\tNegative/Positive\t\nSerology for Coxiella burnetti, Leishmania, Leptospira, Mycoplasma, Toxoplasma\t–\tNegative\t\nIGRA\t–\tNegative\t\nImmunologic\t\nImmunoglobulin G (mg/dL)\t593-1730\t903\t\nImmunoglobulin A (mg/dL)\t33-360\t202\t\nImmunoglobulin M (mg/dL)\t55-210\t83\t\nImmunoglobulin E (KUI/L)\t0-90\t10.2\t\nLymphocyte populations\nAbs value(cel/uL)\nLym B (CD19+ %)\nLym B [CD19+ (cells/uL)]\nPreGerminal %\nPreGerminal(cells/uL)\nPostGerminal %\nPostGerminal(cells/uL)\nUnswitched %\nUnswitched(cells/uL)\nSwitched %\nSwitched(cells/uL)\nLym T (CD3+ %)\nLym T [CD3+ cells/uL)]\nCD3+/CD4+ %\nCD3+/CD4+ (cells/uL)\nNaive %\nNaive(cells/uL)\nCentral Memory %\nCentral Memory(cells/uL)\nEffector Memory %\nEffector Memory(cells/uL)\nCD3+/CD8+ %\nCD3+/CD8+ (cells/uL)\nNaive %\nNaive(cells/uL)\nCentral Memory %\nCentral Memory(cells/uL)\nEffector Memory %\nEffector Memory(cells/uL)\nEffector TD CD27+ %\nEffector TD CD27+(cells/uL)\nEffector TD CD27- %\nEffector TD CD27-(cells/uL)\nT TCRgd+ %\nT TCRgd+(cells/uL)\nT TCRgd- %\nT TCRgd-(cells/uL)\nNK CD3-/CD16 56+ %\nNK CD3-/CD16 56+ (cells/uL)\t1.200-6850\n6,1-25,2\n157-1637\n48-88\n70-1350\n8-33\n35-490\n3-22\n18-333\n2-17,4\n14-200\n55-97\n850-5300\n26-61\n515-3500\n42-100\n265-2900\n1-100\n150-800\n0.2-18\n9-222\n13-47\n188-1800\n16-100\n94-1130\n1-39\n26-450\n0,4-100\n0-151\n0-3,8\n0-385\n0,01-7,2\n1-735\n2-24\n44-748\n0,04-1,3\n3-104\n2-31\n106-1759\t550\n10,58\n58,2\n96,56\n56,2\n3,44\n2\n0,19\n0,11\n3,26\n1,9\n89\n490\n71,27\n390\n26,28\n103\n71,43\n280\n2,4\n9,4\n13,8\n76,1\n46,39\n35,3\n42,05\n32\n1,45\n1\n0,17\n16,5\n0,06\n2,2\n3,37\n16,5\n0,17\n5,5\n0,27\n1,5\t\nIn bold values outside the reference range.\n\nAn excisional biopsy of a lymphadenopathy was suggestive of non-malignant polymorphic EBV (EBER+) T-cell lymphoproliferative disease. This lymphoproliferation was accompanied by infiltration of the digestive tract and he developed severe upper and lower digestive bleeding with two episodes of hemorrhagic shock, needing multiple blood transfusions. A gastric ulcer biopsy confirmed a polymorphic T infiltrate (EBER+) ( Figure 1B ) and rearrangements of T cell receptors and flow cytometry excluded monoclonality. Based on the presence of EBV-LPD in a patient with personal history of microcephaly and psychomotor retardation a presumptive diagnosis of primary immunodeficiency with inability to control EBV was made. He was treated with rituximab for B lymphocyte depletion with resolution of fever and of the gastrointestinal bleeding, which were accompanied by marked decrease in the EBV viral load (viral load 50,000> 1015 copies/mL ( Figure 1D ). Hematopoietic stem cell transplantation (HSCT) was not proposed due to the personal history of severe psychomotor retardation.\n\nBased on the pathologic findings of EBV+ T-cell LPD, and despite the absence of documented T-cell infection in the peripheral blood (5), cyclophosphamide was added to rituximab when the patient eventually presented a disease relapse, with fever, increasing viral load and generalized lymphadenopathies. This led to a dramatic clinical improvement and a decrease in viral load to 20 copies/ml ( Figure 1D ). Unfortunately, in the following months, the patient had several infectious episodes (namely central line related sepsis), leading to intermittent discontinuation of the immunosuppressive treatment and subsequent relapse of the disease with massive lymphoproliferation ( Figure 1C ) and increasing viral loads, eventually leading to his death.\n\nA next-generation sequencing panel of EBV-susceptibility related genes ( Table S1 ) led to the identification of a novel c.301G>A (p.(Ala101Thr)) homozygous ZBTB24 (NM_014797.2) mutation. This residue is highly conserved and there is a physicochemical difference between alanine and threonine ( Table S2 ). This is a very rare variant and no homozygotes have been reported (total allele frequency of around 0.017%, 48 heterozygous; 0 homozygous). Most bioinformatics analysis predicted that the patient’s mutation Ala101Thr was damaging (e.g., SIFT = deleterious; MutationTaster = disease causing), with a CADD score of 17,49. This led to the diagnosis of immunodeficiency, centromeric region instability and facial anomalies syndrome (ICF) type 2. Both parents were found to harbor a heterozygotic mutation which allowed family counseling. Unfortunately, the patient died before karyotyping could be performed. We performed post-mortem Southern blot analysis for SAT2/Alpha-Satellite repeat methylation but did not find the characteristic ICF-associated repeat DNA hypomethylation. This is probably explained by the unusual nature of the mutation: a homozygous missense variant in the BTB domain.\n\nDiscussion\n\nICF is a rare autosomal recessive disorder caused by defective DNA methylation, with approximately 70 cases reported so far (4). Hypomethylation of satellite regions on chromosomes 1, 9, and 16 and subsequent pericentromeric instability leads to chromosomal instability in vitro. Like our patient, individuals with this syndrome present facial anomalies such as ocular hypertelorism, epicanthic folds, broad flat nasal bridge, low-set ears, and macroglossia. Other traits of the disease comprise neurodevelopment disorder, including motor delay, speech delay, and intellectual disability (6). Moreover, patients with ICF have an impaired humoral and cellular immunity (4), leading to recurrent bacterial infections. Viral infections are less common but can have a severe course.\n\nSo far, four types of ICF syndromes have been identified. ICF1 is caused by mutations in DNMT3B, which encodes the DNA methyltransferase 3B and is the most frequent type of ICF syndrome, accounting for more than half of patients. ICF2 accounts for approximately 30% of ICF patients and is caused by mutations in ZBTB24, which encodes the zinc-finger-and BTB-domain (6). The remaining patients have mutations in CDCA7 (ICF3) or HELLS (ICF4) (7). Immunological findings appear to be similar in ICF1 and ICF2, though humoral immunodeficiency has been reported to be more severe in ICF1 still intellectual disability seems to be greater in patients with ICF2 (6).\n\nZBTB24 belongs to family of transcription factors, which form homo- or heterodimers in the nucleus via their BTB domain and bind to target genes via their DNA-binding C2H2 zinc-finger domains (6). ZBTB24 is highly expressed by B-cells and downregulation seems to increase the expression of IRF-4 (interferon regulatory factor 4) and Blimp-1 (B lymphocyte-induced maturation protein 1), two crucial factors involved in the proliferation and differentiation of B cell. These lock the cell-cycle in the G0/1- to S-phase without apoptosis induction (8).\n\nUnlike our patient, that never had hypogammaglobulinemia, most (but not all) of the 40 patients reported with ICF2 presented hypogammaglobulinemia (particularly IgM) (6, 9). On the other hand, he had B cell lymphopenia with particularly low counts of post-germinal B cells, similar to what has been previously reported in these patients (9). Interestingly, five other ICF2 patients have been reported with EBV infection: the first was described as having “severe mononucleosis” (9), the second had persistent EBV infection (10), the third had an EBV-induced hemophagocytic lymphohystiocytosis (11), the fourth had a chronic EBV infection and developed an aggressive Hodgkin lymphoma (4) and the last one had an EBV-driven lymphoproliferative disorder with features of a CD20-negative large B-cell lymphoma (12) (Table S3) This susceptibility to EBV seems to be particular of ICF-2 as it has not been described in the other types of ICF. Similar to our patient, one patient had EBV+ T-cell lymphoproliferation (9) and other had progression of the disease despite rituximab (10). Knowing that EBV promotes epigenetic changes by changing methylation patterns (13) and that ICF patients present a pericentromeric repeat hypomethylation (14), it is possible to assume that differences in methylation profiles between ICF2 and the other types of this syndrome helps to explain their unique susceptibility to EBV (4).\n\nFinally, it is mandatory to raise the hypothesis of an underlying PID in case of severe EBV infection, as HSCT is the only curative treatment in many of these cases. When HSCT is not an available therapeutic option (as in this case) the approach to chronic EBV infection is extraordinarily complex and should be individualized. The experience in controlling EBV in immunosuppressed patients is based on post-transplant lymphoproliferative disorders (PTLD) experience, where the mainstay is reduction of immunosuppression, which is an impossibility in primary immunodeficiency recipients. When B cell depletion with rituximab does not lead to a long-lasting control of the disease, regimens used in lymphoma therapy, such as cyclophosphamide, vincristine and prednisone, have been used despite an unsatisfactory outcome in many of these patients (15).\n\nIn summary, we report a patient who succumbed to EBV-T-cell LPD that harbored a novel homozygous A101T mutation in the ZBTB24 gene, causing ICF2. Future studies [such as the luciferase assay described by Daxinger et al (16)] will hopefully help us describe how this mutation affects ZBTB24’s role in controlling expression of CDCA7. This adds to the 5 previously reported cases in the literature, and we discuss the complex approach to the treatment of these patients in the absence of putative curative treatment.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.\n\nEthics Statement\n\nWritten informed consent was obtained from the minor(s)’ legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nGP designed the study and wrote the paper. CA performed pathology analysis; AIC performed bibliographical research and was medical doctor of the patient; JF performed genetic analysis and reviewed the manuscript; CGM performed immunological analysis. JFN designed the study and analyzed the data. All authors contributed to the article and approved the submitted version.\n\nFunding\n\nThe present publication was funded by Fundação Ciência e Tecnologia, IP national support through CHRC (UIDP/04923/2020).\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2021.654167/full#supplementary-material\n\nClick here for additional data file.\n\nClick here for additional data file.\n\nClick here for additional data file.\n\nClick here for additional data file.\n\nClick here for additional data file.\n\nClick here for additional data file.\n\nClick here for additional data file.\n\nClick here for additional data file.\n==== Refs\nReferences\n\n1 Yin H Qu J Peng Q Gan R . Molecular Mechanisms of EBV-Driven Cell Cycle Progression and Oncogenesis. Med Microbiol Immunol (2019) 208 (5 ):573–83. 10.1007/s00430-018-0570-1\n2 Tangye SG Palendira U Edwards ES . Human Immunity Against EBV-Lessons From the Clinic. J Exp Med (2017) 214 (2 ):269–83. 10.1084/jem.20161846\n3 Tangye SG Latour S . Primary Immunodeficiencies Reveal the Molecular Requirements for Effective Host Defense Against EBV Infection. Blood (2020) 135 (9 ):644–55. 10.1182/blood.2019000928\n4 Licciardi F van den Boogaard M Delle Piane M Tovo PA Montin D . Ebv-Related Hodgkin Lymphoma in an ICF2 Patient: is Ebv Susceptibility a Hallmark of This Icf Subtype? J Clin Immunol (2019) 39 (3 ):234–6. 10.1007/s10875-019-00596-6\n5 Fournier B Boutboul D Bruneau J Miot C Boulanger C Malphettes M . Rapid Identification and Characterization of Infected Cells in Blood During Chronic Active Epstein-Barr Virus Infection. J Exp Med (2020) 217 :(11). 10.1084/jem.20192262\n6 Sogkas G Dubrowinskaja N Bergmann AK Lentes J Ripperger T Fedchenko M . Progressive Immunodeficiency With Gradual Depletion of B and CD4⁺ T Cells in Immunodeficiency, Centromeric Instability and Facial Anomalies Syndrome 2 (Icf2). Dis (Basel Switzerland) (2019) 7 (2 ):34. 10.3390/diseases7020034\n7 Thijssen PE Ito Y Grillo G Wang J Velasco G Nitta H . Mutations in CDCA7 and HELLS Cause Immunodeficiency-Centromeric Instability-Facial Anomalies Syndrome. Nat Commun (2015) 6 :7870. 10.1038/ncomms8870 26216346\n8 Liang J Yan R Chen G Feng J Wu WW Ren W . Downregulation of ZBTB24 Hampers the G0/1- to S-Phase Cell-Cycle Transition Via Upregulating the Expression of IRF-4 in Human B Cells. Genes Immun (2017), 276–82. 10.1038/gene.2016.18\n9 Sterlin D Velasco G Moshous D Touzot F Mahlaoui N Fischer A . Genetic, Cellular and Clinical Features of ICF Syndrome: A French National Survey. J Clin Immunol; (2016) 36 :149–59. 10.1007/s10875-016-0240-2\n10 Kamae C Imai K Kato T Okano T Honma K Nakagawa N . Clinical and Immunological Characterization of ICF Syndrome in Japan. J Clin Immunol (2018) 38 (8 ):927–37. 10.1007/s10875-018-0559-y\n11 Harnisch E Buddingh EP Thijssen PE Brooks AS Driessen GJ Kersseboom R . Hematopoietic Stem Cell Transplantation in a Patient With ICF2 Syndrome Presenting With EBV-Induced Hemophagocytic Lymphohystiocytosis. Transplantation (2016) 100 :e35–6. 10.1097/TP.0000000000001210\n12 Burk CM Coffey KE Mace EM Bostwick BL Chinn IK Coban-Akdemir ZH . Immunodeficiency, Centromeric Instability, and Facial Anomalies (ICF) Syndrome With NK Dysfunction and EBV-Driven Malignancy Treated With Stem Cell Transplantation. J Allergy Clin Immunol In Pract (2020) 8 (3 ):1103–6.e3. 10.1016/j.jaip.2019.08.040 31520839\n13 Schaefer BC Strominger JL Speck SH . Host-Cell-Determined Methylation of Specific Epstein-Barr Virus Promoters Regulates the Choice Between Distinct Viral Latency Programs. Mol Cell Biol (1997) 17 (1 ):364–77. 10.1128/MCB.17.1.364\n14 Camacho-Ordonez N Ballestar E Timmers H Grimbacher B . What Can Clinical Immunology Learn From Inborn Errors of Epigenetic Regulators? J Allergy Clin Immunol (2021) S0091-6749 (21 ):00225-6. 10.1016/j.jaci.2021.01.035\n15 Abbas F El Kossi M Shaheen IS Sharma A Halawa A . Post-Transplantation Lymphoproliferative Disorders: Current Concepts and Future Therapeutic Approaches. World J Transplant (2020) 10 (2 ):29–46. 10.5500/wjt.v10.i2.29 32226769\n16 Wu H Vonk K van der Maarel SM Santen G Daxinger L . A Functional Assay to Classify ZBTB24 Missense Variants of Unknown Significance. Hum Mutat (2019) 40 (8 ):1077–83. 10.1002/humu.23786\n\n", "fulltext_license": "CC BY", "issn_linking": "1664-3224", "issue": "12()", "journal": "Frontiers in immunology", "keywords": "EBV; ICF-2; Primary immune deficiencies; case report; lymphoproliferation", "medline_ta": "Front Immunol", "mesh_terms": "D015415:Biomarkers; D001706:Biopsy; D002675:Child, Preschool; D004198:Disease Susceptibility; D020031:Epstein-Barr Virus Infections; D004854:Herpesvirus 4, Human; D006801:Humans; D008232:Lymphoproliferative Disorders; D008297:Male; D000081207:Primary Immunodeficiency Diseases; D063189:Symptom Assessment; D013601:T-Lymphocytes; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "101560960", "other_id": null, "pages": "654167", "pmc": null, "pmid": "33995370", "pubdate": "2021", "publication_types": "D002363:Case Reports; D013485:Research Support, Non-U.S. Gov't", "references": "30353301;26851945;31942615;33609625;26216346;28108590;31520839;8972217;30987377;27326813;27098601;31066130;30386928;32812031;30719684;32226769", "title": "Case Report: Primary Immunodeficiencies, Massive EBV+ T-Cell Lympoproliferation Leading to the Diagnosis of ICF2 Syndrome.", "title_normalized": "case report primary immunodeficiencies massive ebv t cell lympoproliferation leading to the diagnosis of icf2 syndrome" }

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Case Report: Primary Immunodeficiencies, Massive EBV+ T-Cell Lympoproliferation Leading to the Diagnosis of ICF2 Syndrome.. 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"drugenddate": null, "drugenddateformat": null, "drugindication": "B-lymphocyte count decreased", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunodeficiency", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Epstein-Barr viraemia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Device related sepsis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Disease recurrence", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug effective for unapproved indication", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Padeira G, Araujo C, Cordeiro A I, Freixo J, Martins C G and Neves J F.. Case Report: Primary Immunodeficiencies, Massive EBV+ T-Cell Lympoproliferation Leading to the Diagnosis of ICF2 Syndrome. Frontiers in Immunology. 2021;12:1-6", "literaturereference_normalized": "case report primary immunodeficiencies massive ebv t cell lympoproliferation leading to the diagnosis of icf2 syndrome", "qualification": "3", "reportercountry": "PT" }, "primarysourcecountry": "PT", "receiptdate": "20211123", "receivedate": "20211119", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20088702, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220303" } ]

{ "abstract": "Bowel perforation is a potentially fatal complication of obstruction, ischaemia, trauma, surgery and medications. It is recognised by clinical suspicion based on history, symptoms of severe abdominal pain and signs such as rebound tenderness, as well as imaging showing free air in the abdomen. Bevacizumab (aka avastin) is an antineoplastic recombinant monoclonal antibody that inhibits angiogenesis in a variety of malignancies. Colonic perforation is a recognised but rare complication of this therapy, likely due to aforementioned bowel ischaemia or compromised mucosal microcirculation which increases susceptibility to injury. We are presenting a case of an unrecognised bowel perforation caused in a patient with abdominal carcinomatosis.", "affiliations": "Medicine Department, New York Hospital Queens-Weill Cornell affiliate, Flushing, New York, USA.;Medicine Department, New York Hospital Queens-Weill Cornell affiliate, Flushing, New York, USA.", "authors": "Lazarescu|Roxana Elena|RE|;Bohm|Kelley|K|", "chemical_list": "D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab", "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2014()", "journal": "BMJ case reports", "keywords": null, "medline_ta": "BMJ Case Rep", "mesh_terms": "D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D002277:Carcinoma; D003108:Colonic Diseases; D006801:Humans; D007416:Intestinal Perforation; D008297:Male; D065666:Mesenteric Ischemia; D008875:Middle Aged; D010534:Peritoneal Neoplasms", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "24957587", "pubdate": "2014-06-23", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "21803880", "title": "An unusual case of bowel perforation.", "title_normalized": "an unusual case of bowel perforation" }

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{ "abstract": "We present three cases of patients affected by severe SARS-CoV-2-related pneumonia treated with a low molecular weight heparin for prevention or treatment of pulmonary embolism, who presented a major bleed, in particular an ileopsoas haematoma that caused severe anaemia; in one case it was fatal. In the recent outbreak of novel coronavirus infection, significantly abnormal coagulation parameters in SARS-CoV-2 infection occur very often, but complications in the opposite direction such as bleeding diathesis are very rare. In these cases, there are different levels of gravity: for one patient the major bleed required the anticoagulant therapy to be stopped until bleeding stabilized, one patient needed interventional radiology and one patient died.", "affiliations": "Department of Respiratory Pathophysiology, Monaldi-Cotugno Hospital, Naples. antonietta.coppola84@gmail.com.;Department of Respiratory Pathophysiology, Monaldi-Cotugno Hospital, Naples. anna.annunziata@gmail.com.;Department of Respiratory Pathophysiology, Monaldi-Cotugno Hospital, Naples. s.gioia86@gmail.com.;Department of Respiratory Pathophysiology, Monaldi-Cotugno Hospital, Naples. giuseppefiorentino1@gmail.com.", "authors": "Coppola|Antonietta|A|;Annunziata|Anna|A|;Gioia|Maria Rosaria|MR|;Fiorentino|Giuseppe|G|", "chemical_list": "D000925:Anticoagulants", "country": "Italy", "delete": false, "doi": "10.4081/monaldi.2021.1739", "fulltext": null, "fulltext_license": null, "issn_linking": "1122-0643", "issue": "91(3)", "journal": "Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace", "keywords": null, "medline_ta": "Monaldi Arch Chest Dis", "mesh_terms": "D000925:Anticoagulants; D001778:Blood Coagulation Disorders; D000086382:COVID-19; D006801:Humans; D011655:Pulmonary Embolism; D000086402:SARS-CoV-2", "nlm_unique_id": "9307314", "other_id": null, "pages": null, "pmc": null, "pmid": "33794592", "pubdate": "2021-04-01", "publication_types": "D016428:Journal Article", "references": null, "title": "Bleeding events in COVID-19: the other side of the coin?", "title_normalized": "bleeding events in covid 19 the other side of the coin" }

[ { "companynumb": "IT-LUPIN PHARMACEUTICALS INC.-2022-00665", "fulfillexpeditecriteria": "2", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZITHROMYCIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "065398", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 pneumonia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ENOXAPARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6000 INTERNATIONAL UNIT, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "Thrombosis prophylaxis", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "6000", "drugstructuredosageunit": "025", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ENOXAPARIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ENOXAPARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 INTERNATIONAL UNIT/KILOGRAM, QD (AS REPORTED; WEIGHT-ADJUSTED DOSAGE OF ENOXAPARIN (10UI/KG ONCE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "028", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ENOXAPARIN" } ], "patientagegroup": null, "patientonsetage": "82", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "67", "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Coppola A, Annunziata A, Gioia MR, Fiorentino G. Bleeding events in COVID-19: the other side of the coin. Monaldi Archives for Chest Disease. 2021;91 (3):1739", "literaturereference_normalized": "bleeding events in covid 19 the other side of the coin", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20220123", "receivedate": "20220123", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20365813, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220423" } ]

{ "abstract": "Adamantinoma-like Ewing sarcoma is a rare variant of Ewing sarcoma with histologic and immunohistochemical evidence of squamous differentiation. This variant most commonly occurs in the head and neck region with a few cases reported in the long bones of the limbs. It may be associated with poorer clinical outcome and could pose a diagnostic challenge, particularly if it occurs in older patients or as a metastatic lesion. We present a case of Ewing sarcoma in the metatarsal of an 11-year-old boy that manifested adamantinoma-like morphology after neoadjuvant chemotherapy. Chemotherapy has been reported to induce neuronal maturation and rhabdoid morphology in cases of Ewing sarcoma, but no reports of treatment-induced squamous differentiation with P40/P63 expression have been demonstrated. This is also the first documented case treated with a pedicled osteocutaneous fibular transfer in a metatarsal malignancy, which is usually treated by either ray or below-knee amputation.", "affiliations": "National Health Laboratory Service, 121470Stellenbosch University, Cape Town, South Africa.;26697Division of Orthopaedic Surgery, Stellenbosch University, Cape Town, South Africa.;26697Division of Orthopaedic Surgery, Stellenbosch University, Cape Town, South Africa.;Paediatric Oncology Unit, 26697Stellenbosch University, Cape Town, South Africa.;Division of Plastic and Reconstructive Surgery, 26697Stellenbosch University, Cape Town, South Africa.;Division of Radiodiagnosis, 26697Stellenbosch University, Cape Town, South Africa.;National Health Laboratory Service, 121470Stellenbosch University, Cape Town, South Africa.;National Health Laboratory Service, 121470Stellenbosch University, Cape Town, South Africa.", "authors": "Marais|Yolandi A|YA|https://orcid.org/0000-0003-1170-6378;Saini|Aaron K|AK|;Ferreira|Nando|N|;Reddy|Kershinee|K|;Zühlke|Alexander|A|;Rossouw|Nelmarie|N|;Zaharie|Stefan D|SD|;Schubert|Pawel T|PT|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1177/10668969211001449", "fulltext": null, "fulltext_license": null, "issn_linking": "1066-8969", "issue": "29(7)", "journal": "International journal of surgical pathology", "keywords": "Ewing sarcoma; P40; P63; adamantinoma-like Ewing sarcoma; neoadjuvant; osteocutaneous fibular transfer; squamous differentiation", "medline_ta": "Int J Surg Pathol", "mesh_terms": null, "nlm_unique_id": "9314927", "other_id": null, "pages": "798-803", "pmc": null, "pmid": "33703949", "pubdate": "2021-10", "publication_types": "D016428:Journal Article", "references": null, "title": "Adamantinoma-like Variant of Ewing Sarcoma in the Metatarsal Bone After Chemotherapy: Report of a Case Successfully Treated with Pedicled Osteocutaneous Fibular Transfer.", "title_normalized": "adamantinoma like variant of ewing sarcoma in the metatarsal bone after chemotherapy report of a case successfully treated with pedicled osteocutaneous fibular transfer" }

[ { "companynumb": "ZA-TEVA-2022-ZA-2016755", "fulfillexpeditecriteria": "1", "occurcountry": "ZA", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "75493", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.5 MG/M2, AS PER THE CHILDREN^S ONCOLOGY GROUP EWS PROTOCOL (AEWS0031)", "drugenddate": null, "drugenddateformat": null, "drugindication": "Ewing^s sarcoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.5", "drugstructuredosageunit": "009", "drugtreatmentduration": "48", "drugtreatmentdurationunit": "803", "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "63097", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "75 MG/M2, AS PER THE CHILDREN^S ONCOLOGY GROUP EWS PROTOCOL (AEWS0031)", "drugenddate": null, "drugenddateformat": null, "drugindication": "Ewing^s sarcoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": "48", "drugtreatmentdurationunit": "803", "medicinalproduct": "DOXORUBICIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "74284", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG/M2, FOR 5 DAYS PER COURSE AS PER THE CHILDREN^S ONCOLOGY GROUP EWS PROTOCOL (AEWS0031)", "drugenddate": null, "drugenddateformat": null, "drugindication": "Ewing^s sarcoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "009", "drugtreatmentduration": "48", "drugtreatmentdurationunit": "803", "medicinalproduct": "ETOPOSIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.2 G/M2 (AS PER THE CHILDREN^S ONCOLOGY GROUP EWS PROTOCOL (AEWS0031))", "drugenddate": null, "drugenddateformat": null, "drugindication": "Ewing^s sarcoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": "48", "drugtreatmentdurationunit": "803", "medicinalproduct": "CYCLOPHOSPHAMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "IFOSFAMIDE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.8 G/M2 (FOR 5 DAYS PER COURSE AS PER THE CHILDREN^S ONCOLOGY GROUP EWS PROTOCOL (AEWS0031))", "drugenddate": null, "drugenddateformat": null, "drugindication": "Ewing^s sarcoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": "48", "drugtreatmentdurationunit": "803", "medicinalproduct": "IFOSFAMIDE" } ], "patientagegroup": "3", "patientonsetage": "11", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Ewing^s sarcoma", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Marais YA, Saini AK, Ferreira N, Reddy K, Zuhlke A, Rossouw N, et al. Adamantinoma-like Variant of Ewing Sarcoma in the Metatarsal Bone After Chemotherapy: Report of a Case Successfully Treated with Pedicled Osteocutaneous Fibular Transfer. 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METER, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Chemotherapy", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "009", "drugtreatmentduration": "5", "drugtreatmentdurationunit": "804", "medicinalproduct": "ETOPOSIDE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IFOSFAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.8 GRAM PER SQUARE METRE, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Chemotherapy", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": "5", "drugtreatmentdurationunit": "804", "medicinalproduct": "IFOSFAMIDE" } ], "patientagegroup": null, "patientonsetage": "11", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Ewing^s sarcoma", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Marais YA, Saini AK, Ferreira N, Reddy K, Zuhlke A, Rossouw N, et al. Adamantinoma-like Variant of Ewing Sarcoma in the Metatarsal Bone After Chemotherapy: Report of a Case Successfully Treated with Pedicled Osteocutaneous Fibular Transfer. Int J Surg Pathol. 2021;Mar 11; 29(7):798-803", "literaturereference_normalized": "adamantinoma like variant of ewing sarcoma in the metatarsal bone after chemotherapy report of a case successfully treated with pedicled osteocutaneous fibular transfer", "qualification": "1", "reportercountry": "ZA" }, "primarysourcecountry": "ZA", "receiptdate": "20220323", "receivedate": "20220315", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20592814, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "ZA-STRIDES ARCOLAB LIMITED-2022SP002267", "fulfillexpeditecriteria": "1", "occurcountry": "ZA", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "75 MILLIGRAM/SQ. METER, CYCLICAL", "drugenddate": null, "drugenddateformat": null, "drugindication": "Ewing^s sarcoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": "48", "drugtreatmentdurationunit": "803", "medicinalproduct": "DOXORUBICIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "019557", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MILLIGRAM/SQ. METER, CYCLICAL", "drugenddate": null, "drugenddateformat": null, "drugindication": "Ewing^s sarcoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "009", "drugtreatmentduration": "5", "drugtreatmentdurationunit": "804", "medicinalproduct": "ETOPOSIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.5 MILLIGRAM/SQ. METER, CYCLICAL", "drugenddate": null, "drugenddateformat": null, "drugindication": "Ewing^s sarcoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.5", "drugstructuredosageunit": "009", "drugtreatmentduration": "48", "drugtreatmentdurationunit": "803", "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.2 GRAM PER SQUARE METRE, CYCLICAL", "drugenddate": null, "drugenddateformat": null, "drugindication": "Ewing^s sarcoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": "48", "drugtreatmentdurationunit": "803", "medicinalproduct": "CYCLOPHOSPHAMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "IFOSFAMIDE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.8 GRAM PER SQUARE METRE, CYCLICAL", "drugenddate": null, "drugenddateformat": null, "drugindication": "Ewing^s sarcoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": "5", "drugtreatmentdurationunit": "804", "medicinalproduct": "IFOSFAMIDE" } ], "patientagegroup": null, "patientonsetage": "11", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Ewing^s sarcoma", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Malignant transformation", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Marais YA, Saini AK, Ferreira N, Reddy K, Zuhlke A, Rossouw N, et al.. Adamantinoma-like Variant of Ewing Sarcoma in the Metatarsal Bone After Chemotherapy: Report of a Case Successfully Treated with Pedicled Osteocutaneous Fibular Transfer.. Int-J-Surg-Pathol. 2021;29(7):798-803", "literaturereference_normalized": "adamantinoma like variant of ewing sarcoma in the metatarsal bone after chemotherapy report of a case successfully treated with pedicled osteocutaneous fibular transfer", "qualification": "1", "reportercountry": "ZA" }, "primarysourcecountry": "ZA", "receiptdate": "20220309", "receivedate": "20220309", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20571078, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220423" } ]

{ "abstract": "BACKGROUND\nConversion from calcineurin inhibitor (CNI)-based to belatacept-based immunosuppression has become common; however, numerous protocols have emerged in lieu of a standardized protocol. The purpose of this study was to characterize belatacept conversion protocols from multiple centers and observe outcomes.\n\n\nMETHODS\nThis was a retrospective study that included Kaiser Permanente Southern California members. The primary outcome was rejection 6 months after conversion and secondary outcomes included change in serum creatinine and graft loss.\n\n\nRESULTS\nSeventy-eight patients were included. Thirteen distinct protocols were identified from 8 different transplant centers. Protocols varied by initial dose, induction schedule, and CNI taper. The observed rate of rejection was 6%. There was a trend toward an association of rejection with lower tacrolimus exposure at the time of conversion and lower mycophenolic acid dosing postconversion. Graft survival was 88% and patient survival was 94%. There was a significant improvement in creatinine after conversion. Those with early conversions and creatinine >2.0 mg/dL at the time of conversion had the best response.\n\n\nCONCLUSIONS\nA large variety of belatacept conversion protocols were identified. Protocols were defined by the initial dose, induction regimen, and CNI taper. Rejection rates were low and may be influenced by exposure to maintenance immunosuppression during and after conversion. Most patients showed stabilization and improvement in creatinine postconversion, with the largest effect in those with an early conversion and serum creatinine >2.0 mg/dL.", "affiliations": "Department of Internal Medicine, Kaiser Fontana Medical Center, Fontana, California.;Department of Nephrology, Kaiser Los Angeles Medical Center, Los Angeles, California. Electronic address: Joseph.m.kahwaji@kp.org.;Department of Nephrology, Kaiser Los Angeles Medical Center, Los Angeles, California.;Department of Nephrology, Kaiser Los Angeles Medical Center, Los Angeles, California.", "authors": "Yazdi|Mona|M|;Kahwaji|Joseph M|JM|;Meguerditchian|Sam|S|;Lee|Roland|R|", "chemical_list": "D007166:Immunosuppressive Agents; D000069594:Abatacept", "country": "United States", "delete": false, "doi": "10.1016/j.transproceed.2020.11.001", "fulltext": null, "fulltext_license": null, "issn_linking": "0041-1345", "issue": "53(3)", "journal": "Transplantation proceedings", "keywords": null, "medline_ta": "Transplant Proc", "mesh_terms": "D000069594:Abatacept; D000328:Adult; D057915:Drug Substitution; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies", "nlm_unique_id": "0243532", "other_id": null, "pages": "976-983", "pmc": null, "pmid": "33478745", "pubdate": "2021-04", "publication_types": "D016428:Journal Article", "references": null, "title": "Belatacept Conversion Protocols and Outcomes in Kidney Transplant Recipients.", "title_normalized": "belatacept conversion protocols and outcomes in kidney transplant recipients" }

[ { "companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-017660", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BELATACEPT" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "125288", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INFUSION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BELATACEPT" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Post transplant lymphoproliferative disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "YAZDI M, KAHWAJI J, MEGUERDITCHIAN S, LEE R. BELATACEPT CONVERSION PROTOCOLS AND OUTCOMES IN KIDNEY TRANSPLANT RECIPIENTS. TRANSPLANTATION PROCEEDINGS. 2021", "literaturereference_normalized": "belatacept conversion protocols and outcomes in kidney transplant recipients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210302", "receivedate": "20210302", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18958698, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210420" } ]

{ "abstract": "Non-meningococcal, non-gonococcal Neisseria spp. are typically commensal and rarely cause invasive disease. Eculizumab is a terminal complement inhibitor that increases susceptibility to meningococcal disease, but data on disease caused by typically-commensal Neisseria spp. are lacking. This series describes postmarketing reports of typically-commensal Neisseria spp. disease in patients receiving eculizumab.\n\n\n\nWe searched the FDA Adverse Event Reporting System (FAERS) and medical literature for reports of commensal Neisseria spp. disease in patients receiving eculizumab, from eculizumab U.S. approval (2007) through January 31, 2018.\n\n\n\nWe identified seven FAERS reports (including one case also reported in the literature) of non-meningococcal, non-gonococcal Neisseria disease, including N. sicca (mucosa)/subflava (n = 2), N. cinerea (n = 2), N. sicca (mucosa) (n = 1), N. mucosa (n = 1, with concurrent alpha-hemolytic Streptococcus bacteremia), and N. flavescens (subflava) (n = 1). Four cases had sources of patient immunosuppression in addition to eculizumab. Three patients had sepsis (n = 2) or septic shock (n = 1). Five patients were bacteremic. All patients were hospitalized; the infections resolved with antibiotics.\n\n\n\nOur search identified seven cases of disease from typically commensal Neisseria spp. in eculizumab recipients. These findings suggest that any Neisseria spp. identified from a normally sterile site in an eculizumab recipient could represent true infection warranting prompt treatment.", "affiliations": "Division of Pharmacovigilance, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA. Electronic address: page.crew@fda.hhs.gov.;Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA.;Division of Pharmacovigilance, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.;Division of Pharmacovigilance, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.;Division of Pharmacovigilance, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.;Division of Pharmacovigilance, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.", "authors": "Crew|Page E|PE|;McNamara|Lucy|L|;Waldron|Peter E|PE|;McCulley|Lynda|L|;Jones|S Christopher|SC|;Bersoff-Matcha|Susan J|SJ|", "chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C481642:eculizumab", "country": "England", "delete": false, "doi": "10.1016/j.jinf.2018.10.015", "fulltext": null, "fulltext_license": null, "issn_linking": "0163-4453", "issue": "78(2)", "journal": "The Journal of infection", "keywords": "Bacteremia; Eculizumab; Neisseria cinerea; Neisseria mucosa; Neisseria subflava; Nonpathogenic Neisseria", "medline_ta": "J Infect", "mesh_terms": "D000293:Adolescent; D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D016470:Bacteremia; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D008589:Meningococcal Infections; D009343:Neisseria; D013559:Symbiosis", "nlm_unique_id": "7908424", "other_id": null, "pages": "113-118", "pmc": null, "pmid": "30408494", "pubdate": "2019-02", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "19483662;22511000;29255100;24523465;24822118;28630122;4014264;24512095;25814039;28191300;16297736;29895518;23297179;30015608;19489710;29094316;29021487;10722463;23905778;28704351;3987202;21975499;3384913;25581812;26914632", "title": "Unusual Neisseria species as a cause of infection in patients taking eculizumab.", "title_normalized": "unusual neisseria species as a cause of infection in patients taking eculizumab" }

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null, "activesubstance": { "activesubstancename": "HUMAN IMMUNOGLOBULIN G" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMMUNOGLOBULIN /00025201/" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", 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MCNAMARA, L.? WALDRON, P.E.? MCCULLEY, L.? JONES, SC.? BERSOFF-MATCHA, S.J.. UNUSUAL NEISSERIA SPECIES AS A CAUSE OF INFECTION IN PATIENTS TAKING ECULIZUMAB. 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"actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": null, "patientonsetage": "38", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Peritonitis bacterial", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neisseria infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CREW PE, MCNAMARA L, WALDRON PE, MCCULLEY L, JONES SC, BERSOFF-MATCHA SJ. UNUSUAL NEISSERIA SPECIES AS A CAUSE OF INFECTION IN PATIENTS TAKING ECULIZUMAB. J-INFECT 2019?78(2):113-118.", "literaturereference_normalized": "unusual neisseria species as a cause of infection in patients taking eculizumab", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190328", "receivedate": "20190307", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16046768, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190418" }, { "companynumb": "US-ALEXION-A201814997", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ECULIZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "125166", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CONCENTRATE FOR SOLUTION FOR INFUSION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ATYPICAL HAEMOLYTIC URAEMIC SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SOLIRIS" } ], "patientagegroup": null, "patientonsetage": "4", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Nephroblastoma", "reactionmeddraversionpt": "23.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Febrile neutropenia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CREW, PE? MCNAMARA, L? WALDRON, PE? MCCULLEY, L? JONES, SC? BERSOFF-MATCHA, SJ. UNUSUAL NEISSERIA SPECIES AS A CAUSE OF INFECTION IN PATIENTS TAKING ECULIZUMAB. JOURNAL OF INFECTION. 2018", "literaturereference_normalized": "unusual neisseria species as a cause of infection in patients taking eculizumab", "qualification": "2", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200615", "receivedate": "20181121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15642139, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "US-ALEXION-A201814994", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "ECULIZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "125166", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CONCENTRATE FOR SOLUTION FOR INFUSION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PAROXYSMAL NOCTURNAL HAEMOGLOBINURIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SOLIRIS" } ], "patientagegroup": null, "patientonsetage": "17", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Abdominal pain", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Renal impairment", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Septic shock", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CREW, PE? MCNAMARA, L? WALDRON, PE? MCCULLEY, L? JONES, SC? BERSOFF-MATCHA, SJ. UNUSUAL NEISSERIA SPECIES AS A CAUSE OF INFECTION IN PATIENTS TAKING ECULIZUMAB. JOURNAL OF INFECTION. 2018", "literaturereference_normalized": "unusual neisseria species as a cause of infection in patients taking eculizumab", "qualification": "2", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200618", "receivedate": "20181120", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15635232, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "US-ALEXION PHARMACEUTICALS INC.-A201814995", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PENICILLIN G" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PENICILLIN /00000901/" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "ECULIZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "125166", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CONCENTRATE FOR SOLUTION FOR INFUSION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ATYPICAL HAEMOLYTIC URAEMIC SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SOLIRIS" } ], "patientagegroup": null, "patientonsetage": "38", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Arteriovenous fistula site complication", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Chills", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CREW, PE? MCNAMARA, L? WALDRON, PE? MCCULLEY, L? JONES, SC? BERSOFF-MATCHA, SJ. UNUSUAL NEISSERIA SPECIES AS A CAUSE OF INFECTION IN PATIENTS TAKING ECULIZUMAB. JOURNAL OF INFECTION. 2018", "literaturereference_normalized": "unusual neisseria species as a cause of infection in patients taking eculizumab", "qualification": "2", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20181120", "receivedate": "20181120", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15635483, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" } ]

{ "abstract": "The increasing cases of NSCLC and improved understanding of its molecular biology has lead to identification of its varied driver mutations. cMET amplification has an important role as resistance mechanism for EGFR TKIs. Crizotinib is a drug which shows its anti-tumoral effect in cMET positive cases. Here we present a case series of three such patients who achieved were cMET amplified and showed partial response on Crizotinib.", "affiliations": "Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India.;Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India.;Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India.;Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India.;Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India.", "authors": "Batra|U|U|;Jain|A|A|;Sharma|M|M|;Bajaj|R|R|;Suryavanshis|M|M|", "chemical_list": "D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met", "country": "India", "delete": false, "doi": "10.4103/0019-509X.219592", "fulltext": null, "fulltext_license": null, "issn_linking": "0019-509X", "issue": "54(1)", "journal": "Indian journal of cancer", "keywords": null, "medline_ta": "Indian J Cancer", "mesh_terms": "D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors; D019859:Proto-Oncogene Proteins c-met; D011720:Pyrazoles; D011725:Pyridines", "nlm_unique_id": "0112040", "other_id": null, "pages": "178-181", "pmc": null, "pmid": "29199685", "pubdate": "2017", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Role of crizotinib in c-mesenchymal-epidermal transition-positive nonsmall cell lung cancer patients.", "title_normalized": "role of crizotinib in c mesenchymal epidermal transition positive nonsmall cell lung cancer patients" }

[ { "companynumb": "IN-CIPLA (EU) LIMITED-2018IN00173", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "077383", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, 3 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-SMALL CELL LUNG CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PEMETREXED" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, 3 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-SMALL CELL LUNG CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PEMETREXED." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, 3 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-SMALL CELL LUNG CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BATRA U, JAIN A, SHARMA M, BAJAJ R, SURYAVANSHIS M. ROLE OF CRIZOTINIB IN C-MESENCHYMAL-EPIDERMAL TRANSITION-POSITIVE NONSMALL CELL LUNG CANCER PATIENTS. INDIAN JOURNAL OF CANCER. 2017?54:178 TO 181", "literaturereference_normalized": "role of crizotinib in c mesenchymal epidermal transition positive nonsmall cell lung cancer patients", "qualification": "3", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20180111", "receivedate": "20180111", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14374484, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" } ]

{ "abstract": "Fertility preservation enables patients undergoing gonadotoxic therapies to retain the potential for biological children and now has broader implications in the care of transgender individuals. Multiple medical societies recommend counseling on fertility preservation before initiating therapy for gender dysphoria; however, outcome data pre- and posttreatment are limited in feminizing transgender adolescents and young adults.\n\n\n\nThe University of Pittsburgh Institutional Research Board approved this study. Data were collected retrospectively on transgender patients seeking fertility preservation between 2015 and 2018, including age at initial consultation and semen analysis parameters.\n\n\n\nEleven feminizing transgender patients accepted a referral for fertility preservation during this time; consultation occurred at median age 19 (range 16-24 years). Ten patients attempted and completed at least 1 semen collection. Eight patients cryopreserved semen before initiating treatment. Of those patients, all exhibited low morphology with otherwise normal median semen analysis parameters. In 1 patient who discontinued leuprolide acetate to attempt fertility preservation, transient azoospermia of 5 months' duration was demonstrated with subsequent recovery of spermatogenesis. In a patient who had previously been treated with spironolactone and estradiol, semen analysis revealed persistent azoospermia for the 4 months leading up to orchiectomy after discontinuation of both medications.\n\n\n\nSemen cryopreservation is a viable method of fertility preservation in adolescent and young adult transgender individuals and can be considered in patients who have already initiated therapy for gender dysphoria. Further research is needed to determine the optimal length of time these therapies should be discontinued to facilitate successful semen cryopreservation.", "affiliations": "UPMC Magee-Womens Hospital, Pittsburgh, Pennsylvania.;UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; and.;UPMC Magee-Womens Hospital, Pittsburgh, Pennsylvania.;UPMC Magee-Womens Hospital, Pittsburgh, Pennsylvania.;UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; and.;UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; and.;Magee-Womens Research Institute and Foundation, Pittsburgh, Pennsylvania.;Magee-Womens Research Institute and Foundation, Pittsburgh, Pennsylvania vallih2@mwri.magee.edu.", "authors": "Barnard|Emily P|EP|;Dhar|Cherie Priya|CP|;Rothenberg|Stephanie S|SS|;Menke|Marie N|MN|;Witchel|Selma F|SF|;Montano|Gerald T|GT|;Orwig|Kyle E|KE|;Valli-Pulaski|Hanna|H|", "chemical_list": "D004967:Estrogens; D013148:Spironolactone; D007987:Gonadotropin-Releasing Hormone; D004958:Estradiol", "country": "United States", "delete": false, "doi": "10.1542/peds.2018-3943", "fulltext": null, "fulltext_license": null, "issn_linking": "0031-4005", "issue": "144(3)", "journal": "Pediatrics", "keywords": null, "medline_ta": "Pediatrics", "mesh_terms": "D000293:Adolescent; D003376:Counseling; D015925:Cryopreservation; D004958:Estradiol; D004967:Estrogens; D005260:Female; D059247:Fertility Preservation; D000068116:Gender Dysphoria; D007987:Gonadotropin-Releasing Hormone; D006801:Humans; D008297:Male; D012189:Retrospective Studies; D012661:Semen; D013148:Spironolactone; D055815:Young Adult", "nlm_unique_id": "0376422", "other_id": null, "pages": null, "pmc": null, "pmid": "31383814", "pubdate": "2019-09", "publication_types": "D016428:Journal Article", "references": null, "title": "Fertility Preservation Outcomes in Adolescent and Young Adult Feminizing Transgender Patients.", "title_normalized": "fertility preservation outcomes in adolescent and young adult feminizing transgender patients" }

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FERTILITY PRESERVATION OUTCOMES IN ADOLESCENT AND YOUNG ADULT FEMINIZING TRANSGENDER PATIENTS. PEDIATRICS. 2019?144(3)", "literaturereference_normalized": "fertility preservation outcomes in adolescent and young adult feminizing transgender patients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20191210", "receivedate": "20191210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17136118, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200122" }, { "companynumb": "US-TEVA-2020-US-1182848", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ESTRADIOL" }, "drugadditional": null, "drugadministrationroute": "062", "drugauthorizationnumb": "40197", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TRANSDERMAL PATCH", "drugdosagetext": "TRANSDERMAL ESTRADIOL PATCH WEEKLY, WHICH DELIVERED 75MCG DAILY.", "drugenddate": null, "drugenddateformat": null, "drugindication": "GENDER DYSPHORIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESTRADIOL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "SPIRONOLACTONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "GENDER DYSPHORIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SPIRONOLACTONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Azoospermia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BARNARD EP, DHAR CP, ROTHENBERG SS, MENKE MN, WITCHEL SF, MONTANO GT, ET AL. FERTILITY PRESERVATION OUTCOMES IN ADOLESCENT AND YOUNG ADULT FEMINIZING TRANSGENDER PATIENTS. PEDIATRICS 2019?144:NO. 3.", "literaturereference_normalized": "fertility preservation outcomes in adolescent and young adult feminizing transgender patients", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200211", "receivedate": "20200211", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17403761, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" } ]

{ "abstract": "Approximately 30% of patients with type 2 diabetes mellitus have knee osteoarthritis. IA corticosteroids used to manage osteoarthritis pain can elevate blood glucose in these patients. We compared blood glucose levels following intra-articular injection of triamcinolone acetonide extended-release (TA-ER), an extended-release, microsphere-based triamcinolone acetonide formulation, vs standard triamcinolone acetonide crystalline suspension (TAcs) in patients with knee osteoarthritis and comorbid type 2 diabetes.\n\n\n\nIn this double-blind, randomized, parallel-group, phase 2 study (NCT02762370), 33 patients with knee osteoarthritis (American College of Rheumatology criteria) and type 2 diabetes mellitus (HbA1c 6.5-9.0% [48-75 mmol/mol]; 1-2 oral hypoglycaemic agents) were treated with intra-articular TA-ER (32 mg n = 18) or TAcs 40 mg (n = 15). Continuous glucose monitoring-measured glucose (CGMG) was assessed from 1 week pre-injection through 2 weeks postinjection. Endpoints included change in average daily CGMG from baseline (days -3 to -1) to days 1-3 postinjection (CGMGdays1-3) (primary) and percent time average hourly CGMG levels remained in prespecified glycaemic ranges.\n\n\n\nThe change CGMGdays1-3 was significantly lower following TA-ER vs TAcs (14.7 vs 33.9 mg/dl, least-squares-mean-difference [95% CI]: -19.2 [-38.0, -0.4]; P = 0.0452). The percentage of time over days 1-3 that CGMG was in the target glycaemic range (70-180 mg/dl) was numerically greater for TA-ER (63.3%) vs TAcs (49.7%), and that CGMG was >180 mg/dl was lower for TA-ER (34.5%) vs TAcs (49.9%). Non-glycaemic adverse events were mild and comparable between groups.\n\n\n\nTA-ER may enable intra-articular corticosteroid treatment with minimal blood glucose disruption in patients with knee osteoarthritis and type 2 diabetes mellitus.\n\n\n\nClinicalTrials.gov, https://clinicaltrials.gov, NCT02762370.", "affiliations": "Department of Medicine, Massachusetts General Hospital Diabetes Research Center, Boston, MA, USA.;Dexcom, Inc., Sykesville, MD, USA.;Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds and NIHR Leeds Biomedical Research Centre, Leeds, UK.;Rheumatology Unit, Laniado Hospital, Kiryat Sanz, Netanya, Israel.;Dream Team Clinical Research, Anaheim, CA.;PMG Research of Knoxville, Knoxville, TN.;Altoona Center for Clinical Research, Duncansville, PA.;Coastal Carolina Research Center, Mt. Pleasant, SC.;Flexion Therapeutics, Inc. Burlington, MA, USA.;Summit Analytical, LLC., Denver, CO, USA.;Flexion Therapeutics, Inc. Burlington, MA, USA.;Flexion Therapeutics, Inc. Burlington, MA, USA.", "authors": "Russell|Steven J|SJ|;Sala|Robert|R|;Conaghan|Philip G|PG|;Habib|George|G|;Vo|Quang|Q|;Manning|Rickey|R|;Kivitz|Alan|A|;Davis|Yvonne|Y|;Lufkin|Joelle|J|;Johnson|James R|JR|;Kelley|Scott|S|;Bodick|Neil|N|", "chemical_list": "D000305:Adrenal Cortex Hormones; D001786:Blood Glucose; D003692:Delayed-Action Preparations; D014222:Triamcinolone Acetonide", "country": "England", "delete": false, "doi": "10.1093/rheumatology/key265", "fulltext": "\n==== Front\nRheumatology (Oxford)Rheumatology (Oxford)brheumRheumatology (Oxford, England)1462-03241462-0332Oxford University Press 10.1093/rheumatology/key265key265Basic and Translational ScienceTriamcinolone acetonide extended-release in patients with osteoarthritis and type 2 diabetes: a randomized, phase 2 study Russell Steven J 1Sala Robert 2Conaghan Philip G 3Habib George 4Vo Quang 5Manning Rickey 6Kivitz Alan 7Davis Yvonne 8Lufkin Joelle 9Johnson James R 10Kelley Scott 9Bodick Neil 91 Department of Medicine, Massachusetts General Hospital Diabetes Research Center, Boston, MA, USA2 Dexcom, Inc., Sykesville, MD, USA3 Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds and NIHR Leeds Biomedical Research Centre, Leeds, UK4 Rheumatology Unit, Laniado Hospital, Kiryat Sanz, Netanya, Israel5 Dream Team Clinical Research, Anaheim, CA6 PMG Research of Knoxville, Knoxville, TN7 Altoona Center for Clinical Research, Duncansville, PA8 Coastal Carolina Research Center, Mt. Pleasant, SC9 Flexion Therapeutics, Inc. Burlington, MA, USA10 Summit Analytical, LLC., Denver, CO, USACorrespondence to: Steven J. Russell, Massachusetts General Hospital Diabetes Research Center, 50 Staniford Street, Suite 340, Boston, MA 02114, USA. E-mail: sjrussell@mgh.harvard.edu12 2018 06 9 2018 06 9 2018 57 12 2235 2241 8 3 2018 8 7 2018 © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology.2018This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nObjective\nApproximately 30% of patients with type 2 diabetes mellitus have knee osteoarthritis. IA corticosteroids used to manage osteoarthritis pain can elevate blood glucose in these patients. We compared blood glucose levels following intra-articular injection of triamcinolone acetonide extended-release (TA-ER), an extended-release, microsphere-based triamcinolone acetonide formulation, vs standard triamcinolone acetonide crystalline suspension (TAcs) in patients with knee osteoarthritis and comorbid type 2 diabetes.\n\nMethods\nIn this double-blind, randomized, parallel-group, phase 2 study (NCT02762370), 33 patients with knee osteoarthritis (American College of Rheumatology criteria) and type 2 diabetes mellitus (HbA1c 6.5–9.0% [48–75 mmol/mol]; 1–2 oral hypoglycaemic agents) were treated with intra-articular TA-ER (32 mg n = 18) or TAcs 40 mg (n = 15). Continuous glucose monitoring-measured glucose (CGMG) was assessed from 1 week pre-injection through 2 weeks postinjection. Endpoints included change in average daily CGMG from baseline (days −3 to −1) to days 1–3 postinjection (CGMGdays1–3) (primary) and percent time average hourly CGMG levels remained in prespecified glycaemic ranges.\n\nResults\nThe change CGMGdays1–3 was significantly lower following TA-ER vs TAcs (14.7 vs 33.9 mg/dl, least-squares-mean-difference [95% CI]: −19.2 [−38.0, −0.4]; P = 0.0452). The percentage of time over days 1–3 that CGMG was in the target glycaemic range (70–180 mg/dl) was numerically greater for TA-ER (63.3%) vs TAcs (49.7%), and that CGMG was >180 mg/dl was lower for TA-ER (34.5%) vs TAcs (49.9%). Non-glycaemic adverse events were mild and comparable between groups.\n\nConclusion\nTA-ER may enable intra-articular corticosteroid treatment with minimal blood glucose disruption in patients with knee osteoarthritis and type 2 diabetes mellitus.\n\nTrial registration\nClinicalTrials.gov, https://clinicaltrials.gov, NCT02762370.\n\nknee osteoarthritiscorticosteroidstreatmentFlexion Therapeutics, Inc\n==== Body\nRheumatology key messages\nIntra-articular CS injection can elevate blood glucose in patients with OA and type 2 diabetes.\n\nGlucose levels were more stable in patients with OA and type 2 diabetes treated with extended-release versus standard triamcinolone acetonide.\n\nPatients with OA and type 2 diabetes had minimal glycaemic control disruption following triamcinolone acetonide extended-release injection.\n\n\n\n\nIntroduction\nApproximately 30% of patients with type 2 diabetes mellitus have osteoarthritis of the knee, a painful condition and a leading cause of disability in the United States [1–3]. Limitation of mobility in diabetic patients with osteoarthritis is a risk factor for diabetes-related complications including hyperglycaemia [4].\n\nIA corticosteroids are commonly used to treat osteoarthritic pain [5]. However, rapid and substantial efflux of corticosteroids from the joint begins within hours of IA injection of standard crystalline formulations [6], limiting the magnitude and persistence of pain reduction and potentially causing systemic effects [7]. Blood glucose (BG) elevation has been observed in diabetic patients following IA delivery of traditional corticosteroids [8–11]. In one study, ∼23% of patients receiving IA triamcinolone acetonide crystalline suspension (TAcs) to treat knee osteoarthritis had significant increases in BG levels, peaking at 24–32 h postinjection, that did not return to normal until 2.5–4 days postinjection [10]. As such, potential loss of BG control poses an important clinical challenge for patients with type 2 diabetes mellitus also receiving IA corticosteroids to treat knee osteoarthritis.\n\nTriamcinolone acetonide extended-release (TA-ER, formerly FX006) is a novel, microsphere-based formulation of triamcinolone acetonide. In phase 2b and 3 clinical trials, IA administration of TA-ER 32 mg produced clinically meaningful pain relief and functional improvement relative to saline-placebo and standard TAcs 40 mg in patients with knee osteoarthritis [12, 13]. Pharmacokinetic evaluations demonstrated that a single IA injection of TA-ER 32 mg was associated with prolonged joint residency, diminished peak plasma levels and reduced systemic exposure of triamcinolone acetonide compared with TAcs 40 mg [14]. We hypothesized that BG levels in diabetic patients would be less impacted by TA-ER than TAcs. The current study was conducted to compare BG levels over time in patients with knee osteoarthritis and type 2 diabetes mellitus following a single IA injection of TA-ER 32 mg vs TAcs 40 mg.\n\nMethods\nStudy design and participants\nThis phase 2, double-blind, randomized, parallel-group, single-dose, multicentre study (ClinicalTrials.govidentifier: NCT02762370) was conducted per Declaration of Helsinki and International Conference on Harmonisation Good Clinical Practice guidelines. A central institutional review board (Schulman Central IRB, Cincinnati, OH, USA) approved the protocol (IRB No. 201601317). All patients provided written informed consent.\n\nEligible participants were aged ⩾40 years, with symptomatic osteoarthritis of the knee ⩾6 months meeting American College of Rheumatology clinical and radiographic criteria [15] at screening and with type 2 diabetes mellitus ⩾1 year prior to screening not managed by injectable agents. Participants were receiving treatment with 1–2 oral hypoglycaemic agents (stable doses ⩾2 months) and had haemoglobin-A1c (HbA1c) levels between 6.5–9.0% (48–75 mmol/mol). Only patients with adequate screening continuous glucose monitoring-measured glucose (CGMG) data, i.e. ≥ 1 full day of data with no gaps >3 h and with confirmation of two calibrations performed within that 24-h period, were eligible for study participation. Additional eligibility criteria and CGMG collection methods are provided in the supplementary data, section Methods, available at Rheumatology online.\n\nStudy medication\nPatients were randomized to receive IA administration of TA-ER 32 mg (5 ml) or TAcs 40 mg (Kenalog-40; Bristol-Myers Squibb Company, Princeton, NJ, USA; 1 ml). TA-ER and TAcs were not identical in appearance at the time of administration. For that reason, treatments were prepared and administered by designated unblinded site personnel who had no other contact with participants or study personnel, and the injection syringe was concealed from study participants. The individual responsible for clinical assessments and safety monitoring was blind to treatment. For additional details see supplementary data, section Study Medication, available at Rheumatology online.\n\nBlood glucose monitoring\nIn this study, BG was assessed with the Dexcom G4 Platinum Professional CGM, which employs the same technology as the Dexcom G4 Platinum and has been shown to be highly accurate with an average error of ∼11% [16]. The CGM device, which has the advantage of capturing a comprehensive representation of glucose variability over the entire day and night, was calibrated with the Bayer Contour NEXT glucose-measuring metre, one of the most accurate glucose metres available, with an average error of ∼6% [17].\n\nProcedures\nFollowing screening (days −21 to −7), CGMG data were collected, as described above, from pre-treatment (days −7 to −1) through 2 weeks postinjection (days 1–15). Follow-up visits were scheduled for day 8, day 15 and week 6 post-IA injection. Safety evaluations, including a final safety visit, were scheduled for 6 weeks postinjection. For additional details see supplementary data, section Additional procedures, available at Rheumatology online.\n\nOutcomes\nThe primary outcome was the change in average daily CGMG from baseline (days −3 to −1) to days 1–3 following IA injection of TA-ER vs TAcs. Secondary outcomes included percentage of time average hourly CGMG levels were in or above the target glycaemic range (70–180 mg/dl) [18] during days 1–3 and during days 1–15; area under the effect (AUE) curves for average CGMG and glycaemic variability (coefficient of variation over hours 1–24, days 1–2, days 1–3 and days 1–7 following administration of TA-ER vs TAcs.) For additional details see supplementary data, section Exploratory outcomes, available at Rheumatology online.\n\nSafety outcomes were summarized for the Safety Population (i.e. participants who provided informed consent and received study medication). Analyses of AEs were performed for events considered treatment-emergent (i.e. with onset after the administration of study treatment) or which were present at baseline but worsened in intensity during the study.\n\nStatistical analyses\nApproximately 36 participants were to be randomized/treated to ensure ⩾30 evaluable people (15/treatment group). This sample size provided 72.8% power to reject the null hypothesis of equal means with a population mean difference of 28.0 mg/dl in CGMG change from baseline (days −3 to −1) to days 1–3, with a common SD of 30, at an alpha level of 0.05 for a two-sample t test. For additional details see supplementary data, sections Prespecified interim analysis and Statistical analyses, available at Rheumatology online.\n\nResults\nPatient disposition and baseline characteristics\nBetween 8 April and 30 September 2016, 98 people were screened and 33 were enroled/randomized (TA-ER, n = 17; TAcs, n = 16; Fig. 1). Three participants were randomized correctly but received the incorrect treatment, resulting in 18 TA-ER-treated and 15 TAcs-treated participants. Thirty-two (97.0%) of 33 patients completed the study through week 6 (final safety follow-up visit completed on 11 November 2016). One person in the TA-ER group did not return at week 6 but completed the study through day 15. All participants were analysed as treated for planned and post hoc analyses (Fig. 1).\n\n\nFig. 1 Trial profile\n\n\na3 patients were randomized correctly, but received the incorrect treatment. b1 patient was not willing to return for the final week 6 visit, but did complete the study through day 15. TAcs: triamcinolone acetonide crystalline suspension; TA-ER: triamcinolone acetonide extended-release injectable suspension.\n\nParticipants had a mean (range) age of 61 (46–83) years; the mean times since osteoarthritis and type 2 diabetes mellitus diagnoses were 9.2 and 8.6 years, respectively; and 72.7% of participants were obese (body mass index 30.0–39.9 kg/m2). Baseline average BG categories were not balanced across treatment groups due to incorrect treatment assignment for three patients. More patients treated with TA-ER (n = 5) than TAcs (n = 1) had baseline BG in the 157–177 mg/dl category. Many participants had received prior osteoarthritis treatment; 30.3% had received IA corticosteroids in the index knee at any time prior to screening (Supplementary Table S1, available at Rheumatology online).\n\nCGMG levels\nChange in average daily CGMG from baseline to days 1–3 was significantly lower postinjection of TA-ER than TAcs (14.7 vs 33.9; LSM [95% CI] difference of −19.2 mg/dl [−38.0, −0.4]; P = 0.0452). Mean average daily CGMG increased from baseline (days −3 to −1) to days 1−3 by 8.2 mg/dl in TA-ER (155.2–163.4 mg/dl) and by 37.1 mg/dl in TAcs (161.7–198.8 mg/dl) patients (Figs 2 and 3A). For additional details see supplementary data, section Completeness of CGMG data collection, and Supplementary Tables S2 and S3, available at Rheumatology online.\n\n\nFig. 2 Mean average hourly CGMG levels (FAS; n = 33)\n\nCGMG: continuous glucose monitoring-measured glucose; FAS: full analysis set; LSM: least squares mean; SE: standard error; TAcs: triamcinolone acetonide crystalline suspension; TA-ER: triamcinolone acetonide extended-release.\n\nFig. 3 Changes in blood glucose profile for days 1–3 with TA-ER vs TAcs\n\n(A) Mean change from baseline to days 1–3 for the average CGMG. (B) Percentage of time in target glycaemic range for hourly the average CGMG during days 1–3 (FAS; N = 33). CGMG: continuous glucose monitoring-measured glucose; FAS: full analysis set; LSM: least squares mean; SE: standard error; TAcs: triamcinolone acetonide crystalline suspension; TA-ER: triamcinolone acetonide extended-release.\n\nThe percentage of time that average hourly CGMG levels were in the target glycaemic range (70–180 mg/dl) during days 1–3 was numerically greater after TA-ER than TAcs (63.3 vs 49.7%), and the percentage of time that hourly CGMG levels were above the target range (>180 mg/dl) was numerically less following TA-ER than TAcs (34.5 vs 49.9%; Fig. 3B). Post hoc analyses indicated that the within-group CGMG increase was statistically significant in TAcs-treated, but not in TA-ER-treated, participants (P = 0.0354 and P = 0.6665, respectively). For additional details see supplementary data, section CGMG levels and Supplementary Figs S1 and S2, available at Rheumatology online.\n\nSafety and tolerability\nAEs were reported by 11.1% (2/18) and 13.3% (2/15) of TA-ER- and TAcs-treated participants, respectively (Table 1). All AEs were Grade 1 or 2 (Table 1). No TA-ER-treated person experienced an index-knee-related or injection-related AE, whereas one TAcs-treated person had Grade 1 ecchymosis at the index-knee injection site. One TA-ER-treated patient had an exacerbation of pre-existing hyperglycaemia reported as an AE; no other clinical laboratory AEs were reported.\nTable 1 Summary of adverse events through week 6\n\n\tTreatment group\t\nTA-ER 32 mg n = 18\tTAcs 40 mg n = 15\t\nPatients with ≥1 AE\t2 (11.1)\t2 (13.3)\t\n    Grade 1\t0\t2 (13.3)\t\n    Grade 2\t2 (11.1)\t0\t\n    Not related\t1 (5.6)\t1 (6.7)\t\n    Probably related\t0\t1 (6.7)\t\n    Definitely related\t1 (5.6)a\t0\t\nPatients with ≥1 SAE\t0\t0\t\nPatients discontinuing from study due to an AE\t0\t0\t\nPatients with ≥1 index-knee AE\t0\t1 (6.7)b\t\nPatients with ≥1 AE related to injection procedure\t0\t1 (6.7)b\t\nData presented are n (%).\n\na Grade 2 hyperglycaemia assessed by the investigator as related to study drug.\n\nb Grade 1 ecchymosis at the injection site assessed by the investigator to be probably related to study agent injection.\n\nAE: adverse event; SAE: serious adverse event; TAcs: triamcinolone acetonide crystalline suspension; TA-ER: triamcinolone acetonide extended-release.\n\n\n\nDiscussion\nIn this randomized, double-blind, parallel group study in people with osteoarthritis of the knee and type 2 diabetes mellitus, treatment with TA-ER 32 mg (a dose that demonstrated improved pain relief and improved function relative to TAcs 40 mg in previous clinical trials) [12, 13] resulted in a statistically significant reduction in CGMG relative to TAcs 40 mg over days 1–3 following IA injection. In addition, the within-group CGMG increase after IA injection was statistically significant in TAcs-treated, but not in TA-ER-treated, participants, suggesting that TA-ER did not significantly disrupt the glycaemic control of participants with type 2 diabetes mellitus. The perturbation of glucose control produced by TAcs appeared to be maximal during the first 2 days postinjection, an effect consistent with prior literature [9].\n\nThe average daily and average hourly CGMG levels during days 1–3 following TA-ER injection were well within the target glycaemic range of 70–180 mg/dl recommended by the American Diabetes Association [18]. Conversely, participants who received TAcs had average daily and average hourly CGMG levels above that range, often exceeding 200 mg/dl (Figs 2 and 3).\n\nThese observations are consistent with the pharmacokinetic profiles for TAcs and TA-ER generated in a recent phase 2 open-label study in 63 patients with knee osteoarthritis. In this study, peak plasma exposure in the days following a single IA injection was 966.7 pg/ml for TA-ER (32 mg) and 11, 064.7 pg/ml for TAcs (40 mg) [14]. In the earlier study, peak plasma TA concentrations were observed by 4 h postinjection among the 18 people who received IA TAcs. Conversely, IA TA-ER gradually increased plasma triamcinolone acetonide concentrations, which did not peak until 24 h postinjection; at this time point, plasma triamcinolone acetonide levels associated with TA-ER were ∼80% lower than those associated with TAcs [14]. These pharmacokinetic data are consistent with a slow release of triamcinolone acetonide from TA-ER, whereby only triamcinolone acetonide crystals near the surface of the poly (lactic-co-glycolic acid) (PLGA) microsphere dissolve initially, resulting in a low absorption into the systemic circulation following IA injection (Data on File, Flexion Therapeutics). Furthermore, the same study showed that IA triamcinolone acetonide concentrations at 6 weeks postinjection were notably higher following TA-ER (3, 590.0 pg/ml) than TAcs (7.7 pg/ml) [14]. The systemic and IA pharmacokinetic profiles of TA-ER are consistent with slow release of triamcinolone acetonide from the PLGA matrix in the joint, and the resulting slow efflux of triamcinolone acetonide from the joint, an effect that limits peak systemic levels.\n\nIn the current study, both TA-ER and TAcs were similarly well tolerated, with no SAEs reported. These findings are consistent with previous reports from phase 2 and 3 studies in people with knee osteoarthritis, which showed similar AE profiles for TA-ER 32 mg, TAcs 40 mg and saline-placebo [12, 13, 19].\n\nThis study has limitations in sample size, the diabetic population studied and the treatment comparisons. The sample size of 33 patients for this phase 2 pharmacodynamic study provided sufficient power to demonstrate statistically significant differences for the primary and some secondary outcomes. The study also assessed the responses to IA injection only in people with type 2 diabetes mellitus not managed by injectables, receiving 1–2 oral agents and with HbA1c levels between 6.5–9.0% (48–75 mmol/mol). The applicability of these findings to diabetic patients not meeting these criteria is unknown. An imbalance in treatment assignment is noted in patients with BG of >157.33 to <177.43, which is attributable to the incorrect treatment assignment at the time of randomization in three patients. All patients were analysed as treated. All other baseline characteristics were well-balanced. The two IA treatments used different injection volumes based upon product preparation: TA-ER is reconstituted and injected as 5 ml, while TAcs is injected as 1 ml. However, the syringe was concealed from the patient during the injection and a blinded-assessor technique was employed to minimize the potential for bias while allowing comparison of TA-ER and TAcs delivered in their respective recommended volumes.\n\nIn conclusion, TA-ER resulted in statistically significant and clinically relevant mitigation of CGMG elevation, with more time in target range, compared with TAcs over the first several days postinjection. These findings support previously identified disruption of glycaemic control with TAcs in diabetic patients; this is the first study to show negligible effects on CGMG after an IA corticosteroid (TA-ER) injection. The results are consistent with the relatively low systemic exposure to TA afforded by the extended-release formulation TA-ER, and suggest that TA-ER may be administered with minimal disruption of glycaemic control in people with knee osteoarthritis and type 2 diabetes mellitus.\n\nSupplementary Material\nSupplementary Data Click here for additional data file.\n\n Acknowledgements\nThe authors thank the patients who participated in this trial and their enroling investigators. Some of the information in this paper was presented in abstract form at the 77th Scientific Sessions of the American Diabetes Association, and this abstract was published in the journal Diabetes [20]. The authors also thank Karen Ozer, Teresa Curto, and Ashish Aggarwal of Cytel, Inc., Waltham, MA, USA for statistical analyses. Professional medical writing and editing assistance was provided by Michelle Perate, MS, and assistance with graphics was provided by ApotheCom (Yardley, PA, USA); this support was funded by Flexion Therapeutics, Inc. (Burlington, MA, USA). P.G.C. is supported in part by the National Institute for Health Research (NIHR) Leeds Biomedical Research Centre, Leeds, UK. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. S.J.R., R.S., J.L., J.R.J. and N.B. contributed to trial conception and design; R.S., Q.V., R.M., A.K., Y.D., J.L. and N.B. contributed to data acquisition; and S.J.R., R.S., P.G.C., G.H., Q.V., R.M., A.K., Y.D., J.R.J., S.K. and N.B. interpreted the data. All authors were involved in drafting the article or revising it critically for important intellectual content; provided final approval of the version to be submitted/published; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.\n\n\nFunding: This work was supported by Flexion Therapeutics, Inc.\n\n\nDisclosure statement: S.J.R. has served on advisory panels for Companion Medical, Tandem Diabetes Care, Inc., and Unomedical A/S, as a consultant for Beta Bionics and Flexion Therapeutics, Inc., has received either financial or in-kind research support from Abbott Diabetes Care Inc., Dexcom, Inc., Eli Lilly and Company, Senseonics, SweetSpot Diabetes, Tandem Diabetes Care, Inc. and Zealand Pharma A/S, owns stock/shares in Companion Medical and has received honoraria for lectures from Ascensia Diabetes Care, Dexcom, Inc., Eli Lilly and Company, Novo Nordisk, Roche Diabetes Care, Sanofi-Aventis, and Tandem Diabetes Care, Inc. R.S. is employed by Dexcom, Inc. P.G.C. has received compensation for consultancies from AbbVie, Flexion Therapeutics, Inc., Infirst, Medivir, Merck Serono and ONO Pharmaceutical Co. Q.V. has received research support from BioDelivery Science International, GlaxoSmithKline, Oramed Pharmaceuticals, Inc. and Sanofi. R.M. has received research support from Novo Nordisk, Inc. and Sanofi. J.L., S.K. and N.B. are employed by, and/or own stock in, Flexion Therapeutics Inc., Burlington, MA, USA. J.R.J. was employed by Flexion Therapeutics, Inc. at the time of data analysis, is currently employed by Summit Analytical, LLC and has received personal fees for statistical and pharmacokinetic support from Acura Pharmaceuticals, Flexion Therapeutics, Inc., Iroko Pharmaceuticals, IX Biopharma, GNC and Tolmar, Inc. All other authors have declared no conflicts of interest.\n==== Refs\nReferences\n1 \nRobinson WH , Lepus CM , Wang Q \net al\nLow-grade inflammation as a key mediator of the pathogenesis of osteoarthritis . Nat Rev Rheumatol 2016 ;12 :580 –92 .27539668 \n2 \nAbate M , Schiavone C , Salini V , Andia I. \nManagement of limited joint mobility in diabetic patients . Diabetes Metab Syndr Obes 2013 ;6 :197 –207 .23690694 \n3 \nLouati K , Vidal C , Berenbaum F , Sellam J. \nAssociation between diabetes mellitus and osteoarthritis: systematic literature review and meta-analysis . RMD Open 2015 ;1 :e000077 .26535137 \n4 \nHawker GA , Croxford R , Bierman AS \net al\nOsteoarthritis-related difficulty walking and risk for diabetes complications. Osteoarthritis \nCartilage \n2017 ;25 :67 –75 .\n5 \nDouglas RJ. \nCorticosteroid injection into the osteoarthritic knee: drug selection, dose, and injection frequency . Int J Clin Pract 2012 ;66 :699 –704 .22698422 \n6 \nDerendorf H , Möllmann H , Grüner A , Haack D , Gyselby G. \nPharmacokinetics and pharmacodynamics of glucocorticoid suspensions after intra-articular administration . Clin Pharmacol Ther 1986 ;39 :313 –7 .3948470 \n7 \nZhang W , Moskowitz RW , Nuki G \net al\nOARSI recommendations for the management of hip and knee osteoarthritis, part II: oARSI evidence-based, expert consensus guidelines . Osteoarthritis Cartilage 2008 ;16 :137 –62 .18279766 \n8 \nHabib GS. \nSystemic effects of intra-articular corticosteroids . Clin Rheumatol 2009 ;28 :749 –56 .19252817 \n9 \nHabib G , Bashir M , Jabbour A. \nIncreased blood glucose levels following intra-articular injection of methylprednisolone acetate in patients with controlled diabetes and symptomatic osteoarthritis of the knee . Ann Rheum Dis 2008 ;67 :1790 –1 .19005159 \n10 \nHabib GS , Miari W. \nThe effect of intra-articular triamcinolone preparations on blood glucose levels in diabetic patients: a controlled study . J Clin Rheumatol 2011 ;17 :302 –5 .21869712 \n11 \nHabib G , Khazin F , Chernin M. \nContinuous blood glucose monitoring in a patient with type 2 diabetes who underwent intraarticular betamethasone injection for knee osteoarthritis . Arthritis Rheumatol 2014 ;66 :230 .24449590 \n12 \nConaghan PG , Cohen S , Berenbaum F \net al\nBrief report: a phase IIb trial of a novel extended-release microsphere formulation of triamcinolone acetonide for intraarticular injection in knee osteoarthritis . Arthritis Rheumatol 2018 ;70 :204 –11 .29088579 \n13 \nConaghan PG , Hunter DJ , Cohen SB \net al\nEffects of a single intra-articular injection of a microsphere formulation of triamcinolone acetonide on knee osteoarthritis pain: a double-blinded, randomized, placebo-controlled, multinational study . J Bone Joint Surg Am 2018 ;100 :666 –77 .29664853 \n14 \nKraus VB , Aazami HA , Mehra P \net al\nSynovial and systemic pharmacokinetics (PK) of triamcinolone acetonide (TA) following intra-articular (IA) injection of an extended-release microsphere-based formulation (FX006) or standard crystalline suspension in patients with knee osteoarthritis (OA) . Osteoarthritis Cartilage 2018 ;26 :34 –42 .29024802 \n15 \nAltman R , Asch E , Bloch D \net al\nDevelopment of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association . Arthritis Rheumatol 1986 ;29 :1039 –49 .\n16 \nDamiano ER , McKeon K , El-Khatib FH \net al\nA comparative effectiveness analysis of three continuous glucose monitors: the Navigator, G4 Platinum and Enlite . J Diabetes Sci Technol 2014 ;8 :699 –708 .24876423 \n17 \nEkhlaspour L , Mondesir D , Lautsch N \net al\nComparative accuracy of 17 point-of-care glucose meters . J Diabetes Sci Technol 2017 ;11 :558 –66 .27697848 \n18 \nAmerican Diabetes Association . Position statement 5. Glycemic targets . Diabetes Care 2016 ;39 :S39 –46 .26696679 \n19 \nBodick N , Lufkin J , Willwerth C \net al\nAn intra-articular, extended-release formulation of triamcinolone acetonide prolongs and amplifies analgesic effect in patients with osteoarthritis of the knee: a randomized clinical trial . J Bone Joint Surg Am 2015 ;97 :877 –88 .26041848 \n20 \nRussell SJ , Sala R , Conaghan PG \net al In type 2 diabetes mellitus patients with knee osteoarthritis intra-articular injection of FX006 (extended release triamcinolone) is associated with reduced BG elevation vs standard triamcinolone: a randomized, blinded, parallel-group study. Diabetes. 2017;66(Suppl 1):A289(abstract).\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1462-0324", "issue": "57(12)", "journal": "Rheumatology (Oxford, England)", "keywords": null, "medline_ta": "Rheumatology (Oxford)", "mesh_terms": "D000305:Adrenal Cortex Hormones; D000368:Aged; D000369:Aged, 80 and over; D001786:Blood Glucose; D015190:Blood Glucose Self-Monitoring; D003692:Delayed-Action Preparations; D003924:Diabetes Mellitus, Type 2; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007270:Injections, Intra-Articular; D007719:Knee Joint; D008297:Male; D008875:Middle Aged; D020370:Osteoarthritis, Knee; D016896:Treatment Outcome; D014222:Triamcinolone Acetonide", "nlm_unique_id": "100883501", "other_id": null, "pages": "2235-2241", "pmc": null, "pmid": "30203101", "pubdate": "2018-12-01", "publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": "26535137;19005159;29088579;27697848;18279766;3948470;26041848;27539890;21869712;3741515;26696679;24449590;22698422;29664853;27539668;19252817;24876423;23690694;29024802", "title": "Triamcinolone acetonide extended-release in patients with osteoarthritis and type 2 diabetes: a randomized, phase 2 study.", "title_normalized": "triamcinolone acetonide extended release in patients with osteoarthritis and type 2 diabetes a randomized phase 2 study" }

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TRIAMCINOLONE ACETONIDE EXTENDED-RELEASE IN PATIENTS WITH OSTEOARTHRITIS AND TYPE 2 DIABETES: A RANDOMIZED, PHASE 2 STUDY. 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TRIAMCINOLONE ACETONIDE EXTENDED-RELEASE IN PATIENTS WITH OSTEOARTHRITIS AND TYPE 2 DIABETES: A RANDOMIZED, PHASE 2 STUDY. 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TRIAMCINOLONE ACETONIDE EXTENDED-RELEASE IN PATIENTS WITH OSTEOARTHRITIS AND TYPE 2 DIABETES: A RANDOMIZED, PHASE 2 STUDY. 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TRIAMCINOLONE ACETONIDE EXTENDED-RELEASE IN PATIENTS WITH OSTEOARTHRITIS AND TYPE 2 DIABETES: A RANDOMIZED, PHASE 2 STUDY. 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TRIAMCINOLONE ACETONIDE EXTENDED-RELEASE IN PATIENTS WITH OSTEOARTHRITIS AND TYPE 2 DIABETES: A RANDOMIZED, PHASE 2 STUDY. 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TRIAMCINOLONE ACETONIDE EXTENDED-RELEASE IN PATIENTS WITH OSTEOARTHRITIS AND TYPE 2 DIABETES: A RANDOMIZED, PHASE 2 STUDY. 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TRIAMCINOLONE ACETONIDE EXTENDED-RELEASE IN PATIENTS WITH OSTEOARTHRITIS AND TYPE 2 DIABETES: A RANDOMIZED, PHASE 2 STUDY. 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TRIAMCINOLONE ACETONIDE EXTENDED-RELEASE IN PATIENTS WITH OSTEOARTHRITIS AND TYPE 2 DIABETES: A RANDOMIZED, PHASE 2 STUDY. 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TRIAMCINOLONE ACETONIDE EXTENDED-RELEASE IN PATIENTS WITH OSTEOARTHRITIS AND TYPE 2 DIABETES: A RANDOMIZED, PHASE 2 STUDY. 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TRIAMCINOLONE ACETONIDE EXTENDED-RELEASE IN PATIENTS WITH OSTEOARTHRITIS AND TYPE 2 DIABETES: A RANDOMIZED, PHASE 2 STUDY. 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TRIAMCINOLONE ACETONIDE EXTENDED-RELEASE IN PATIENTS WITH OSTEOARTHRITIS AND TYPE 2 DIABETES: A RANDOMIZED, PHASE 2 STUDY. 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TRIAMCINOLONE ACETONIDE EXTENDED-RELEASE IN PATIENTS WITH OSTEOARTHRITIS AND TYPE 2 DIABETES: A RANDOMIZED, PHASE 2 STUDY. RHEUMATOLOGY. 2018", "literaturereference_normalized": "triamcinolone acetonide extended release in patients with osteoarthritis and type 2 diabetes a randomized phase 2 study", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20181024", "receivedate": "20181024", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15546063, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "IL-ALKEM LABORATORIES LIMITED-IL-ALKEM-2018-07992", "fulfillexpeditecriteria": "2", "occurcountry": "IL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": "3", "drugadministrationroute": "014", "drugauthorizationnumb": "207651", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE ACETONIDE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Blood glucose increased", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "RUSSELL SJ, SALA R, CONAGHAN PG, HABIB G, ET AL.. TRIAMCINOLONE ACETONIDE EXTENDED-RELEASE IN PATIENTS WITH OSTEOARTHRITIS AND TYPE 2 DIABETES: A RANDOMIZED, PHASE 2 STUDY. RHEUMATOLOGY (OXFORD).. 2018", "literaturereference_normalized": "triamcinolone acetonide extended release in patients with osteoarthritis and type 2 diabetes a randomized phase 2 study", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "IL", "receiptdate": "20181024", "receivedate": "20181024", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15546053, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" } ]

{ "abstract": "A 23-year-old woman was admitted with a history of 2 weeks of cough, fever and bilateral lung infiltrates. She had been diagnosed 2 months before as having ulcerative proctitis and was treated with mesalamine, which induced a full remission, but 3 antibiotic regimens failed to improve her lung disease. Since computerized tomography revealed bilateral peripheral lung infiltrates and her eosinophile count was elevated, the diagnosis of drug-induced eosinophilic pneumonia was suggested. Mesalamine and antibiotics were stopped and oral corticosteroids begun. She became almost asymptomatic a week after mesalamine withdrawal, and the x-ray became normal.", "affiliations": "Dept. of Medicine A, Hillel Yaffe Medical Center, Hadera.", "authors": "Zamir|D|D|;Weizman|J|J|;Zamir|C|C|;Fireman|Z|Z|;Weiner|P|P|", "chemical_list": "D000305:Adrenal Cortex Hormones; D000894:Anti-Inflammatory Agents, Non-Steroidal; D019804:Mesalamine", "country": "Israel", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0017-7768", "issue": "137(1-2)", "journal": "Harefuah", "keywords": null, "medline_ta": "Harefuah", "mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003093:Colitis, Ulcerative; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D019804:Mesalamine; D011014:Pneumonia; D011349:Proctitis", "nlm_unique_id": "0034351", "other_id": null, "pages": "28-30, 87, 86", "pmc": null, "pmid": "10959271", "pubdate": "1999-07", "publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article", "references": null, "title": "Mesalamine-induced hypersensitivity pneumonitis.", "title_normalized": "mesalamine induced hypersensitivity pneumonitis" }

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{ "abstract": "Advanced age and immunosuppressed states allow for complications of herpes zoster such as encephalitis. In this case report, we describe a patient with encephalopathy two days after initiation of antiviral therapy. After the necessary imaging and cerebrospinal fluid (CSF) analysis, it became evident that the neurological syndrome was due to acyclovir. Despite currently practised renal dose modification, the patient developed acyclovir-induced neurotoxicity and required intensification of his dialysis schedule to eliminate the drug. Acyclovir-induced neurotoxicity is a rare clinical presentation and presents a clinical dilemma to the physician who has to distinguish this entity from herpes zoster encephalitis and posterior circulation stroke.", "affiliations": "Department of Nephrology, SRIHER, Porur, Tamil Nadu, India.;Department of Nephrology, SRMIST, Kattankulathur, Tamil Nadu, India.;Department of Nephrology, SRIHER, Porur, Tamil Nadu, India.;Department of Nephrology, SRIHER, Porur, Tamil Nadu, India.", "authors": "Jose|Nisha|N|;Jayaprakash|V|V|;Deiva|A|A|;Jayakumar|M|M|", "chemical_list": null, "country": "India", "delete": false, "doi": "10.4103/ijn.IJN_11_20", "fulltext": "\n==== Front\nIndian J Nephrol\nIndian J Nephrol\nIJN\nIndian Journal of Nephrology\n0971-4065\n1998-3662\nWolters Kluwer - Medknow India\n\nIJN-31-293\n10.4103/ijn.IJN_11_20\nCase Report\nAn Unusual Neurological Syndrome in a Haemodialysis Patient\nJose Nisha\nJayaprakash V 1\nDeiva A\nJayakumar M\nDepartment of Nephrology, SRIHER, Porur, Tamil Nadu, India\n1 Department of Nephrology, SRMIST, Kattankulathur, Tamil Nadu, India\nAddress for correspondence: Dr. Jayaprakash V, Department of Nephrology, SRMIST, Kattankulathur, Tamil Nadu, India. E-mail: jayaprakash2k@gmail.com\nMay-Jun 2021\n10 4 2021\n31 3 293295\n09 1 2020\n02 4 2020\n14 4 2020\nCopyright: © 2021 Indian Journal of Nephrology\n2021\nhttps://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.\nAdvanced age and immunosuppressed states allow for complications of herpes zoster such as encephalitis. In this case report, we describe a patient with encephalopathy two days after initiation of antiviral therapy. After the necessary imaging and cerebrospinal fluid (CSF) analysis, it became evident that the neurological syndrome was due to acyclovir. Despite currently practised renal dose modification, the patient developed acyclovir-induced neurotoxicity and required intensification of his dialysis schedule to eliminate the drug. Acyclovir-induced neurotoxicity is a rare clinical presentation and presents a clinical dilemma to the physician who has to distinguish this entity from herpes zoster encephalitis and posterior circulation stroke.\n\nAcyclovir\nencephalopathy\nherpes zoster\ndose adjustment\n==== Body\nIntroduction\n\nHerpes zoster is a common problem with an incidence of 3-4 cases per 1000 people per year.[1] Incidence increases with increasing age. Chronic kidney disease (CKD) is an immunosuppressed state allowing flares of herpes zoster. The altered sensorium in the setting of a zoster patient could represent encephalopathy due to the virus or drug toxicity. These represent opposite ends of the spectrum requiring entirely contradictory treatment paths. Hence, the importance of defining these entities and distinguishing between them need to be emphasized. Acyclovir toxicity in the setting of CKD leading to encephalopathy has been described in very few cases of herpes zoster across the world and one case with valacyclovir-induced neurotoxicity in a hemodialysis patient had been previously described from India.[2] This case report highlights the salient clinical features and clinical course of acyclovir-induced encephalopathy (AIE) in a dialysis patient.\n\nCase Presentation\n\nA 65-year-old gentleman who was on twice weekly dialysis presented with a history of vesicular rash in the thoracic dermatome for 2 days. He was a known diabetic and hypertensive and had developed end-stage renal disease due to diabetes. His dialysis vintage was 4 months. He was also on the maintenance phase of antituberculous therapy, which included isoniazid and rifampicin for pulmonary tuberculosis. He was conscious, oriented, was able to give history coherently. In view of advanced age and immunosuppressed state, he was prescribed acyclovir at a dose of 400 mg thrice daily.\n\nTwo days after the initiation of acyclovir, he was brought into the emergency department with dysarthria, drowsiness, and disorientation. His blood pressure on arrival was 150/90 mm Hg. Neurological evaluation revealed cerebellar signs such as past pointing and rebound in bilateral upper limbs along with slow speech. The rash of herpes zoster exhibited crusting. The differential diagnoses considered at this time were posterior circulation stroke, herpes zoster encephalitis, acyclovir toxicity, isoniazid psychosis, and metabolic or septic encephalopathy. Except for low hemoglobin (9.5 g/dl) and increased urea and serum creatinine, rest of the biochemistry was normal. Magnetic resonance imaging (MRI) brain was normal with only age-related cerebral atrophy. Intravenous acyclovir at a dose of 5 mg/kg once daily was started empirically.\n\nBlood culture showed no growth. Cerebrospinal fluid (CSF) analysis showed no evidence of pus cells [Table 1]. Quantitative polymerase chain reaction (PCR) for the Varicella zoster virus was negative. To rule out other causes of viral encephalitis endemic to the region, multiplex PCR analysis was done. Bacterial, fungal and tuberculous cultures, as well as cytology of CSF, were done and negative [Table 1]. The diagnosis of probable acyclovir-induced encephalopathy was made and the patient was given frequent sittings of hemodialysis to remove the drug along with stopping the medication. Within three days, his sensorium showed gradual improvement and cerebellar signs regressed and over the next couple of days, his sensorium normalized.\n\nTable 1 Cerebrospinal fluid analysis of a patient with VZV\n\nCSF Laboratory analysis\tReport of test\t\nWBC count\tNIL\t\nRBC count\tNIL\t\nProtein\t65.3 mg/dl\t\nGlucose\t50 mg/dl\t\nAdenosine Deaminase (ADA)\t1.9 IU/L\t\nAppearance\tStraw color\t\nQuantitative VZV Panel PCR\tnegative\t\nViral encephalitis PCR panel\t\t\nEBV\tnegative\t\nCMV\tnegative\t\nAdenovirus\tnegative\t\nHSV1\tnegative\t\nHSV2\tnegative\t\nWNV\tnegative\t\nEV\tnegative\t\nJEV-\tnegative\t\nBacterial Culture\tnegative\t\nFungal Culture\tnegative\t\nX-pert -TB PCR\tnegative\t\nCytology CSF\tNegative\t\nCSF: Cerebrospinal fluid; TB PCR: tuberculosis polymerase chain reaction; JEV: Japanese encephalitis virus; HSV1: herpes simplex virus 1; EV: Enterovirus; WNV: West Nile virus; CMV: Cytomegalovirus; EBV: Epstein-Barr virus; VZV: Varicella Zoster Viral; WBC: white blood cell; RBC: red blood cell\n\nDiscussion\n\nHerpes zoster is a common entity among the elderly population with an incidence of 1 million cases per year in the US.[3] Uremic patients have defective innate and adaptive immunity. It has been noted that patients on hemodialysis have an increased risk of varicella-zoster virus (VZV) infections compared to the general population.[4] Risk factors for cranial herpes infection include dissemination and immunosuppression. Tremors and disorientation are the most common clinical manifestations, seen in 40% of people each, while agitation and hallucinations are seen in 22 and 25% of cases, respectively.[5] Hallucinations, death delusions, and involuntary movements are features that are specific of toxicity due to acyclovir. In comparison, high fever, headache, and seizures are more suggestive of encephalitis.[6]\n\nCutaneous herpes and cranial herpes usually do not occur concomitantly. Median duration of 15 days between the two in immunosuppressed and 5 days in immunocompetent patients have been previously described.[5] Individuals over 50 years and immunocompromised individuals require antiviral therapy for the treatment of herpes zoster lesions.\n\nAcyclovir is commonly prescribed for herpes zoster and is cost-effective. Acyclovir was first developed in 1974. Its oral bioavailability is only about 10-30%. About 60-90% of the drug undergoes renal elimination through filtration and secretion. About 9-33% is protein bound.[7] In those with renal failure, there is a linear increase in acyclovir levels as renal function declines with a predicted intercept value of 28.7 ml/min/1.73 m.[8] This is the rate of acyclovir clearance in anuric patients and this value is used to calculate renal dose adjustment of acyclovir.\n\nThere are no typical imaging findings of AIE. Some case reports have described multifocal white matter signal intensities in the cerebellum, pons and periventricular region. There is also one reported case of posterior leukoencephalopathy due to acyclovir in literature.[9] Our patient did not have any abnormal imaging findings.\n\nPlasma levels of acyclovir can be checked using high -performance liquid chromatography or radioimmunoassay. 9-Carboxymethoxy methylguanine (CMMG), the active metabolite of acyclovir can be measured from serum or CSF. High levels seem to correlate well with neurotoxicity. This assay is only available at few centers and is not routinely done for diagnosis. A study by Helleden et al. showed that CMMG levels have a sensitivity of 91% and specificity of 93% for the development of neuropsychiatric symptoms.[10] Acyclovir levels have shown a poor correlation with clinical recovery. Despite the rapid fall of acyclovir levels after drug removal through dialysis, clinical response is not rapid. This is probably explained by slow equilibration between blood and brain levels of the drug. In our opinion, the routine measurement of acyclovir levels to determine neurotoxicity is not required.\n\nIn those with renal failure, dose is adjusted in a stepwise manner according to the glomerular filtration rate (GFR). Despite following manufacturers' available renal adjustment, in a study by Kransy et al., acyclovir levels were are two times the upper limit of normal in the CSF than that in patients with normal renal function.[11] This call into question the precision of our currently available renal dose adjustment system? Perhaps the renal adjustment needs to decrease doses further to maintain therapeutic targets but maintain drug efficacy.\n\nTreatment of AIE involves dialysis for drug removal. Within 48-72 hours there is usually improvement of symptoms. Still, other authors have suggested a therapeutic trial of hemodialysis as a means to diagnose AIE in patients who are encephalopathic where it is difficult to distinguish between zoster-related encephalitis and AIE.[12] In the study by Kransky et al., the extraction ratio of acyclovir for each dialysis session was found to be 0.45 ± 12. Since then more efficient dialyzers have evolved and with better blood and dialysate flow, up to 45%, of removal from a single 3-hour dialysis session has been reported by Leiken et al.[13] Experience with peritoneal dialysis for acyclovir removal is limited and it was found to eliminate only 10% of the total drug dose.[14]\n\nThe diagnosis of acyclovir-induced neurotoxicity hinges on the temporal profile of toxicity developing within 72 hours of exposure to acyclovir in the absence of other clinical and laboratory features that are typical of herpes zoster encephalitis and improvement with drug withdrawal and/or removal through dialysis.\n\nNo doubt, herpes zoster lesion should be treated keeping in mind the patient's age and immunosuppressed state. But does the dose currently prescribed need amendment? Existing renal drug dosage schedules are not precise and have currently lead to case reports of neurotoxicity and excessive levels of acyclovir or its active metabolite even when the drug is administered in recommended doses. Should we have used intravenous acyclovir at 2.5 mg/kg body weight? In the medical literature, no pharmacokinetic studies on acyclovir levels in renal failure patients are available after 1980s. Further research on appropriate drug dosage and recommendations from professional bodies are well overdue.\n\nConclusions\n\nEncephalopathy in a hemodialysis patient should be approached diligently. Even with the currently prescribed Renal adjusted acyclovir dose, drug toxicity can occur. Newer pharmacokinetic studies on acyclovir and other commonly prescribed drugs in renal failure patients are recommended.\n\nDeclaration of consent\n\nThe authors confirm that the patient consent was obtained and all efforts to maintain anonymity were followed although anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\n\nNil.\n\nConflicts of interest\n\nThere are no conflicts of interest.\n==== Refs\n1 Cohen JI Clinical practice: Herpes zoster N Engl J Med 2013 369 255 63 23863052\n2 Singh NP Shah HR Aggarwal N Jha LK Behura S Valacyclovir associated neurotoxicity in a patient on dialysis Indian J Nephrol 2014 24 128 9 24701050\n3 Rimland D Moanna A Increasing incidence of herpes zoster among veterans Clin Infect Dis 2010 50 1000 5 20178416\n4 Al-Mula Abed YW Varicella-zoster virus associated encephalitis in a patient undergoing hemodialysis Qatar Med J 2015 2 19\n5 Peterslund NA Herpes zoster associated encephalitis: Clinical findings and acyclovir treatment Scand J Infect Dis 1988 20 583 92 3222675\n6 Gentry JL 3rd Peterson C Death delusions and myoclonus: Acyclovir toxicity Am J Med 2015 127 692 4\n7 Richards DM Carmine AA Brogden RN Heel RC Speight TM Avery GS Acyclovir: A review of its pharmacodynamics properties and therapeutic efficacy Drug 1983 26 378 438\n8 Laskin OL Clinical Pharmacokinetics of acyclovir Clin Pharmacokinet 1983 8 187 201 6342900\n9 Mahad D Jarvis J Chinnery PF Mitra D Gholkar A Helldén A Acyclovir induced posterior leukoencephalopathy J Neurol Neurosurg Psychiatry 2005 76 1308 10 16107379\n10 Helldén A Odar-Cederlöf I Diener P Barkholt L Medin C Svensson JO High serum concentrations of the acyclovir main metabolite 9 CMMG in renal failure patients with acyclovir induced neuropsychiatric side effects: An observational study Nephro Dial Transplant 2003 18 1135 41\n11 Kransy HC Liao SHT De Miranda PDE Laskin OL Whelton A Lietman PS Influence of hemodialysis on acyclovir pharmacokinetics in patients with chronic renal failure Am J Med 1983 73 202 4\n12 Sacchetti D Alawadhi A Albakour M Rapose A Herpes zoster encephalopathy or acyclovir neurotoxicity: A management dilemma BMJ Case Rep 2014 bcr2013201941. doi: 10.1136/bcr-2013-201941\n13 Leiken JB Shicker L Orlowski J Blair AT McAllister K Hemodialysis removal of acyclovir Vet Hum Toxicol 1995 37 233 4 7571352\n14 Shah GM Winer RL Kransy HC Acyclovir pharmacokinetics in a patient on ambulatory peritoneal dialysis Am J Kidney Dis 1986 7 507 10 3717158\n\n", "fulltext_license": "CC BY-NC-SA", "issn_linking": "0971-4065", "issue": "31(3)", "journal": "Indian journal of nephrology", "keywords": "Acyclovir; dose adjustment; encephalopathy; herpes zoster", "medline_ta": "Indian J Nephrol", "mesh_terms": null, "nlm_unique_id": "8914356", "other_id": null, "pages": "293-295", "pmc": null, "pmid": "34376947", "pubdate": "2021", "publication_types": "D002363:Case Reports", "references": "7102703;6315332;3222675;6342900;3717158;12748346;20178416;16107379;24777077;26865994;25784625;24701050;23863052;7571352", "title": "An Unusual Neurological Syndrome in a Haemodialysis Patient.", "title_normalized": "an unusual neurological syndrome in a haemodialysis patient" }

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AN UNUSUAL NEUROLOGICAL SYNDROME IN A HAEMODIALYSIS PATIENT. 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{ "abstract": "Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disease (PTLD) with central nervous system (CNS) involvement is a severe complication after solid organ transplantation. Standard treatment with reduction of immunosuppression and anti-CD20 antibody application often fails leading to poor outcome. Here, we report the case of an 11-year-old boy with multilocular EBV-positive CNS PTLD 10 years after liver transplantation. Complete remission was achieved by repeated intravenous and intrathecal anti-CD20 antibody rituximab administration combined with intrathecal chemotherapy (methotrexate, cytarabine, prednisone) over a time period of 3 months. Due to the poor prognosis of CNS PTLD and lack of EBV-specific T-cells (EBV-CTLs) in patient's blood, we decided to perform EBV-directed T-cell immunotherapy as a consolidating treatment. The patient received five infusions of allogeneic EBV-CTLs from a 5/10 HLA-matched unrelated third-party donor. No relevant acute toxicity was observed. EBV-CTLs became detectable after first injection and increased during the treatment course. Next-generation sequencing (NGS) TCR-profiling verified the persistence and expansion of donor-derived EBV-specific clones. After two transfers, epitope spreading to unrelated EBV antigens occurred suggesting onset of endogenous T-cell production, which was supported by detection of recipient-derived clones in NGS TCR-profiling. Continuous complete remission was confirmed 27 months after initial diagnosis.", "affiliations": "Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.;Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany.;Hannover Medical School, Institute of Immunology, Hannover, Germany.;Department of Pediatric Hematology and Oncology, Berlin Institute of Health, Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Berlin, Germany.;Department of Neuropathology, Berlin Institute of Health, Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Berlin, Germany.;Department of Pathology, Berlin Institute of Health, Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Berlin, Germany.;Hannover Medical School, Institute of Immunology, Hannover, Germany.;Hannover Medical School, Institute for Transfusion Medicine, Hannover, Germany.;Hannover Medical School, Institute of Immunology, Hannover, Germany.;Hannover Medical School, Institute of Immunology, Hannover, Germany.;Hannover Medical School, Institute for Transfusion Medicine, Hannover, Germany.;Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany.;Hannover Medical School, Institute for Transfusion Medicine, Hannover, Germany.;Hannover Medical School, Institute of Immunology, Hannover, Germany.;Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany.;Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.", "authors": "Schultze-Florey|Rebecca E|RE|;Tischer|Sabine|S|;Kuhlmann|Leonie|L|;Hundsdoerfer|Patrick|P|;Koch|Arend|A|;Anagnostopoulos|Ioannis|I|;Ravens|Sarina|S|;Goudeva|Lilia|L|;Schultze-Florey|Christian|C|;Koenecke|Christian|C|;Blasczyk|Rainer|R|;Koehl|Ulrike|U|;Heuft|Hans-Gert|HG|;Prinz|Immo|I|;Eiz-Vesper|Britta|B|;Maecker-Kolhoff|Britta|B|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.3389/fimmu.2018.01475", "fulltext": "\n==== Front\nFront ImmunolFront ImmunolFront. Immunol.Frontiers in Immunology1664-3224Frontiers Media S.A. 10.3389/fimmu.2018.01475ImmunologyCase ReportDissecting Epstein-Barr Virus-Specific T-Cell Responses After Allogeneic EBV-Specific T-Cell Transfer for Central Nervous System Posttransplant Lymphoproliferative Disease Schultze-Florey Rebecca E. 12†Tischer Sabine 23†Kuhlmann Leonie 4†Hundsdoerfer Patrick 5Koch Arend 6Anagnostopoulos Ioannis 7Ravens Sarina 4Goudeva Lilia 3Schultze-Florey Christian 48Koenecke Christian 48Blasczyk Rainer 3Koehl Ulrike 29Heuft Hans-Gert 3Prinz Immo 4Eiz-Vesper Britta 23†Maecker-Kolhoff Britta 12*†1Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany2Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany3Hannover Medical School, Institute for Transfusion Medicine, Hannover, Germany4Hannover Medical School, Institute of Immunology, Hannover, Germany5Department of Pediatric Hematology and Oncology, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Freie Universität Berlin, Berlin, Germany6Department of Neuropathology, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Freie Universität Berlin, Berlin, Germany7Department of Pathology, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Freie Universität Berlin, Berlin, Germany8Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany9Hannover Medical School, Institute of Cellular Therapeutics, Hannover, GermanyEdited by: Arian Dominic John Laurence, Newcastle University, United Kingdom\n\nReviewed by: William K. Decker, Baylor College of Medicine, United States; Heather Long, University of Birmingham, United Kingdom\n\n*Correspondence: Britta Maecker-Kolhoff, maecker.britta@mh-hannover.de†These authors have contributed equally to this work.\n\nSpecialty section: This article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Immunology\n\n27 6 2018 2018 9 147507 12 2017 13 6 2018 Copyright © 2018 Schultze-Florey, Tischer, Kuhlmann, Hundsdoerfer, Koch, Anagnostopoulos, Ravens, Goudeva, Schultze-Florey, Koenecke, Blasczyk, Koehl, Heuft, Prinz, Eiz-Vesper and Maecker-Kolhoff.2018Schultze-Florey, Tischer, Kuhlmann, Hundsdoerfer, Koch, Anagnostopoulos, Ravens, Goudeva, Schultze-Florey, Koenecke, Blasczyk, Koehl, Heuft, Prinz, Eiz-Vesper and Maecker-KolhoffThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Epstein–Barr virus (EBV)-associated posttransplant lymphoproliferative disease (PTLD) with central nervous system (CNS) involvement is a severe complication after solid organ transplantation. Standard treatment with reduction of immunosuppression and anti-CD20 antibody application often fails leading to poor outcome. Here, we report the case of an 11-year-old boy with multilocular EBV-positive CNS PTLD 10 years after liver transplantation. Complete remission was achieved by repeated intravenous and intrathecal anti-CD20 antibody rituximab administration combined with intrathecal chemotherapy (methotrexate, cytarabine, prednisone) over a time period of 3 months. Due to the poor prognosis of CNS PTLD and lack of EBV-specific T-cells (EBV-CTLs) in patient’s blood, we decided to perform EBV-directed T-cell immunotherapy as a consolidating treatment. The patient received five infusions of allogeneic EBV-CTLs from a 5/10 HLA-matched unrelated third-party donor. No relevant acute toxicity was observed. EBV-CTLs became detectable after first injection and increased during the treatment course. Next-generation sequencing (NGS) TCR-profiling verified the persistence and expansion of donor-derived EBV-specific clones. After two transfers, epitope spreading to unrelated EBV antigens occurred suggesting onset of endogenous T-cell production, which was supported by detection of recipient-derived clones in NGS TCR-profiling. Continuous complete remission was confirmed 27 months after initial diagnosis.\n\nposttransplant lymphoproliferative diseaseadoptive T cell therapyT cell receptor sequencingtransplantationEpstein–Barr virusDeutsche Kinderkrebsstiftung10.13039/5011000073112011.05Bundesministerium für Bildung und Forschung10.13039/50110000234701EO1302\n==== Body\nIntroduction\nPosttransplant lymphoproliferative disease (PTLD) constitutes a heterogeneous group of lymphoproliferative disorders occurring as severe complications of immunosuppression after solid organ transplantation (SOT). Acquired by up to 15% of pediatric transplant recipients, most cases of childhood PTLD are of B-cell origin and associated with Epstein–Barr virus (EBV) infection or reactivation (1, 2). Long-lasting immunosuppressive therapy to prevent graft rejection as well as lack of EBV-specific immunity at the time of transplantation contribute to the high incidence and unfavorable prognosis of PTLD in children (1). Up to 20% of affected patients eventually succumb to the disease (1). While modulation of immunosuppressive therapy may be sufficient in some patients, multi-agent immuno-/chemotherapy serves as the primary treatment option for advanced stage PTLD in children resulting in 80% overall survival (3). In the PTLD-1 study, complete response to Rituximab conferred a favorable outcome in adults (4). Central nervous system (CNS) PTLD displays an unfavorable outcome with 30–50% overall survival (isolated disease) (5–7) and as low as 0–10% (combined systemic and CNS disease) (7, 8). For these high-risk patients, very limited treatment options are available. Intrathecal rituximab as a combination to intravenous immuno-/chemotherapy is a promising treatment option (9). In addition, transfer of EBV-specific T-cell lines manufactured from healthy volunteers has shown promise in some patients with CNS involvement (10). Here, we report the first case of treatment of an SOT patient with CNS PTLD receiving freshly isolated, partially HLA-matched EBV-specific T-cells (EBV-CTLs) from an unrelated third party donor in addition to intravenous and intrathecal chemo-/immunotherapy.\n\nMethods\nEthical Approval and Patient Informed Consent\nThe study was approved by the IRB of Hannover Medical School. The patient’s legal guardian gave written informed consent to both participation in the research project and publication of the case report.\n\nDonor Pre-Testing, Production of EBV-CTLs, and Application\nFrequencies of EBV-CTLs were determined in patient mother’s blood (not sufficient for transfer) as well as in five partially HLA-matched potential donors from the alloCELL T-cell donor registry (www.alloCELL.org, Tables 1 and 2) as described using EBV peptide pools EBV nuclear antigen 1 (ppEBNA-1) and EBV Select (ppSelect) (Miltenyi Biotec, Bergisch-Gladbach, Germany) (11).\n\nTable 1 Donor selection: HLA characteristics and verification of donor’s Epstein–Barr virus (EBV)-specific memory T cells.\n\n\tDonor type\tHLA-type\tHLA match\tIFN-γ EliSpot (spw/2.5 × 105 PBMCs)\tIFN-γ CSA [% IFN-γ CD3+ T cells]\t\n\t\t\t\nHLA-A\tHLA-B\tHLA-C\tHLA-DR\tHLA-DQ\tEBNA1\tSelect\tEBNA1 + Select\tEBNA1 + Select\t\nOF\tTCF\t\nPatient\t\t03\t07/14\t07/08\t01/15\t05\t\t0\t1\t/\t/\t/\t\nMother\tPMRD\t\t\t\t\t\t\t0\t16\t10\t0.04\t4.26\t\nTPD 1\tPMUD\t03/11\t07\t07\t15/16\t05/06\t5/10\t23\tTNTC\t108\t1.25\t48.35\t\nTPD 2\tPMUD\t03\t07\t07\t15\t06\t5/10\t3\t8\t3\t0.01\t5.28\t\nTPD 3\tPMUD\t03\t07\t07\t15\t03/06\t5/10\t5\t61\t13\t0.09\t56.35\t\nTPD 4\tPMUD\t03/11\t07\t07\t15\t06\t4/10\t35\t120\t114\t0.04\t16.36\t\nTPD 5\tPMUD\t03\t07/18\t07\t12/15\t06/07\t5/10\t32\t162\t141\t0.21\t68.85\t\nFor EliSpot assay and CSA, EBV-specific T cells were activated by 4 h in vitro restimulation with peptide pools EBNA1, Select and both in combination (EBNA1 + Consensus), respectively. TPD, third party donor; PMRD, partially matched related donor; PMUD, partially matched unrelated donor; HLA, human leukocyte antigen; IFN-γ, interferon-gamma; spw, spot per well; CSA, cytokine secretion assay; OF, original fraction, before enrichment; TCF, T-cell fraction, after magnetic enrichment; TNTC, too numerous to count.\n\nTable 2 T-cell receptor CDR3 sequences of clones displayed in Figures 3A,B.\n\ncdr3 clones selectively detected in T cell product (donor = D) and post transfer\tcdr3 clones detected in recipient (R) before transfer and post transfer\t\nEBNA.D1\tCASSSKRQVPDTQYF\tSelect.Dl\tCASSPRQADEQFF\tEBNA.R1\tCASSDDFFSHTDTQYF\tSelect.Rl\tCASSDDFFSHTDTQYF\t\nEBNA.D2\tSSARDGDLRGQFF\tSelect.D2\tCSVGQAAYEQYF\tEBNA.R2\tCASSLTGRTVTDTQYF\tSelect.R2\tCASSLTGRTVTDTQYF\t\nEBNA.D3\tCSAPGQVQETQYF\tSelect.D3\tCSAPGQVQETQYF\tEBNA.R3\tCASSRVGAANEQFF\tSelect.R3\tCASSRVGAANEQFF\t\nEBNA.D4\tCASSFASGGSSYNEQFF\tSelect.D4\tCASSPSGVPGANVLTF\tEBNA.R4\tCASSFRDRQDYEQYF\tSelect.R4\tCATSPGVEQYF\t\nEBNA.D5\tCASSLRGTEAFF\tSelect.D5\tCASSLLQGADTEAFF\tEBNA.R5\tCASSQDLAGGLLSYEQYF\tSelect.R5\tCASSLEGPGYNEQFF\t\nEBNA.D6\tCASSLEGDRHQHF\tSelect.D6\tCASSPVRSSETQYF\tEBNA.R6\tCASSNTDTQYF\tSelect.R6\tCASNNLPGLETQYF\t\nEBNA.D7\tCASSLERDRPQHF\tSelect.D7\tCASSLPTGGYYEQYF\tEBNA.R7\tCATSPGVEQYF\tSelect.R8\tCASSPSRNTEAFF\t\nEBNA.D8\tCASSAGPATNEKLFF\tSelect.D8\tCASSLSYEQYF\tEBNA.R8\tCAISKRLFSYNEQFF\tSelect.RS\tCASSFRDRQDYEQYF\t\nEBNA.D9\tCASSTTDTQYF\tSelect.D9\tCASNKLPGLETQYF\tEBNA.R9\tCSARDGDLRGQFF\tSelect.R9\tCAISKRLFSYNEQFF\t\nEBNA.D10\tCASSQFGGNTIYF\tSelect.D10\tCASSVRASPLHF\tEBNA.RI0\tCASSQDRGRSPLHF\tSelect.Rl0\tCASSQTSGDGDTQYF\t\nEBNA.D11\tCASNVGYSRPDNEQFF\tSelect.D11\tCASSLRTGELFF\tEBNA.R11\tCASRTPSGGAWETQYF\tSelect.Rll\tCASSQDPSAEQFF\t\nEBNA.D12\tCASSLSGAYEQYF\tSelect.D12\tCASSLVTNEQFF\tEBNA.R12\tCASSYRLGRLNQPQHF\tSelect.R12\tCASSQGRDNSYEQYF\t\nEBNA.D13\tCASSLGGDRPQHF\tSelect.D13\tCASSHQGGGQMRTGELFF\tEBNA.R13\tCASSSGIFNYGYTF\tSelect.R13\tCASSGDIPTEHRDTQYF\t\nEBNA.D14\tCSAPGQVRETQYF\tSelect.D14\tCAWRETGGEVSEQYF\tEBNA.R14\tCASSPSRNTEAFF\tSelect.R14\tCASRTPSGGAWETQYF\t\nEBNA.D15\tCASSWEGDRPQHF\tSelect.D15\tCASSPPGGGDQETQYF\tEBNA.R15\tCASSSGTGFQETQYF\tSelect.R15\tCASSQDLAGGLLSYEQYF\t\nEBNA.D16\tCASSLEGDRPQHC\tSelect.D16\tCASKRGGNTEAFF\tEBNA.R16\tCASSYLRIARPDYGYTF\tSelect.R16\tCASSNTDTQYF\t\nEBNA.D17\tCSVGEQYI\tSelect.D17\tCASSQETGSYEQYF\tEBNA.R17\tCAWSPGFTEAFF\tSelect.R17\tCASSSGIFNYGYTF\t\nE8NA.D18\tCASSHDSSDEQYF\tSelect.D18\tCASSEAVPGHQNTEAFF\tEBNA.R18\tCASSDPRGHEQYF\tSelect.R18\tCASSYRLGRLNQPQHF\t\n\t\tSelect.D19\tCASSSGDEQYF\tEBNA.R19\tCASSEEELDNNQPQHF\tSelect.R19\tCASSSGTGFQETQYF\t\n\t\tSelect.D20\tCASSVSEGNTIYF\tEBNA.R20\tCASSFETGGTGELFF\tSelect.R20\tCSARDGDLRGQFF\t\n\t\tSelect.D21\tCASSLTGFLNTEAFF\tEBNA.R21\tCASSQAWYSGNTIYF\tSelect.R21\tCASSQDRGRSPLHF\t\n\t\tSelect.D22\tCASSFSRDWNTEAFF\tEBNA.R22\tCSVEVENRNTEAFF\tSelect.R22\tCASSDPRGHEQYF\t\n\t\tSelect.D23\tCAVNGGQFSGNTIYF\tEBNA.R23\tCASSPGQHNSPLHF\tSelect.R23\tCAWSPGFTEAFF\t\n\t\tSelect.D24\tCASTFRMRPQDTQYF\tEBNA.R24\tCSARPRGQPYEQYF\tSelect.R24\tCASSFETGGTGELFF\t\n\t\tSelect.D25\tCSAPGRVQETQYF\tEBNA.R25\tCASSQDPSAEQFF\tSelect.R25\tCASSYLRIARPDYGYTF\t\n\t\tSelect.D26\tCASSRDKAYEQYF\tEBNA.R26\tCASNNLPGLETQYF\tSelect.R26\tCASSPGQHNSPLHF\t\n\t\tSelect.D27\tCASTFRMLPQDAQYF\tEBNA.R27\tCASSIVNEAFF\tSelect.R27\tCASSEEELDNNQPQHF\t\n\t\tSelect.D28\tCASS F PAVGLPSSSYN EQF F\t\t\tSelect.R28 Select.R29\tCASSQAWYSGNTIYF CSARPRGQPYEQYF\t\nManufacturing of clinical-grade EBV-specific CD4+ and CD8+ T-cells from EBV-seropositive allogeneic 5/10 HLA-matched third party donor (TPD 1, Tables 1 and 2) was performed on a CliniMACS device using ppEBNA1 and ppSelect in combination and the IFN-γ Cytokine Capture System (Miltenyi Biotech). Quality control of the final T-cell product was done as described (11). Details on the T-cell manufacturing and product can be found in the Supplementary Material. The patient got one fresh and four cryopreserved EBV-specific T-cell products from a single manufacturing process.\n\nMonitoring\nMonitoring of viral load and EBV-specific T-cell frequencies in patient’s blood was done before and after T-cell transfer by IFN-γ ELISpot assay as described and using the following peptide pools: ppEBNA1, ppSelect, ppLMP2a, ppBZLF1 (all Miltenyi Biotec) (12, 13). If suitable numbers of PBMCs were obtained, EBV-CTLs were expanded over 7 days using the respective antigens ppEBNA1 and ppSelect in TexMACS media (Miltenyi Biotec) containing 50 U/ml IL-2 (Peprotec). After 7 days, IFN-γ ELISpot assay was repeated using the respective antigens. Expanded cells were used for TCR beta chain repertoire analysis.\n\nTCR Beta Chain Repertoire Analysis\nThe stimulated and expanded PBMCs were stained with following antibodies: dead/alive (DAPI), hCD45+ (APC-Vio770), hCD3+ (PE-Cy7), hTCR αβ+ (FITC), and hCD8+ (VioGreen). They were sorted into CD8+ T-cells with a FACS Aria Fusion flow cytometer. mRNA was extracted using the RNeasy Plus Micro Kit (QIAGEN) and then reverse-transcribed into cDNA according to the SMARTer RACE 5′-3′ PCR Kit (Clontech) manual. Then, a combined amplification of the TCR β CDR3-region and Illumina adaptor sequences were performed with the Advantage 2 PCR Kit (Clontech). After a DNA sample size identifying gel electrophoresis, the bands were extracted with the Gel extraction Kit (QIAGEN). Indexing of the samples was performed with Nextera Primer Kit (Illumina) in another Advantage 2 PCR and the product was purified with the Agencourt AMPure XP Kit. The DNA concentration was measured with the Qubit 2.0 fluorometer, samples were pooled, and the pool was set to 4 nM. Denaturation and dilution of the pool was done as described at the Illumina MiSeq Dilution and Denaturation Guide. Finally, next generation sequencing (NGS) was performed on the Illumina MiSeq System. For the analysis, the FastQ files were annotated at IMGT/HighV-Quest database and processed with tcR-package and VDJtools.\n\nCase Presentation\nAn 11-year-old boy with Alagille syndrome received a related liver allograft during first year of life. Being EBV-negative at transplantation, seroconversion occurred 2 years later. Initial immunosuppression was based on tacrolimus, followed by a combination with mycophenolate mofetil. Ten years after transplantation, he suffered from severe headache, nausea, vomiting, and phono-/photophobia without B symptoms. Funduscopic examination revealed bilateral papilledema. Magnetic resonance imaging (MRI) studies of the brain demonstrated multifocal lesions in the left hemisphere (Figure 1A). After initial treatment for suspected toxoplasmosis, biopsy of the lesion revealed a monomorphic EBV-associated PTLD with features of a diffuse large B-cell lymphoma without MYC translocation (Figure 1B). Immunohistochemistry showed expression of CD20 and CD30. Most lymphoma cells expressed EBERs (Epstein–Barr encoded RNAs), LMP1 (EBV latent membrane protein 1), and LMP2a while EBNA2 (Epstein–Barr nuclear antigen 2) and BZLF1 (EBV immediate-early protein) were detected in a low number of neoplastic cells (Figure 1C). EBV PCR was negative in cerebrospinal fluid and weakly positive in peripheral blood (<1,000 copies/ml). Therefore, the diagnosis of EBV-related primary CNS PTLD was made.\n\nFigure 1 Posttransplant lymphoproliferative disease (PTLD) characteristics and composition of third party donor Epstein–Barr virus (EBV)-specific T-cell product. TPD-derived EBV-CTLs were manufactured by the clinical-scale IFN-γ-based CliniMACS cytokine capture system (CCS) and used for adoptive T-cell transfer (ACT). (A) Contrast-enhanced sagittal T1-weighted magnetic resonance imaging images of the patient’s central nervous system at diagnosis of PTLD. Images demonstrate multifocal hyperintense lesions in the left hemisphere in temporal, insular, and parietal lobe. (B) Histology of a brain lesion biopsy with staining for H&E and CD20. EBV-association was proven by EBER in situ hybridization. (C) Expression of EBV products in the lymphoma. LMP1, LMP2a, EBNA2, and BZLF1 were stained by immunohistochemistry. (D,E) Composition of the EBV-specific T-cell graft. Proportion of leukocyte subsets and the percentage of IFN-γ secreting EBV-specific T cells were detected after 4 h of ex vivo stimulation with the GMP-grade peptide pools EBV ppEBNA1 and ppSelect by flow cytometry. (D) Fractions collected during the EBV-specific T-cell manufacturing process [leukapheresis (LA), preselection (PreS), and positive fraction (PF)] were assessed for the proportion of lymphocyte and leukocyte subsets including: CD3+ T-cells, CD19+ B cells, CD56+ NK cells, CD3+CD56+ NKT cells, CD3−CD56+ NK cells, CD33+ granulocytes, and CD14+ monocytes. The compositions of the different cell subsets in the fractions LA, PreS, and PFs are shown. (E) The frequencies (left y-axis) and numbers (right y-axis) of IFN-γ+ cells (×106) within the CD3, CD4, and CD8 T-cell populations were analyzed in the PF of the CliniMACS CCS enrichment process to determine the efficiency of the process.\n\nTotal body imaging and bone marrow aspirate histology displayed no evidence for systemic disease. During initial treatment with dexamethasone, symptoms rapidly improved. Immunosuppression was stopped and immune-/chemotherapy was initiated with six doses of intravenous (i.v.) rituximab (375 mg/m2) and weekly intrathecal (i.th.) therapy with rituximab (40 mg), methotrexate (12 mg), cytarabine (30 mg), and prednisone (10 mg) over 10 weeks (9). A partial response by MRI was observed after 3 weeks evolving to complete remission at the end of immuno-/chemotherapy. Due to poor prognosis and the lack of EBV-specific T cells in the patient’s peripheral blood, we decided to consolidate treatment by transfer of partially HLA-matched EBV-CTLs.\n\nResults and Discussion\nThe patient received five doses of 2.5 × 104 EBV-CTLs/kg body weight from a 5/10 HLA-matched third party donor (TPD; Table 1). During the production process, CD3+ T-cells were enriched to >80% in the T-cell product with a predominance of CD8+ T-cells (Figures 1D,E; Data Sheet S1 in Supplemental Material). T-cells were administered every 3 weeks in the absence of graft-versus-host disease. After the second injection, the patient developed a skin rash around the neck, which turned out to be atopic dermatitis on histology and responded well to topical steroids without recurrence after subsequent T-cell injections. No other acute or chronic side effects were observed. EBV-PCR remained negative in peripheral blood throughout the whole course. After the end of treatment, immunosuppression was re-introduced with everolimus. At the last follow-up, 2 years after end of cellular therapy, the patient is in continuous remission of PTLD with good organ graft function.\n\nNo EBV-CTLs were detectable in patient blood on two occasions before adoptive immunotherapy (Figure 2A). In contrast, EBV-CTLs against ppEBNA1 and ppSelect became immediately and constantly detectable 4 days after the first T-cell transfer. While total numbers of CD3+, CD4+, and CD8+ T-cells remained stable throughout the treatment course, EBV-CTLs increased to a maximum of 40 per 250,000 PBMC before the second adoptive transfer. Over time, the target antigens of T-cell response broadened from initially EBNA1 and ppSelect to a broader response including T-cells against LMP2a and BZLF1, respectively (Figure 2A). Since epitopes from these two proteins matching the patient’s or donor’s HLA-type are not contained in the peptide pools used for manufacturing, this suggests that transfer of EBV-specific TPD cells induced an endogenous EBV-directed immune response in the patient, which was absent prior to immunotherapy. Frequency of EBV-CTLs increased during a 7-day in vitro restimulation and expansion demonstrating proliferative capacity (Figure 2B).\n\nFigure 2 Adoptive T-cell therapy and patient follow-up. (A) Monitoring of patients’ cellular immunity was performed with blood samples collected at different time points before and after adoptive T-cell transfer (ACT). Frequencies of CD3, CD4, and CD8 T-cells were assessed by flow cytometry following detection of the Epstein–Barr virus (EBV)-specific T-cell (EBV-CTL) repertoire in response to ppEBNA1, ppSelect, ppBZLF1, and ppLMP2a by using IFN-γ EliSpot. EBV copy numbers were determined in blood and stool samples by quantitative PCR. (B)\nEx vivo expansion of EBV-CTLs. PBMCs were isolated at different time points after ACT [white bars (before expansion, day 0)] and restimulated with the premium-grade peptide pools ppEBNA1 or ppSelect over 7 days [black bars (after expansion, day 7)] followed by the assessment of the EBV-CTL response against ppEBNA1 and ppSelect by IFN-γ Elispot.\n\nOccasionally, transferred cells could be detected in patient material after transfer, but most authors were unable to retrieve TPD cells on analysis (14). We aimed at dissecting EBV-directed T-cell responses in the T-cell graft and the patient on a clonal molecular level. We performed TCR beta chain (TRB) repertoire analyses by NGS to follow-up the transferred cells and to monitor their expansion to EBV-associated antigens. Investigating the 77 shared clonotypes 41 were identified as expanding clones in CD8+ T cells after the transfer (Figures 3A,B). Four clones could be detected in both follow-up samples at 6 and 7 months after T-cell transfer, while the remaining 37 clones were picked up only once. Notably, the most abundant clone (EBNA.D8 = CASSAGPATNEKLFF, Figure 3A; Table 2) in the enriched T-cell product was not recovered at high abundance while two other clones that made up only 0.001% each of the donor’s CD8 + TRB sequences appeared to expand to 0.51 and 0.17% in two patient samples obtained 7 months after transfer (EBNA.D1 = CASSSKRQVPDTQYF; Select.D6 = CASSPVRSSETQYF, Figure 3A and Table 2). These findings suggest that at least a fraction of the transferred TPD T-cells were expanding and presumably contributing to EBV-specific T-cell responses in the patient. At the same time, we observed a sustained EBNA1-specific expansion of endogenous TRB sequences that were already present in the recipient’s CD8+ T-cell pool before TPD T-cell treatment (Figure 3B). This is consistent with the idea that exogenous T-cells stimulated an efficient endogenous anti-EBV T-cell response and may explain the finding that EBV-T-cell responses against unrelated antigens (LMP2, BZLF1) newly arise after T-cell transfer. Due to limited material availability, we performed the analyses on expanded cells after one in vitro peptide pool restimulation, which leaves the possibility of ex vivo TCR skewing. These limitations need to be considered in future clinical trials.\n\nFigure 3 TCR beta chain sequencing of Epstein–Barr virus-stimulated T-cells before and after adoptive transfer. TCR beta chain sequencing was performed on blood samples at different timepoints before and after adoptive T-cell transfer and on the input sample itself. The left panel shows the samples enriched by stimulation with the ppEBNA1 peptide pool, whereas the right panel shows the ones after stimulation with ppSelect. Expansion of different shared clones is shown in both panels for exogenous (A) and endogenous (B) origin. Clones are labeled according to the antigen, origin (D, donor; R, recipient) and number. TCR sequences can be found in Table S1 in Supplementary Material.\n\nPrognosis of CNS PTLD is very poor with 30% overall survival (7, 8). We and others have reported successful administration of intrathecal rituximab; however, efficacy has not been validated in larger series (9, 15). Several studies and case reports show an effect of adoptive T-cell transfer in PTLD (10, 16–19). In particular, patients with CNS PTLD with poor outcome may benefit from this new treatment strategy (8, 9). Haque and colleagues reported responses in 3/5 patients with CNS PTLD after SOT using in vitro expanded EBV-specific TPD T-cell lines and lymphoma regression in CNS B-cell lymphoma in an immunodeficiency patient (10, 20). The efficacy of directly isolated EBV-CTLs in CNS PTLD after SOT is still unknown. Studies from patients after stem cell transplantation indicate that these cells are effective in CNS PTLD (19). In the case reported here, combined therapy with intrathecal chemotherapy and rituximab led to sustained complete remission of CNS PTLD. Transfer of partially HLA-matched EBV-CTLs provoked a robust anti-EBV T-cell response containing both exogenous and endogenous TRB signatures; the contribution of T-cell induction to ongoing remission remains uncertain.\n\nPartially HLA-matched TPDs are an attractive source of virus-specific T-cells readily available if pre-screened and registered in T-cell donor registries (13). We did not observe any side effects of TPD T-cell transfer similar to other studies employing virus-specific T-cell therapy, which supports their feasibility and safety. Prospective studies are warranted to prove safety and efficacy of freshly isolated EBV-CTLs from TPDs in this vulnerable patient population.\n\nEthics Statement\nThis case study was carried out in accordance with the Declaration of Helsinki. Treatment was provided on a compassionate use basis. The monitoring protocol was approved by the “ethics committee of Hannover Medical School.” Patient and legal representatives gave written informed consent to the diagnostic program.\n\nAuthor Contributions\nBM-K and BE-V designed research. RS-F, ST, LK, SR, and CS-F performed research. PH, LG, RB, UK, H-GH, and BE-V manufactured cell product and treated the patient. AK and IA performed histological analysis. ST, LK, SR, CK, IP, BE-V, and BM-K analyzed and interpreted data. RS-F, ST, LK, IP, PH, BE-V, and BM-K wrote the manuscript. All authors read the manuscript and approved the final version.\n\nConflict of Interest Statement\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nThis work was supported by the German children’s cancer fund (DKS 2011.05) and the German Federal Ministry of Education and Research (01EO1302). PH is participant in the BIH Charité Clinical Fellows Program funded by the Charité—Universitätsmedizin Berlin and the Berlin Institute of Health. We thank Nicole Neumann, Dörthe Rokitta, Marina Kramer, and Christopher Mielke for excellent technical assistance.\n\nSupplementary Material\nThe Supplementary Material for this article can be found online at https://www.frontiersin.org/articles/10.3389/fimmu.2018.01475/full#supplementary-material.\n\nClick here for additional data file.\n==== Refs\nReferences\n1 Mynarek M Schober T Behrends U Maecker-Kolhoff B . Posttransplant lymphoproliferative disease after pediatric solid organ transplantation . Clin Dev Immunol (2013 ) 2013 :814973 .10.1155/2013/814973 24174972 \n2 Wistinghausen B Gross TG Bollard C . Post-transplant lymphoproliferative disease in pediatric solid organ transplant recipients . 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Clin Infect Dis (2012 ) 55 :1064 –73 .10.1093/cid/cis625 22806594 \n15 Rubenstein JL Combs D Rosenberg J Levy A McDermott M Damon L \nRituximab therapy for CNS lymphomas: targeting the leptomeningeal compartment . Blood (2003 ) 101 :466 –8 .10.1182/blood-2002-06-1636 12393404 \n16 Moosmann A Bigalke I Tischer J Schirrmann L Kasten J Tippmer S \nEffective and long-term control of EBV PTLD after transfer of peptide-selected T cells . Blood (2010 ) 115 :2960 –70 .10.1182/blood-2009-08-236356 20103780 \n17 Doubrovina E Oflaz-Sozmen B Prockop SE Kernan NA Abramson S Teruya-Feldstein J \nAdoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation . Blood (2012 ) 119 :2644 –56 .10.1182/blood-2011-08-371971 22138512 \n18 Heslop H Slobod K Pule M Hale G Rousseau A Smith C \nLong term outcome of EBV specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients . Blood (2009 ) 115 :925 –36 .10.1182/blood-2009-08-239186 19880495 \n19 Icheva V Kayser S Wolff D Tuve S Kyzirakos C Bethge W \nAdoptive transfer of Epstein-Barr virus (EBV) nuclear antigen 1-specific T cells as treatment for EBV reactivation and lymphoproliferative disorders after allogeneic stem-cell transplantation . J Clin Oncol (2013 ) 31 :39 –48 .10.1200/JCO.2011.39.8495 23169501 \n20 Wynn RF Arkwright PD Haque T Gharib MI Wilkie G Morton-Jones M \nTreatment of Epstein-Barr-virus-associated primary CNS B-cell lymphoma with allogeneic T-cell immunotherapy and stem-cell transplantation . Lancet Oncol (2005 ) 6 :344 –6 .10.1016/S1470-2045(05)70171-6 15863383\n\n", "fulltext_license": "CC BY", "issn_linking": "1664-3224", "issue": "9()", "journal": "Frontiers in immunology", "keywords": "Epstein–Barr virus; T cell receptor sequencing; adoptive T cell therapy; posttransplant lymphoproliferative disease; transplantation", "medline_ta": "Front Immunol", "mesh_terms": null, "nlm_unique_id": "101560960", "other_id": null, "pages": "1475", "pmc": null, "pmid": "29997626", "pubdate": "2018", "publication_types": "D016428:Journal Article", "references": "15863383;24174972;17668865;24877879;22138512;20052713;23891747;22173060;23802715;22883417;15848587;17971586;20103780;23169501;17468341;22806594;23721553;12393404;25510656;19880495", "title": "Dissecting Epstein-Barr Virus-Specific T-Cell Responses After Allogeneic EBV-Specific T-Cell Transfer for Central Nervous System Posttransplant Lymphoproliferative Disease.", "title_normalized": "dissecting epstein barr virus specific t cell responses after allogeneic ebv specific t cell transfer for central nervous system posttransplant lymphoproliferative disease" }

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{ "abstract": "Fournier's gangrene (FG) is an uncommon form of necrotizing fasciitis, localized on the external genital organs, perianal region, and abdominal wall, accompanied by thrombosis of the feeding arteries, leading to gangrene of the skin and subcutaneous tissue, with manifestations of rapid clinical progression and multiple organ failure. Ramucirumab is a recombinant human immunoglobulin G1 monoclonal antibody that binds to the extracellular binding domain of vascular endothelial growth factor receptor-2 (VEGFR-2) and prevents the binding of all VEGFR ligands. The literature describes bevacizumab, aflibercept, and regorafenib associated with FG in patients with colorectal cancer. According to our knowledge this is the first report of FG possibly related to ramucirumab in a patient with gastric cancer. If not recognized in time, it can lead to fatal complications.", "affiliations": "Department of Oncology, University Hospital Centre Zagreb; School of Medicine, University of Zagreb, Kispaticeva 12, Zagreb, 10000, Croatia.;Department of Oncology, University Hospital Centre Zagreb, Zagreb, Croatia.;Department of Diagnostic and Interventional Radiology, University Hospital Centre, Zagreb, Croatia.", "authors": "Rakusic|Zoran|Z|https://orcid.org/0000-0002-5148-336X;Krpan|Ana Misir|AM|https://orcid.org/0000-0002-6184-7104;Sjekavica|Ivica|I|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1177/2042098620946556", "fulltext": "\n==== Front\nTher Adv Drug Saf\nTher Adv Drug Saf\nTAW\nsptaw\nTherapeutic Advances in Drug Safety\n2042-0986 2042-0994 SAGE Publications Sage UK: London, England \n\n10.1177/2042098620946556\n10.1177_2042098620946556\nCase Report\nFulminant Fournier’s gangrene in a patient with gastric cancer treated with ramucirumab and paclitaxel\nhttps://orcid.org/0000-0002-5148-336XRakusic Zoran Department of Oncology, University Hospital Centre Zagreb; School of Medicine, University of Zagreb, Kispaticeva 12, Zagreb, 10000, Croatia\n https://orcid.org/0000-0002-6184-7104Krpan Ana Misir Department of Oncology, University Hospital Centre Zagreb, Zagreb, Croatia\n Sjekavica Ivica Department of Diagnostic and Interventional Radiology, University Hospital Centre, Zagreb, Croatia\nSchool of Medicine, University of Zagreb, Zagreb, Croatia\n zrakusic@kbc-zagreb.hr\n17 8 2020 \n2020 \n11 204209862094655613 12 2019 2 7 2020 © The Author(s), 20202020SAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons LicensesThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Fournier’s gangrene (FG) is an uncommon form of necrotizing fasciitis, localized on the external genital organs, perianal region, and abdominal wall, accompanied by thrombosis of the feeding arteries, leading to gangrene of the skin and subcutaneous tissue, with manifestations of rapid clinical progression and multiple organ failure. Ramucirumab is a recombinant human immunoglobulin G1 monoclonal antibody that binds to the extracellular binding domain of vascular endothelial growth factor receptor-2 (VEGFR-2) and prevents the binding of all VEGFR ligands. The literature describes bevacizumab, aflibercept, and regorafenib associated with FG in patients with colorectal cancer. According to our knowledge this is the first report of FG possibly related to ramucirumab in a patient with gastric cancer. If not recognized in time, it can lead to fatal complications.\n\nFournier’s gangrenegastric cancerpaclitaxelramucirumabcover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nFournier’s gangrene (FG) is an uncommon disease of the genitals, found almost exclusively in men. It is a specific form of necrotizing fasciitis, localized on the external genital organs, the perianal region, as well as in the abdominal wall, accompanied by thrombosis of the feeding arteries, leading to gangrene of the skin and subcutaneous tissue, with manifestations of severe intoxication, rapid clinical progression, and multiple organ failure.1 Several predisposing factors are described, such as diabetes, obesity, and malignant disease, often accompanied with immunocompromised status resulting in high mortality rates. Four agents that target angiogenic pathways (i.e. bevacizumab, ramucirumab, aflibercept, and regorafenib) in combination with standard chemotherapy are approved for metastatic colorectal cancer. Ramucirumab is the preferred agent in combination with paclitaxel for the treatment of unresectable, locally advanced, recurrent or metastatic gastric cancer. In contrast to other agents, ramucirumab is a recombinant human immunoglobulin G1 monoclonal antibody that binds to the extracellular binding domain of VEGFR-2 and prevents the binding of all VEGFR ligands: VEGF-A, VEGF-C, and VEGF-D. Through blocking activation of VEGFR-2 by VEGF-A and the other VEGF ligands, ramucirumab inhibits the angiogenesis pathways involved in the development and progression of gastric cancer.2 Anti-angiogenic drugs, such as bevacizumab, aflibercept, and regorafenib, have already been described to have a possible connection with FG in patients with colorectal cancer. According to our knowledge this is the first case of FG reported in patients with gastric cancer and in patients treated with ramucirumab.\n\nCase presentation\nA 76-year-old man with gastric cancer was surgically treated in June 2017 (gastrectomy, omentectomy, splenectomy, and subtotal pancreatic resection, esophagojejunostomy, and entero-enteral anastomosis Roux); pathohistology findings confirmed gastric adenocarcinoma, pT4N2bM0, Her-2 negative. He received five cycles of adjuvant chemotherapy with cisplatin and 5-fluorouracil from July 2017 to October 2017. The planned sixth cycle of chemotherapy was refused by the patient. He was in follow up until August 2018 when magnetic resonance imaging confirmed liver metastases and ascites, general condition ECOG 0.\n\nIn September 2018 he started first-line chemotherapy for metastatic gastric cancer with ramucirumab 8 mg/kg on day 1 and day 15, and paclitaxel 80 mg/m2 on day 1, day 8, and day 15 every 4 weeks. During hospitalization for the second cycle of chemotherapy, the patient had mild upper abdominal pain, fatigue, suprapubic discomfort, and generalized edema including face, arms, legs, and scrotum. He had no fever and no other major changes in his condition. Laboratory findings showed insignificant decreases in potassium and calcium levels, serum albumin was 24.8 g/L (range 35.0–52.0 g/L), leukocytes 12.1 × 109/L (range 3.4–9.7 × 109/L), hemoglobin 105 g/L (range 139–175 g/L), and C-reactive protein (CRP) 84 mg/L (normal <5 mg/L. After the appearance of scrotal and penile edema associated with leukocytosis and CRP elevation, and oliguria, a urinary catheter was inserted. Computed tomography (CT) scan showed stable hepatic and lymph node metastases and ascites. A urologist was consulted because of signs of scrotal inflammation and antimicrobial therapy was started. After 2 days, the left scrotal sac perforated with abundant purulent drainage and suspected leakage of testicular tissue (Figure 1). Ultrasound and pelvic and scrotal CT scan showed extensive inflammation, multiple and confluent abscesses of pelvic and perirectal fat tissue, involving the ischiorectal fossa, perineum, suprapubic fat tissue, and scrotum. There was no sign of intestinal herniation (Figure 2).\n\nFigure 1. Scrotal perforation in a patient with necrotizing fasciitis.\n\nFigure 2. Sagittal CT scan with bubble gas appearance in the scrotum and perirectal and presacral space with fat tissue inflammation. CT, computed tomography.\n\nWith the diagnosis of FG, the patient was taken for an urgent operation, which included drainage of purulent secretion from the scrotum, bilateral orchiectomy, circular incision around the penile glans, and removal of penile skin. The histology report described large areas of necrotic skin, however, the testicles were intact. Blood and tissue cultures were collected and broad-spectrum antibiotic treatment was initiated; Proteus mirabilis, Pseudomonas aeruginosa, and Enterococcus faecalis were isolated. In the following days he underwent two additional excisional debridements and thereafter autologous split-thickness skin graft for penile coverage. These two additional interventions were complicated by postoperative hemorrhage. The patient died about 7 weeks after the diagnosis of FG and a prolonged treatment with antibiotics, parenteral nutrition, analgesics, and intensive supportive care.\n\nDiscussion\nFG in oncological patients has been described as being related to tumor location (e.g. rectal/sigmoid cancer), factors which increase the risk of infection in the area of impaired microvascularization (e.g. immunosuppression, diabetes), or adverse events of anti-angiogenic therapy that lead to blood supply disorder. Known risk factors for FG are diabetes mellitus type 2, i.v. drug use, obesity, malignant disease, immunosuppression, recent surgery, and trauma. Rare cases where the occurrence of this complication is unrelated to any known cause are classified as idiopathic. Treatment consists of an urgent surgical procedure of necrectomy, application of antimicrobial therapy, and other measures of supportive treatment, and plastic-reconstructive surgery. Despite the long and complex treatment, mortality is still high.\n\nIn this case, the patient was in very good overall condition without comorbidities. He did not take any medication, smoke, or consume alcohol, and did not report any trauma. Risk factors in our patient included immunosuppression related to chemotherapy and treatment with the anti-angiogenic drug ramucirumab.\n\nRamucirumab can cause arterial thrombosis which could have triggered the necrotizing fasciitis. Thereafter, necrotizing fasciitis rapidly develops without systemic clinical signs of inflammation or significantly changed laboratory parameters, possibly due to the age and general anergy of the patient. Also, fever, which is typical for this condition, was notably absent.3 Although artery thrombosis is a pathognomonic sign of FG, the tissue has not been analyzed histologically due to the extent of the necrosis.\n\nThe testicular tissue is not typically affected due to the different blood supply of the tissue contrary to the scrotum and perineum.4 The testicular artery is a branch of the abdominal aorta that supplies blood to the testis. The scrotum is supplied from the arteries that arise from the internal iliac artery, external iliac artery, and femoral artery. In our case, despite the extensive skin and subcutaneous tissue necrosis, the testes were not affected, which is an indirect sign of blood supply disturbance.\n\nThe mechanism of action of anti-angiogenic drugs is inhibition of VEGF signaling by blocking the VEGF ligand or VEGF receptor function and altering tissue and tumor vascularization. Arterial thrombotic events are well-described side effects of anti-angiogenic therapy. In addition a patient with VEGF inhibitor therapy has an increased tendency for bleeding and prolonged wound healing, which can further complicate postoperative recovery.\n\nCases of FG described in the literature were associated with colorectal cancer and the use of anti-angiogenic drugs like bevacizumab,5–8 aflibercept,9 and regorafenib.10 Mechanisms of FG included subcutaneous artery thrombosis and tissue ischemia.\n\nThere is no reported causal relationship of paclitaxel and FG in the literature. The use of chemotherapy may mask the clinical picture with the lack of an inflammatory response.\n\nThe exact mechanism of the onset of FG by the action of VEGF inhibitors has not been elucidated, although the occurrence of necrotizing fasciitis has been officially reported as a possible rare complication in patients with cancer during bevacizumab administration.6 In the affected area, VEGF inhibitors impede anti-inflammatory response by acting on blood vessels, reducing neoangiogenesis and impairing healing. Also, the thrombogenic effect leads to ischemic injuries that further support the progression of necrosis. Therefore, it is necessary to keep in mind the possibility of this complication while administering VEGF inhibitors, due to early diagnosis and early initiation of treatment. Further investigations into the mechanism of FG are certainly needed.\n\nThis case presented with rapid, fulminant progression of FG and lack of clinical signs and symptoms as well as no major changes in laboratory parameters. We described the case of FG in a patient with gastric cancer with atypical onset of disease complications possibly related to ramucirumab treatment. It is important to consider this complication in patients treated with anti-angiogenics because of high mortality and morbidity, and the need for urgent surgical procedure.\n\nConflict of interest statement: The authors declare that there is no conflict of interest.\n\nFunding: The authors received no financial support for the research, authorship, and/or publication of this article.\n\nInformed consent: Written informed consent for patient information and images to be published was provided by the patient.\n\nORCID iDs: Zoran Rakusic \nhttps://orcid.org/0000-0002-5148-336X\n\nAna Misir Krpan \nhttps://orcid.org/0000-0002-6184-7104\n==== Refs\nReferences\n1. \nAliev SA Rafiev SF Rafiev FS , et al\nFournier’s disease in surgeon’s practice\n. Khirurgiia (Mosk) \n2008 ; 58 –63\n.\n2. \nHopirtean C Nagy V \nOptimizing the use of anti VEGF targeted therapies in patients with metastatic colorectal cancer: review of literature\n. Clujul Med \n2018 ; 91 : 12 –17\n.29440946 \n3. \nChernyadyev SA Ufimtseva MA Vishnevskaya IF , et al\nFournier’s gangrene: literature review and clinical cases\n. Urol Int \n2018 ; 101 : 91 –97\n.29949811 \n4. \nEphimenko NA Privolnee VV \nFournier’s gangrene\n. Clin Microbiol Antimicrob Chemother \n2008 ; 10 : 25 –34\n.\n5. \nGamboa EO Rehmus EH Haller N \nFournier’s gangrene as a possible side effect of bevacizumab therapy for resected colorectal cancer\n. Clin Colorectal Cancer \n2010 ; 9 : 55 –58\n.20100690 \n6. \nShamloo BK Chhabra P Freedman AN , et al\nNovel adverse events of bevacizumab in the US FDA adverse event reporting system database: a disproportionality analysis\n. Drug Saf \n2012 ; 35 : 507 –518\n.22612854 \n7. \nIshida T Shinozaki H Ozawa H , et al\nA case of Fournier’s gangrene caused by small intestinal perforation during bevacizumab combination chemotherapy\n. Gan To Kagaku Ryoho \n2016 ; 43 : 909 –911\n.27431640 \n8. \nFukuhisa H Baba K Kita Y , et al\nA case of Fournier’s gangrene due to perforation of lower rectal cancer during chemotherapy\n. Gan To Kagaku Ryoho \n2017 ; 44 : 935 –937\n.29066701 \n9. \nGonzaga-López A Muñoz-Rodriguez J Ruiz-Casado A \nNecrotising fasciitis in a patient treated with FOLFIRI-aflibercept for colorectal cancer: a case report\n. Ann R Coll Surg Engl \n2017 ; 99 : e225 –e226\n.28768426 \n10. \nKoyama M Kitazawa M Ehara T , et al\nTwo cases of Fournier’s gangrene that occurred during chemotherapy for rectal cancer\n. Gan To Kagaku Ryoho \n2017 ; 44 : 169 –171\n.28223677\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2042-0986", "issue": "11()", "journal": "Therapeutic advances in drug safety", "keywords": "Fournier’s gangrene; gastric cancer; paclitaxel; ramucirumab", "medline_ta": "Ther Adv Drug Saf", "mesh_terms": null, "nlm_unique_id": "101549074", "other_id": null, "pages": "2042098620946556", "pmc": null, "pmid": "32874533", "pubdate": "2020", "publication_types": "D002363:Case Reports", "references": "29440946;27431640;28768426;22612854;29066701;19301497;28223677;20100690;29949811", "title": "Fulminant Fournier's gangrene in a patient with gastric cancer treated with ramucirumab and paclitaxel.", "title_normalized": "fulminant fournier s gangrene in a patient with gastric cancer treated with ramucirumab and paclitaxel" }

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FULMINANT FOURNIER^S GANGRENE IN A PATIENT WITH GASTRIC CANCER TREATED WITH RAMUCIRUMAB AND PACLITAXEL. THER?ADV?DRUG?SAF 2020?11:NO PAGINATION.", "literaturereference_normalized": "fulminant fournier s gangrene in a patient with gastric cancer treated with ramucirumab and paclitaxel", "qualification": "3", "reportercountry": "HR" }, "primarysourcecountry": "HR", "receiptdate": "20210505", "receivedate": "20210505", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19215802, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210717" }, { "companynumb": "HR-ACCORD-201378", "fulfillexpeditecriteria": "1", "occurcountry": "HR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "205720", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ON DAY 1, DAY 8, AND DAY 15 EVERY 4WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTATIC GASTRIC CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201809", "drugstartdateformat": "610", "drugstructuredosagenumb": "80", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL/PACLITAXEL LIPOSOME" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RAMUCIRUMAB" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ON DAY 1 AND DAY 15", "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTATIC GASTRIC CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201809", "drugstartdateformat": "610", "drugstructuredosagenumb": "8", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RAMUCIRUMAB" } ], "patientagegroup": null, "patientonsetage": "76", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Fournier^s gangrene", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RAKUSIC Z, KRPAN AM, SJEKAVICA I. FULMINANT FOURNIER^S GANGRENE IN A PATIENT WITH GASTRIC CANCER TREATED WITH RAMUCIRUMAB AND PACLITAXEL. THER ADV DRUG SAF. 2020 AUG 17?11:2042098620946556.", "literaturereference_normalized": "fulminant fournier s gangrene in a patient with gastric cancer treated with ramucirumab and paclitaxel", "qualification": "3", "reportercountry": "HR" }, "primarysourcecountry": "HR", "receiptdate": "20200917", "receivedate": "20200917", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18277010, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "HR-FRESENIUS KABI-FK202104241", "fulfillexpeditecriteria": "1", "occurcountry": "HR", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "RAMUCIRUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN,UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "FIRST?LINE CHEMOTHERAPY, ON DAY 1 AND DAY 15 EVERY 4 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA GASTRIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201809", "drugstartdateformat": "610", "drugstructuredosagenumb": "8", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RAMUCIRUMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "077574", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "FIRST?LINE CHEMOTHERAPY, ON DAY 1, DAY 8, AND DAY 15 EVERY 4 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA GASTRIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201809", "drugstartdateformat": "610", "drugstructuredosagenumb": "80", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL (MANUFACTURER UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": "76", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Abdominal pain upper", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Generalised oedema", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fournier^s gangrene", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oliguria", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RAKUSIC Z, KRPAN A, SJEKAVICA I. FULMINANT FOURNIER`S GANGRENE IN A PATIENT WITH GASTRIC CANCER TREATED WITH RAMUCIRUMAB AND PACLITAXEL. THERAPEUTIC ADVANCES IN DRUG SAFETY. 2020 JAN?11:.", "literaturereference_normalized": "fulminant fournier s gangrene in a patient with gastric cancer treated with ramucirumab and paclitaxel", "qualification": "3", "reportercountry": "HR" }, "primarysourcecountry": "HR", "receiptdate": "20210430", "receivedate": "20210430", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19201081, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]

{ "abstract": "We report a case of drug-induced myoclonus possibly related to palonosetron, a second-generation 5-hydroxytryptamine-3 receptor antagonist which was administered as a prophylaxis for postoperative nausea and vomiting in a 28-year-old female. The recurrent episodes of myoclonus jerk involving the head, neck and shoulder persisted for a period of 4 days. The patient also exhibited an episode of severe bradycardia leading to hypotension 7 h after surgery. To our knowledge, this is the first report presenting these adverse events potentially associated with the use of palonosetron.", "affiliations": "Department of Anaesthesiology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia. sh_chaw@yahoo.com.;Department of Anaesthesiology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia.;Department of Anaesthesiology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia.;Darul Ehsan Medical Centre Specialist Hospital, 40000, Shah Alam, Selangor, Malaysia.;Darul Ehsan Medical Centre Specialist Hospital, 40000, Shah Alam, Selangor, Malaysia.;Department of Anaesthesiology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia.", "authors": "Chaw|Sook Hui|SH|0000-0003-3886-6435;Chan|Lucy|L|;Lee|Pui Kuan|PK|;Bakar|Jaseemuddeen A|JA|;Rasiah|Raveenthiran|R|;Foo|Li Lian|LL|", "chemical_list": "D000932:Antiemetics; D007546:Isoquinolines; D011812:Quinuclidines; D000077924:Palonosetron", "country": "Japan", "delete": false, "doi": "10.1007/s00540-016-2228-8", "fulltext": null, "fulltext_license": null, "issn_linking": "0913-8668", "issue": "30(6)", "journal": "Journal of anesthesia", "keywords": "5- hydroxytryptamine-3 receptor antagonist; Drug-induced myoclonus; Palonosetron", "medline_ta": "J Anesth", "mesh_terms": "D000328:Adult; D000932:Antiemetics; D005260:Female; D006801:Humans; D007546:Isoquinolines; D009207:Myoclonus; D000077924:Palonosetron; D020250:Postoperative Nausea and Vomiting; D011812:Quinuclidines", "nlm_unique_id": "8905667", "other_id": null, "pages": "1063-1066", "pmc": null, "pmid": "27510560", "pubdate": "2016-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "9174325;19602754;11888546;8403171;11046230;10895777;9915363;19836386;12707136;7249508;18633025;9650847;11351116;22194808", "title": "Prolonged drug-induced myoclonus: is it related to palonosetron?", "title_normalized": "prolonged drug induced myoclonus is it related to palonosetron" }

[ { "companynumb": "MY-HTU-2016MY012049", "fulfillexpeditecriteria": "1", "occurcountry": "MY", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "PALONOSETRON HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "021372", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.075 MG, SINGLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS OF NAUSEA AND VOMITING", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".075", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALOXI" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FENTANYL" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 ?G, SINGLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SEVOFLURANE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SEVOFLURANE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CEFUROXIME" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.5 G, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.5", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFUROXIME." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PARECOXIB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANALGESIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PARECOXIB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG, SINGLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPOFOL." } ], "patientagegroup": null, "patientonsetage": "28", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myoclonus", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Bradycardia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dizziness", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHAW SH ET AL.. PROLONGED DRUG-INDUCED MYOCLONUS: IS IT RELATED TO PALONOSETRON?. J ANESTH. 2016", "literaturereference_normalized": "prolonged drug induced myoclonus is it related to palonosetron", "qualification": "1", "reportercountry": "MY" }, "primarysourcecountry": "MY", "receiptdate": "20161123", "receivedate": "20160825", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12684512, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" } ]

{ "abstract": "OBJECTIVE\nDrug-induced hepatotoxicity is potentially lethal. Liver transplant patients receive a large number of medications and adverse drug reactions, and drug-drug interactions must be closely monitored.\n\n\nMETHODS\nWe report a case of a 29-year-old liver transplant patient who suffered liver injury most likely induced by drug interaction between capecitabine and warfarin. Vitamin K1 caused skin rash possibly because of the distribution and metabolism characteristic of the drug in this patient.\n\n\nCONCLUSIONS\nClose monitoring and prompt discontinuation of the drugs with high volume of distribution and metabolized through the liver are necessary to avoid drug-drug interaction in liver transplant patients.", "affiliations": "Department of Pharmacy, Tianjin First Central Hospital, Tianjin, China.", "authors": "Zhu|L Q|LQ|;Jiang|W T|WT|;Pan|C|C|;Liu|Y H|YH|;Thian|Y|Y|", "chemical_list": "D000925:Anticoagulants; D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D014859:Warfarin; D000069287:Capecitabine; D010837:Vitamin K 1; D005472:Fluorouracil", "country": "England", "delete": false, "doi": "10.1111/jcpt.12150", "fulltext": null, "fulltext_license": null, "issn_linking": "0269-4727", "issue": "39(4)", "journal": "Journal of clinical pharmacy and therapeutics", "keywords": "capecitabine; drug interaction; liver injury; liver transplant; warfarin", "medline_ta": "J Clin Pharm Ther", "mesh_terms": "D000328:Adult; D000925:Anticoagulants; D000964:Antimetabolites, Antineoplastic; D000069287:Capecitabine; D056486:Chemical and Drug Induced Liver Injury; D003841:Deoxycytidine; D003875:Drug Eruptions; D004347:Drug Interactions; D016903:Drug Monitoring; D005472:Fluorouracil; D005500:Follow-Up Studies; D006801:Humans; D016031:Liver Transplantation; D008297:Male; D014018:Tissue Distribution; D010837:Vitamin K 1; D014859:Warfarin", "nlm_unique_id": "8704308", "other_id": null, "pages": "439-41", "pmc": null, "pmid": "24661191", "pubdate": "2014-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Liver injury possibly related to drug interaction after liver transplant: a case report.", "title_normalized": "liver injury possibly related to drug interaction after liver transplant a case report" }

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null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PHYTONADIONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COAGULOPATHY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VITAMIN K1" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "40196", "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "20130328", "drugenddateformat": "102", "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": null, "patientonsetage": "29", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatic encephalopathy", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Liver injury", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "17.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "17.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ZHU LQ, JIANG WT, PAN C, LIU YH, THIAN Y. LIVER INJURY POSSIBLY RELATED TO DRUG INTERACTION AFTER LIVER TRANSPLANT: A CASE REPORT. JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS. 2014;39(4):439-441", "literaturereference_normalized": "liver injury possibly related to drug interaction after liver transplant a case report", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20140804", "receivedate": "20140804", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10360254, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150326" }, { "companynumb": "CN-ROCHE-1441607", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, 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null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ENTECAVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS B", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ENTECAVIR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "GANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GANCICLOVIR" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CAPECITABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "020896", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "20130318", "drugenddateformat": "102", "drugindication": "HEPATIC CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAPECITABINE" } ], "patientagegroup": null, "patientonsetage": "29", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Liver injury", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ZHU L, JIANG W, PAN C, LIU Y AND THIAN Y. LIVER INJURY POSSIBLY RELATED TO DRUG INTERACTION AFTER LIVER TRANSPLANT: A CASE REPORT. JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS 2014 AUG 01;39(4):439-441.", "literaturereference_normalized": "liver injury possibly related to drug interaction after liver transplant a case report", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20140807", "receivedate": "20140807", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10367286, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150326" }, { "companynumb": "CN-WATSON-2015-09433", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "090402", "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS (UNKNOWN)" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090402", "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "1 G, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOMODULATORY THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS (UNKNOWN)" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOMODULATORY THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LIVER TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LIVER TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CAPECITABINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOMODULATORY THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAPECITABINE (UNKNOWN)" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "UNK", "drugenddate": "20150328", "drugenddateformat": "102", "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20150302", "drugstartdateformat": "102", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN (UNKNOWN)" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOMODULATORY THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CAPECITABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "UNK", "drugenddate": "20140318", "drugenddateformat": "102", "drugindication": "LIVER TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20130302", "drugstartdateformat": "102", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAPECITABINE (UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": "29", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Liver injury", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Hepatic encephalopathy", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "18.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "ZHU LQ, JIANG WT, PAN C, LIU YH, THIAN Y. LIVER INJURY POSSIBLY RELATED TO DRUG INTERACTION AFTER LIVER TRANSPLANT: A CASE REPORT. J CLIN PHARM THER. 2014;39(4):439-41", "literaturereference_normalized": "liver injury possibly related to drug interaction after liver transplant a case report", "qualification": "2", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20150511", "receivedate": "20150511", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11103439, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150821" }, { "companynumb": "CN-MYLAN-2014M1001037", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PHYTONADIONE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COAGULOPATHY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VITAMIN K" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CAPECITABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "20130318", "drugenddateformat": "102", "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAPECITABINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "040415", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "20130328", "drugenddateformat": "102", "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.5MG EVERY 12 HOURS", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Alanine aminotransferase increased", "reactionmeddraversionpt": "17.1", "reactionoutcome": null }, { "reactionmeddrapt": "Aspartate aminotransferase increased", "reactionmeddraversionpt": "17.1", "reactionoutcome": null }, { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatic encephalopathy", "reactionmeddraversionpt": "17.1", "reactionoutcome": null }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "17.1", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "ZHU LQ, JIANG WT, PAN C, LIU YH, THIAN Y. LIVER INJURY POSSIBLY RELATED TO DRUG INTERACTION AFTER LIVER TRANSPLANT: A CASE REPORT. J-CLIN-PHARM-THER 2014; 39(4) 439-441", "literaturereference_normalized": "liver injury possibly related to drug interaction after liver transplant a case report", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20140812", "receivedate": "20140812", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10377985, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150326" } ]

{ "abstract": "Analysis of maternal and neonatal blood samples for cholinesterase-activity determination revealed a case of hypoventilation in the newborn to be apparently secondary to succinylcholine administration to the mother during obstetric anesthesia.", "affiliations": null, "authors": "Owens|W D|WD|;Zeitlin|G L|GL|", "chemical_list": "D002802:Cholinesterases; D013390:Succinylcholine", "country": "United States", "delete": false, "doi": "10.1213/00000539-197501000-00007", "fulltext": null, "fulltext_license": null, "issn_linking": "0003-2999", "issue": "54(1)", "journal": "Anesthesia and analgesia", "keywords": null, "medline_ta": "Anesth Analg", "mesh_terms": "D000328:Adult; D000771:Anesthesia, Intravenous; D000773:Anesthesia, Obstetrical; D002585:Cesarean Section; D002802:Cholinesterases; D005260:Female; D006801:Humans; D007040:Hypoventilation; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases; D011247:Pregnancy; D013390:Succinylcholine", "nlm_unique_id": "1310650", "other_id": null, "pages": "38-40", "pmc": null, "pmid": "1167759", "pubdate": "1975", "publication_types": "D016428:Journal Article", "references": null, "title": "Hypoventilation in a newborn following administration of succinylcholine to the mother: a case report.", "title_normalized": "hypoventilation in a newborn following administration of succinylcholine to the mother a case report" }

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HYPOVENTILATION IN A NEWBORN FOLLOWING ADMINISTRATION OF SUCCINYLCHOLINE TO THE MOTHER: A CASE REPORT. ANESTHESIA AND ANALGESIA. 1975?54 (1):38-40", "literaturereference_normalized": "hypoventilation in a newborn following administration of succinylcholine to the mother a case report", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190523", "receivedate": "20190515", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16316314, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "US-PFIZER INC-2019375785", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "SUCCINYLCHOLINE CHLORIDE" }, 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null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THIOPENTAL SODIUM." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoventilation neonatal", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypotonia neonatal", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Muscular weakness", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Respiratory depth decreased", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Reflexes abnormal", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood cholinesterase abnormal", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Maternal exposure during delivery", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OWENS, W.. HYPOVENTILATION IN A NEWBORN FOLLOWING ADMINISTRATION OF SUCCINYLCHOLINE TO THE MOTHER: A CASE REPORT. ANESTHESIA + ANALGESIA. 1975?54(1):38-40", "literaturereference_normalized": "hypoventilation in a newborn following administration of succinylcholine to the mother a case report", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190917", "receivedate": "20190905", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16776558, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191005" } ]

{ "abstract": "A 72-year-old man underwent transarterial chemoembolization (TACE) for solitary hepatocellular carcinoma (HCC) located on the S6 segment. He had a history of anti-viral therapy for hepatitis C virus and was being treated for diabetes mellitus with inadequate control. On day 28 after TACE, he visited our hospital again, with complaints of fever and abdominal pain in the right upper quadrant. Blood examination showed elevated levels of white blood cells and C-reactive protein. Computed tomography showed a poorly marginated, low-density lesion measuring 9.5 × 8.0 × 4.0 cm, forming multiple small gas bubbles, located superiorly, and in contact with HCC treated by TACE. Ultrasound-guided puncture revealed whiffy and muddy pus. Gram staining of the pus showed the presence of numerous gram-positive rods, which were identified as Cutibacterium namnetense. He underwent percutaneous trans-hepatic abscess drainage and received antibiotics treatment. The abscess was successfully treated, and he was discharged on day 19. The incidence of liver abscess after TACE is rare, and intestinal microbiota have been reported to be the common pathogens. To the best of our knowledge, this is the first case of liver abscess caused by Cutibacterium namnetense.", "affiliations": "Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.;Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.;Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.;Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.;Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.;Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.;Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.;Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.;Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.;Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan. kodama@med.kobe-u.ac.jp.", "authors": "Yasutomi|Eiichiro|E|;Ueda|Yoshihide|Y|;Asaji|Naoki|N|;Yamamoto|Atsushi|A|;Yoshida|Ryutaro|R|;Hatazawa|Yuri|Y|;Hayashi|Hiroki|H|;Shiomi|Yuuki|Y|;Yano|Yoshihiko|Y|;Kodama|Yuzo|Y|http://orcid.org/0000-0003-1223-7147", "chemical_list": null, "country": "Japan", "delete": false, "doi": "10.1007/s12328-020-01283-5", "fulltext": null, "fulltext_license": null, "issn_linking": "1865-7265", "issue": "14(1)", "journal": "Clinical journal of gastroenterology", "keywords": "Cutibacterium namnetense; Liver abscess; Transarterial chemoembolization", "medline_ta": "Clin J Gastroenterol", "mesh_terms": "D000368:Aged; D006528:Carcinoma, Hepatocellular; D016461:Chemoembolization, Therapeutic; D006801:Humans; D008100:Liver Abscess; D008113:Liver Neoplasms; D008297:Male; D011423:Propionibacteriaceae; D012189:Retrospective Studies; D016896:Treatment Outcome", "nlm_unique_id": "101477246", "other_id": null, "pages": "246-250", "pmc": null, "pmid": "33174157", "pubdate": "2021-02", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "33488781;31950044;30547767", "title": "Liver abscess caused by Cutibacterium namnetense after transarterial chemoembolization for hepatocellular carcinoma.", "title_normalized": "liver abscess caused by cutibacterium namnetense after transarterial chemoembolization for hepatocellular carcinoma" }

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LIVER ABSCESS CAUSED BY CUTIBACTERIUM NAMNETENSE AFTER TRANSARTERIAL CHEMOEMBOLIZATION FOR HEPATOCELLULAR CARCINOMA. CLINICAL JOURNAL OF GASTROENTEROLOGY. 2021?14:246?250. DOI:HTTPS://DOI.ORG/10.1007/S12328?020?01283?5", "literaturereference_normalized": "liver abscess caused by cutibacterium namnetense after transarterial chemoembolization for hepatocellular carcinoma", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210610", "receivedate": "20210503", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19206246, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210717" }, { "companynumb": "JP-TEVA-2021-JP-1904453", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, 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"ETHIODIZED OIL" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS A PART OF TRANSARTERIAL CHEMOEMBOLIZATION; OIL", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATOCELLULAR CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIPIODOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TELMISARTAN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "80 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TELMISARTAN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROCHLOROTHIAZIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "12.5 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "12.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCHLOROTHIAZIDE." } ], "patientagegroup": "6", "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Therapy non-responder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bacterial infection", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Liver abscess", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "YASUTOMI E, UEDA Y, ASAJI N, YAMAMOTO A, YOSHIDA R, HATAZAWA Y, ET AL. LIVER ABSCESS CAUSED BY CUTIBACTERIUM NAMNETENSE AFTER TRANSARTERIAL CHEMOEMBOLIZATION FOR HEPATOCELLULAR CARCINOMA. CLIN?J?GASTROENTEROL 2021?14(1):246?250.", "literaturereference_normalized": "liver abscess caused by cutibacterium namnetense after transarterial chemoembolization for hepatocellular carcinoma", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210427", "receivedate": "20210427", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19182113, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210717" } ]

{ "abstract": "A 28-year-old woman with anorexia nervosa (AN) and Candida brain abscesses was transferred to our hospital for intensive treatment. On admission, she had a low-grade fever but no clinical neurological abnormalities were observed, even though she had a high-grade fever in the previous hospital. These clinical findings did not suggest a serious disorder in the brain. However, magnetic resonance imaging showed mass lesions in bilateral lentiform nuclei in addition to several abscesses in the whole body. The fungal cultures of specimens from abscesses on the anterior chest wall and iliopsoas muscle detected Candida albicans. She was treated with antifungal therapy (fosfluconazole, fluconazole, liposomal amphotericin B, and flucytosine) and two emergent craniotomies for drainage of the intracranial fluid. Thereafter, antifungal medications (voriconazole and flucytosine) were administered for six months as a longterm treatment, which abolished most abscesses. However, severe frontal lobe dysfunction persisted as a residual symptom. This case suggests that AN can mask clinical manifestations of infection. We should always consider the possibility of infectious complications in these patients.", "affiliations": "Department of Neurology, Fukushima Medical University, Fukushima, Japan. Electronic address: yoshiken@fmu.ac.jp.;Department of Neurology, Fukushima Medical University, Fukushima, Japan.;Department of Neurosurgery, Fukushima Medical University, Fukushima, Japan.;Department of Neurosurgery, Aichi Medical University, Nagakute, Japan.;Department of Infection Control, Fukushima Medical University, Fukushima, Japan.;Department of Neurosurgery, Fukushima Medical University, Fukushima, Japan.;Department of Neurology, Fukushima Medical University, Fukushima, Japan.;Department of Human Nuerophysiology, School of Medicine, Fukushima Medical University, Fukushima, Japan.", "authors": "Yoshida|Kenji|K|;Matsuda|Nozomu|N|;Sato|Taku|T|;Watanabe|Tadashi|T|;Nakamura|Kiwamu|K|;Saito|Kiyoshi|K|;Kanai|Kazuaki|K|;Ugawa|Yoshikazu|Y|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.clineuro.2021.107058", "fulltext": null, "fulltext_license": null, "issn_linking": "0303-8467", "issue": "212()", "journal": "Clinical neurology and neurosurgery", "keywords": "Anorexia nervosa; Antifungal agents; Brain abscess; Candida albicans; Catheter; Central venous", "medline_ta": "Clin Neurol Neurosurg", "mesh_terms": null, "nlm_unique_id": "7502039", "other_id": null, "pages": "107058", "pmc": null, "pmid": "34844162", "pubdate": "2021-11-24", "publication_types": "D016428:Journal Article", "references": null, "title": "Candida brain abscesses in a patient with anorexia nervosa receiving total parenteral nutrition.", "title_normalized": "candida brain abscesses in a patient with anorexia nervosa receiving total parenteral nutrition" }

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{ "abstract": "A 34-year-old female presented with fever and abdominal pain. Past medical history includes Crohn's and Behcet's disease. Examination revealed multiple skin ulcerations, oral aphthae, and bilateral coarse rales. She developed respiratory distress with diffuse bilateral alveolar infiltrates on chest radiograph requiring intubation. PaO2/FiO2 ratio was 132. The chest computed tomography revealed extensive nodular and patchy ground-glass opacities. Bronchoalveolar lavage demonstrated a predominance of neutrophils. Methylprednisolone 60 mg every 6 h and broad-spectrum antimicrobials were initiated. No infectious etiologies were identified. Surgical lung biopsy demonstrated diffuse alveolar damage (DAD) mixed with lymphocytic and necrotizing vasculitis with multiple small infarcts and thrombi consistent with Behcet's vasculitis. As she improved, steroids were tapered and discharged home on oral cyclophosphamide. Pulmonary involvement in Behcet's is unusual and commonly manifests as pulmonary artery aneurysms, thrombosis, infarction, and hemorrhage. Lung biopsy findings demonstrating DAD are consistent with the clinical diagnosis of adult respiratory distress syndrome. The additional findings of necrotizing vasculitis and infarcts may have led to DAD.", "affiliations": "Department of Pulmonary and Critical Care Medicine, Lenox Hill Hospital, New York, USA.;Department of Pulmonary and Critical Care Medicine, Lenox Hill Hospital, New York, USA.;Department of Pulmonary and Critical Care Medicine, Lenox Hill Hospital, New York, USA.;Department of Pulmonary and Critical Care Medicine, Lenox Hill Hospital, New York, USA.", "authors": "Vydyula|Ravikanth|R|;Allred|Charles|C|;Huartado|Mariana|M|;Mina|Bushra|B|", "chemical_list": null, "country": "India", "delete": false, "doi": "10.4103/0970-2113.142127", "fulltext": "\n==== Front\nLung IndiaLung IndiaLILung India : Official Organ of Indian Chest Society0970-21130974-598XMedknow Publications & Media Pvt Ltd India LI-31-38710.4103/0970-2113.142127Case ReportSurgical lung biopsy to diagnose Behcet's vasculitis with adult respiratory distress syndrome Vydyula Ravikanth MDAllred Charles Huartado Mariana Mina Bushra Department of Pulmonary and Critical Care Medicine, Lenox Hill Hospital, New York, USAAddress for correspondence: Dr. Ravikanth Vydyula, Department of Pulmonary and Critical Care Medicine, Lenox Hill Hospital, 100E 77th ST, New York - 10075, USA. E-mail: drvydyula@gmail.comOct-Dec 2014 31 4 387 389 Copyright: © Lung India2014This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.A 34-year-old female presented with fever and abdominal pain. Past medical history includes Crohn's and Behcet's disease. Examination revealed multiple skin ulcerations, oral aphthae, and bilateral coarse rales. She developed respiratory distress with diffuse bilateral alveolar infiltrates on chest radiograph requiring intubation. PaO2/FiO2 ratio was 132. The chest computed tomography revealed extensive nodular and patchy ground-glass opacities. Bronchoalveolar lavage demonstrated a predominance of neutrophils. Methylprednisolone 60 mg every 6 h and broad-spectrum antimicrobials were initiated. No infectious etiologies were identified. Surgical lung biopsy demonstrated diffuse alveolar damage (DAD) mixed with lymphocytic and necrotizing vasculitis with multiple small infarcts and thrombi consistent with Behcet's vasculitis. As she improved, steroids were tapered and discharged home on oral cyclophosphamide. Pulmonary involvement in Behcet's is unusual and commonly manifests as pulmonary artery aneurysms, thrombosis, infarction, and hemorrhage. Lung biopsy findings demonstrating DAD are consistent with the clinical diagnosis of adult respiratory distress syndrome. The additional findings of necrotizing vasculitis and infarcts may have led to DAD.\n\nKEY WORDS\nAdult respiratory distress syndromeBehcet's diseaseBehcet's vasculitisdiffuse alveolar damagelung injuryvasculitis\n==== Body\nINTRODUCTION\nBehcet's disease is an idiopathic vasculitis characterized by recurrent mucocutaneous ulcerations and uveitis. The diagnosis is made on the basis of clinical findings.[123] It is very prevalent in Turkey, but also seen worldwide.[4] Although Behcet's disease can affect any organ system, pulmonary involvement is uncommon and typically manifests as pulmonary vascular lesions. Pulmonary artery aneurysms involving the large proximal branches of the pulmonary arteries are the most common finding on chest computed tomography[5678] and hemoptysis is a common presenting symptom. Pulmonary small vessel vasculitis and lung parenchymal involvement is rarely reported, although the true incidence is uncertain given that histopathologic correlation is seldom pursued.[9] This is an unusual case of Behcet's disease complicated by hypoxemic respiratory failure and acute respiratory distress syndrome. To our knowledge, this is the first case of adult respiratory distress syndrome associated with Behcet's disease with diffuse alveolar damage (DAD) and vasculitis on lung biopsy.\n\nCASE REPORT\nA 34 year-old, non-Turkish, Caucasian female with a history of Behcet's disease refractory to multiple immunosuppressive regimens presents with severe diffuse abdominal pain. She also reported a recent exacerbation of her Behcet's disease with skin ulcerations and orogenital aphthae. Past medical history included chronic sinusitis, migraine headaches, and Crohn's disease. She smokes one pack of cigarettes a day. Since the diagnosis of Behcet's, she had failed single-agent therapies, and therefore had required treatment with various combinations of immunosuppressants. Her current regimen included concomitant use of mycophenolate mofetil, methotrexate, azathioprine, infliximab, and prednisone at a dose of 50 mg daily. She self-discontinued methotrexate 2 weeks prior to her presentation due to gastrointestinal upset and the prednisone dose was increased to 80 mg given her current symptoms. The prednisone dose was then reduced to 50 mg several days later to avoid side effects from high-dose steroids. On day 2 of admission, she experienced rapidly progressive shortness of breath and hypoxemia requiring intubation and mechanical ventilation. She was febrile with a temperature of 102.7°F. Physical examination revealed a cushingoid-appearing female with a left mandibular healing ulcer, multiple punched out mucocutaneous ulcerations, and bilateral diffuse wheeze on auscultation. Her PaO2/FiO2 ratio was 132. An echocardiogram was normal. Chest radiography showed extensive bilateral alveolar infiltrates [Figure 1a]. Computed tomography of the chest revealed numerous small nodules and patchy areas of ground glass opacity [Figure 1b]. Bronchoscopy reveals numerous upper airway aphthous ulcers. Bronchoalveolar lavage showed a predominance of neutrophils. Intravenous methylprednisolone 60 mg every 6 h and empiric broad-spectrum antimicrobials were initiated. Bacterial, fungal, and viral cultures, including studies for Aspergillus and Pneumocystis jirovecii were unremarkable. Serology and immunology including polymerase chain reaction (PCR) for cytomegalovirus, flu antigens A and B, rapid human immunodeficiency virus (HIV) antibody, Mycoplasma pneumoniae antibody immunoglobulin (Ig) G and IgM, Legionella, and Cryptococcal antigens were negative. CD4 count was 96. Vasculitis panel, which includes serum myeloperoxidase antibodies (cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA)), serum proteinase 3 antibody (perinuclear-ANCA (p-ANCA)), rheumatoid factor, serum antinuclear antibodies (ANA) titers, creatinine kinase, and aldolase levels were all unremarkable. Urine analysis was normal and renal function remained stable. Antibiotics were subsequently discontinued several days later. On day 5, a surgical lung biopsy was performed that revealed areas of necrosis and DAD mixed with lymphocytic and necrotizing vasculitis with multiple small infarcts and thrombi [Figures 1c and d]. She recovered over the next 10 days and was successfully extubated. Steroids were slowly tapered and she was discharged home on combination therapy with cyclophosphamide and prednisone.\n\nFigure 1 (a) Extensive bilateral infiltrates. (b) Numerous patchy areas of ground glass opacities. (c) Diffuse alveolar damage characterized by intra-alveolar fibrin and hyaline membranes (hematoxylin and eosin stain (H and E)). (d) Multiple thrombi and infracts (H and E)\n\nDISCUSSION\nThis is a case of Behcet's disease complicated by an acute fulminant pulmonary syndrome. The findings of necrotizing vasculitis with multiple infarcts and thrombi are consistent with previously described pulmonary manifestations of Behcet's disease.[10] The literature pertaining to pulmonary involvement in Behcet's disease is mostly limited to case reports and case series describing large vessel vasculitis such as pulmonary artery aneurysms and their sequelae. Data on lung parenchymal involvement in Behcet's disease is scarce. The various pathologic findings reported include pulmonary infarction, hemorrhage, interstitial lung disease, and small vessel vasculitis. DAD in association with Behcet's disease has rarely been described.[11] As surgical lung biopsy in Behcet's disease is seldom pursued, true incidence of pulmonary Behcet's disease is likely underdiagnosed. To our knowledge, this is the first case of Behcet's disease with pulmonary involvement manifesting as DAD mixed with necrotizing vasculitis on lung biopsy.\n\nDAD is a well-described lung injury pattern which can occur in many settings including infection, collagen vascular disease, drug toxicity, inhalational injury, and uremia. It may be idiopathic. In the absence of any identifiable cause, the clinical diagnosis of acute interstitial pneumonia is appropriate. In this case, the coexistent vasculitis with multiple small infarcts consistent with lung involvement by Behcet's disease may have triggered the onset of DAD, and it provides an explanation for the clinical presentation. It is possible the abrupt tapering of steroids prior to her presentation led to an exacerbation of Behcet's disease.\n\nDiffuse alveolar hemorrhage (DAH), another diagnosis to consider in the setting of vasculitis, is a syndrome characterized by injury or inflammation of the pulmonary arterioles, venules, or alveolar septal capillaries, and is associated with three different histologic patterns, including pulmonary capillaritis, bland alveolar hemorrhage, and DAD. DAH can result from a variety of conditions, such as coagulation disorders, drugs, toxins, collagen vascular diseases, and mitral stenosis. DAH is also commonly associated with ANCA positive vasculitis presenting as a pulmonary renal syndrome. Alveolar hemorrhage in Behcet's vasculitis is rare but may occur in the setting of DAD.[1213]\n\nDrug-induced lung injury is another possible explanation for her presentation. Immunosuppressive therapy is the mainstay of treatment for Behcet's disease, although evidence supporting specific agents is limited. Several immunomodulators and biologic agents, some of which our patient was using, have been reported to cause lung injury. Methotrexate, azathioprine, mycophenolate mofetil, as well as the tumor necrosis factor alpha inhibitor infliximab, have all been associated with varying degrees of pulmonary toxicity, including DAD.[14] A cohort study of 514 patients with acute lung injury reported an incidence of drug-associated lung injury of 9.5%.[15]\n\nPulmonary involvement in Behcet's disease, although uncommon, is a real entity and can be life-threatening. Physicians who treat patients with Behcet's disease, especially those with unexplained respiratory complaints, must keep this in their differential. Patients with Behcet's disease, especially those on immunosuppressant therapy should be frequently evaluated for any such evolving respiratory complications as well as drug-related pulmonary toxicity. For those on chronic steroid therapy, abrupt withdrawal or rapid tapering of steroids should be avoided to prevent an exacerbation of underlying vasculitis. High-dose corticosteroids appeared to have benefited our patient who had a complete recovery. Future lung biopsy-confirmed cases of DAD in association with Behcet's disease may help elucidate pathophysiologic mechanisms and optimize treatment.\n\nIn conclusion, this is a case of pulmonary Behcet's disease presenting as adult respiratory distress syndrome with DAD and vasculitis on lung biopsy. Physicians must maintain a high index of suspicion and early lung biopsy may help in the diagnosis and management of patients with Behcet's disease who present with unexplained respiratory failure.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\nREFERENCES\n1 Gurler A Boyvat A Tursen U Clinical manifestations of Behcet's disease: An analysis of 2147 patients Yonsei Med J 1997 38 423 7 9509912 \n2 Sakane T Takeno M Suzuki N Inaba G Behcet's disease N Engl J Med 1999 341 1284 91 10528040 \n3 Saadoun D Wechsler B Behcet's disease Orphanet J Rare Dis 2012 7 20 22497990 \n4 Davatchi F Shahram F Chams-Davatchi C Shams H Nadji A Akhlaghi M Behcet's disease: From east to west Clin Rheumatol 2010 29 823 33 20354748 \n5 Uzun O Akpolat T Erkan L Pulmonary vasculitis in behcet disease: A cumulative analysis Chest 2005 127 2243 53 15947344 \n6 Uzon O Erkan L Akpolat I Findik S Atici AG Akpolat T Pulmonary involvement in Behcet's disease Respiration 2008 75 310 21 17446699 \n7 Akoglu T Paydas S Sarpel S Tunali N Tuncer I Incomplete Behcet's syndrome with unusual manifestations Ann Rheum Dis 1987 46 632 3 3662652 \n8 Tunaci A Berkmen YM Gokmen E Thoracic involvement in Behcet's disease: Pathologic, clinical, and imaging features AJR Am J Roentgenol 1995 164 51 6 7998568 \n9 Jennette JC Falk RJ Small-vessel vasculitis N Engl J Med 1997 337 1512 23 9366584 \n10 Seyahi E Melikoglu E Akman C Hamuryudan V Ozer H Hatemi G Pulmonary artery involvement and associated lung disease in Behçet disease: A series of 47 patients Medicine (Baltimore) 2012 91 35 48 22210555 \n11 Kim HK Yong HS Oh YW Shim JJ Kim HK Kang EY Behcet's disease complicated by diffuse alveolar damage J Thorac Imaging 2005 20 55 7 15729125 \n12 Grosso V Boveri E Bogliolo L Montecucco C Caporali R Diffuse alveolar hemorrhage as a manifestation of Behcet's disease Reumatismo 2013 65 138 41 23884031 \n13 West S Arulkumaran N Ind PW Pusey CD Diffuse alveolar haemorrhage in ANCA-associated vasculitis Intern Med 2013 52 5 13 23291668 \n14 Rokutanda R Okada M Yamaguchi K Nozaki T Deshpande GA Kishimoto M Infliximab for Behcet disease with aortic involvement: Two novel case reports without concurrent use of immunosuppressive agents or corticosteroids Mod Rheumatol 2013 23 412 3 22821442 \n15 Dhokarh R Li G Schmikl CN Kashyap R Assudani J Limper AH Drug-associated acute lung injury: A population-based cohort study Chest 2012 142 845 50 22539646\n\n", "fulltext_license": "CC BY-NC-SA", "issn_linking": "0970-2113", "issue": "31(4)", "journal": "Lung India : official organ of Indian Chest Society", "keywords": "Adult respiratory distress syndrome; Behcet's disease; Behcet's vasculitis; diffuse alveolar damage; lung injury; vasculitis", "medline_ta": "Lung India", "mesh_terms": null, "nlm_unique_id": "8405380", "other_id": null, "pages": "387-9", "pmc": null, "pmid": "25378849", "pubdate": "2014-10", "publication_types": "D016428:Journal Article", "references": "17446699;15729125;20354748;10528040;22821442;22539646;22497990;15947344;3662652;23884031;7998568;9366584;9509912;23291668;22210555", "title": "Surgical lung biopsy to diagnose Behcet's vasculitis with adult respiratory distress syndrome.", "title_normalized": "surgical lung biopsy to diagnose behcet s vasculitis with adult respiratory distress syndrome" }

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"reactionoutcome": "1" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute respiratory distress syndrome", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Vasculitis necrotising", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cushingoid", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diffuse alveolar damage", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VYDYULA R, ALLRED C, HUARTADO M, MINA B.. 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"AZATHIOPRINE." } ], "patientagegroup": null, "patientonsetage": "34", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Diffuse alveolar damage", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute respiratory distress syndrome", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Vasculitis necrotising", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Abdominal discomfort", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "VYDYULA R,ALLRED C,HUARTADO M,MINA B. SURGICAL LUNG BIOPSY TO DIAGNOSE BEHCET^S VASCULITIS WITH ADULT RESPIRATORY DISTRESS SYNDROME.. 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"reactionmeddrapt": "Behcet^s syndrome", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Vasculitis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Aphthous ulcer", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute respiratory distress syndrome", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Rales", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Abdominal pain", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Ulcer", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "VYDYULA R, ALLRED C, HUARTADO M, MINA B. SURGICAL LUNG BIOPSY TO DIAGNOSE BEHCET^S VASCULITIS WITH ADULT RESPIRATORY DISTRESS SYNDROME.. LUNG-INDIA. 2014;31(4):387-9", "literaturereference_normalized": "surgical lung biopsy to diagnose behcet s vasculitis with adult respiratory distress syndrome", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150720", "receivedate": "20150720", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11285426, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20151125" }, { "companynumb": "US-APOTEX-2015AP010749", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": 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null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "BEHCET^S SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "80 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Behcet^s syndrome", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute respiratory distress syndrome", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Diffuse alveolar damage", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulmonary vasculitis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "VYDYULA R, ALLRED C, HUARTADO M, MINA B.. SURGICAL LUNG BIOPSY TO DIAGNOSE BEHCET^S VASCULITIS WITH ADULT RESPIRATORY DISTRESS SYNDROME. ;. LUNG-INDIA. 2014;31(4):387-389", "literaturereference_normalized": "surgical lung biopsy to diagnose behcet s vasculitis with adult respiratory distress syndrome", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150722", "receivedate": "20150722", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11292409, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20151125" }, { "companynumb": "US-TEVA-580870USA", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", 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"drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AND THEN TAPERED TO 50MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "BEHCET^S SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": 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"reactionmeddrapt": "Behcet^s syndrome", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Diffuse alveolar damage", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute respiratory distress syndrome", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulmonary vasculitis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Abdominal discomfort", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VYDYULA R, ALLRED C, HUARTADO M, MINA B. SURGICAL LUNG BIOPSY TO DIAGNOSE BEHCET^S VASCULITIS WITH ADULT RESPIRATORY DISTRESS SYNDROME. LUNG-INDIA 2014; 31(4):387-389.", "literaturereference_normalized": "surgical lung biopsy to diagnose behcet s vasculitis with adult respiratory distress syndrome", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150728", "receivedate": "20150728", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11317572, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20151125" }, { "companynumb": "US-ORION CORPORATION ORION PHARMA-TREX2015-0486", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, 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"Diffuse alveolar damage", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Behcet^s syndrome", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute respiratory distress syndrome", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Vasculitis necrotising", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "VYDYULA R,ALLRED C. SURGICAL LUNG BIOPSY TO DIAGNOSE BEHCET^S VASCULITIS WITH ADULT RESPIRATORY DISTRESS SYNDROME. LUNG INDIA. 2014 OCT;31(4):387-9.", "literaturereference_normalized": "surgical lung biopsy to diagnose behcet s vasculitis with adult respiratory distress syndrome", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150722", "receivedate": "20150722", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11291152, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20151125" }, { "companynumb": "US-HORIZON-PRE-0107-2015", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, 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SURGICAL LUNG BIOPSY TO DIAGNOSE BEHCET^S VASCULITIS WITH ADULT RESPIRATORY DISTRESS SYNDROME. LUNG INDIA. 2014 OCT;31(4):387-9. ?", "literaturereference_normalized": "surgical lung biopsy to diagnose behcet s vasculitis with adult respiratory distress syndrome", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150805", "receivedate": "20150727", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11313990, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20151125" }, { "companynumb": "US-MYLANLABS-2015M1024053", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, 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"drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BEHCET^S SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulmonary vasculitis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute respiratory distress syndrome", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Behcet^s syndrome", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Abdominal discomfort", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diffuse alveolar damage", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "VYDYULA R, ALLRED C, HUARTADO M, MINA B. SURGICAL LUNG BIOPSY TO DIAGNOSE BEHCET^S VASCULITIS WITH ADULT RESPIRATORY DISTRESS SYNDROME. LUNG-INDIA 2014; 31(4):387-389.", "literaturereference_normalized": "surgical lung biopsy to diagnose behcet s vasculitis with adult respiratory distress syndrome", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150721", "receivedate": "20150721", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11289923, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20151125" }, { "companynumb": "US-JNJFOC-20141114352", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "103772", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LYOPHILIZED POWDER", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BEHCET^S SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INFLIXIMAB, RECOMBINANT" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." } ], "patientagegroup": "5", "patientonsetage": "34", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VYDYULA R, ALLRED C, HUARTADO M, MINA B. SURGICAL LUNG BIOPSY TO DIAGNOSE BEHCET^S VASCULITIS WITH ADULT RESPIRATORY DISTRESS SYNDROME. LUNG INDIA 2014;31/4:387-389.", "literaturereference_normalized": "surgical lung biopsy to diagnose behcet s vasculitis with adult respiratory distress syndrome", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150525", "receivedate": "20150405", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10988853, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150821" } ]

{ "abstract": "OBJECTIVE\nTo investigate word recognition in noise in subjects treated in childhood with chemotherapy, study benefits of open-fitting hearing-aids for word recognition, and investigate whether self-reported hearing-handicap corresponded to subjects' word recognition ability.\n\n\nMETHODS\nSubjects diagnosed with cancer and treated with platinum-based chemotherapy in childhood underwent audiometric evaluations.\n\n\nMETHODS\nFifteen subjects (eight females and seven males) fulfilled the criteria set for the study, and four of those received customized open-fitting hearing-aids.\n\n\nRESULTS\nSubjects with cisplatin-induced ototoxicity had severe difficulties recognizing words in noise, and scored as low as 54% below reference scores standardized for age and degree of hearing loss. Hearing-impaired subjects' self-reported hearing-handicap correlated significantly with word recognition in a quiet environment but not in noise. Word recognition in noise improved markedly (up to 46%) with hearing-aids, and the self-reported hearing-handicap and disability score were reduced by more than 50%.\n\n\nCONCLUSIONS\nThis study demonstrates the importance of testing word recognition in noise in subjects treated with platinum-based chemotherapy in childhood, and to use specific custom-made questionnaires to evaluate the experienced hearing-handicap. Open-fitting hearing-aids are a good alternative for subjects suffering from poor word recognition in noise.", "affiliations": "Department of Clinical Sciences, Lund University, Sweden. einar-jon.einarsson@med.lu.se", "authors": "Einarsson|Einar-Jón|EJ|;Petersen|Hannes|H|;Wiebe|Thomas|T|;Fransson|Per-Anders|PA|;Magnusson|Måns|M|;Moëll|Christian|C|", "chemical_list": "D000970:Antineoplastic Agents; D002945:Cisplatin", "country": "England", "delete": false, "doi": "10.3109/14992027.2011.585667", "fulltext": null, "fulltext_license": null, "issn_linking": "1499-2027", "issue": "50(10)", "journal": "International journal of audiology", "keywords": null, "medline_ta": "Int J Audiol", "mesh_terms": "D000161:Acoustic Stimulation; D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents; D001301:Audiometry, Pure-Tone; D001302:Audiometry, Speech; D001309:Auditory Threshold; D002648:Child; D002945:Cisplatin; D012048:Correction of Hearing Impairment; D004185:Disability Evaluation; D005260:Female; D006310:Hearing Aids; D034381:Hearing Loss; D006801:Humans; D008297:Male; D009622:Noise; D010470:Perceptual Masking; D019986:Persons With Hearing Impairments; D021641:Recognition, Psychology; D020127:Recovery of Function; D012189:Retrospective Studies; D013067:Speech Perception; D011795:Surveys and Questionnaires; D013548:Sweden; D016896:Treatment Outcome; D055815:Young Adult", "nlm_unique_id": "101140017", "other_id": null, "pages": "642-51", "pmc": null, "pmid": "21812630", "pubdate": "2011-10", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Severe difficulties with word recognition in noise after platinum chemotherapy in childhood, and improvements with open-fitting hearing-aids.", "title_normalized": "severe difficulties with word recognition in noise after platinum chemotherapy in childhood and improvements with open fitting hearing aids" }

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SEVERE DIFFICULTIES WITH WORD RECOGNITION IN NOISE AFTER PLATINUM CHEMOTHERAPY IN CHILDHOOD, AND IMPROVEMENTS WITH OPEN-FITTING HEARING-AIDS. 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SEVERE DIFFICULTIES WITH WORD RECOGNITION IN NOISE AFTER PLATINUM CHEMOTHERAPY IN CHILDHOOD, AND IMPROVEMENTS WITH OPEN-FITTING HEARING-AIDS. 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"reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Deafness", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "EINARSSON EJ, PETERSEN H, WIEBE T, FRANSSON PA, GRENNER J, MAGNUSSON M, MOELL C.. SEVERE DIFFICULTIES WITH WORD RECOGNITION IN NOISE AFTER PLATINUM CHEMOTHERAPY IN CHILDHOOD, AND IMPROVEMENTS WITH OPEN-FITTING HEARING-AIDS. INTERNATIONAL JOURNAL OF AUDIOLOGY. 2011?50:642-51", "literaturereference_normalized": "severe difficulties with word recognition in noise after platinum chemotherapy in childhood and improvements with open fitting hearing aids", "qualification": "3", "reportercountry": "SE" }, "primarysourcecountry": "SE", "receiptdate": "20181115", "receivedate": "20181115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15620077, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "SE-JNJFOC-20190804887", "fulfillexpeditecriteria": "1", "occurcountry": "SE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": 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"activesubstancename": "BLEOMYCIN SULFATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EWING^S SARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BLEOMYCIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", 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"reactionoutcome": "3" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Deafness", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tinnitus", "reactionmeddraversionpt": "22.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "EINARSSON E, PETERSEN H, WIEBE T, FRANSSON P, GRENNER J, MAGNUSSON M, MOELL C. SEVERE DIFFICULTIES WITH WORD RECOGNITION IN NOISE AFTER PLATINUM CHEMOTHERAPY IN CHILDHOOD, AND IMPROVEMENTS WITH OPEN-FITTING HEARING-AIDS.. INTERNATIONAL JOURNAL OF AUDIOLOGY. 2011?50:642-51.", "literaturereference_normalized": "severe difficulties with word recognition in noise after platinum chemotherapy in childhood and improvements with open fitting hearing aids", "qualification": "3", "reportercountry": "SE" }, "primarysourcecountry": "SE", "receiptdate": "20190806", "receivedate": "20190806", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16675093, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191004" } ]

{ "abstract": "OBJECTIVE\nTo report a case of Zostavax-associated acute retinal necrosis in a patient with chronic lymphocytic leukemia.\n\n\nMETHODS\nCase report.\n\n\nMETHODS\nA 76-year-old white man.\n\n\nRESULTS\nUnilateral acute retinal necrosis with obliterative angiopathy developed in close proximity of a Zostavax vaccine. Treatment with valacyclovir hydrochloride (1 g orally three times a day) and intravitreal ganciclovir (4 mg/0.1 mL) was initiated on presentation. Because of continuous increase of the retinal necrosis, patient was switched to intravenous acyclovir (7.5 mg/kg body weight, adapted to reduced glomerular filtration rate) and given intravitreal foscarnet (2.4 mg/0.1 mL). Despite being on maximal antiviral therapy, the patient suffered a central retinal artery occlusion.\n\n\nCONCLUSIONS\nAcute retinal necrosis is a severe complication and potentially blinding disease of herpes zoster, and can occur in association with herpes zoster immunization, in particular, in immune suppressed patients.", "affiliations": "Department of Ophthalmology, Sir Charles Gairdner Hospital, Hospital Ave, Western Australia, Australia.;Department of Ophthalmology, Sir Charles Gairdner Hospital, Hospital Ave, Western Australia, Australia.;Private Ophthalmology Practice, Karrinyup, Washington, Australia; and.;Department of Ophthalmology, Sir Charles Gairdner Hospital, Hospital Ave, Western Australia, Australia.;Department of Ophthalmology, Sir Charles Gairdner Hospital, Hospital Ave, Western Australia, Australia.", "authors": "Menghini|Moreno|M|;Raja|Vignesh|V|;Raiter|Jeremy|J|;Balaratnasingam|Chandrakumar|C|;Constable|Ian J|IJ|", "chemical_list": "D000998:Antiviral Agents; D005938:Glucocorticoids; D053061:Herpes Zoster Vaccine; D008775:Methylprednisolone", "country": "United States", "delete": false, "doi": "10.1097/ICB.0000000000000761", "fulltext": null, "fulltext_license": null, "issn_linking": "1935-1089", "issue": "15(2)", "journal": "Retinal cases & brief reports", "keywords": null, "medline_ta": "Retin Cases Brief Rep", "mesh_terms": "D000368:Aged; D000998:Antiviral Agents; D015828:Eye Infections, Viral; D005938:Glucocorticoids; D006562:Herpes Zoster; D006563:Herpes Zoster Ophthalmicus; D053061:Herpes Zoster Vaccine; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D008775:Methylprednisolone; D015882:Retinal Necrosis Syndrome, Acute; D014611:Vaccination", "nlm_unique_id": "101298744", "other_id": null, "pages": "166-168", "pmc": null, "pmid": "30048403", "pubdate": "2021-03-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "ACUTE RETINAL NECROSIS ASSOCIATED WITH HERPES ZOSTER VACCINATION.", "title_normalized": "acute retinal necrosis associated with herpes zoster vaccination" }

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"6" }, { "reactionmeddrapt": "Retinal artery occlusion", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MORENO M, VIGNESH R, RAITER J, BALARATNASINGAM C, CONSTABLE I. ACUTE RETINAL NECROSIS ASSOCIATED WITH HERPES ZOSTER VACCINATION. RETINAL CASES AND BRIEF REPORTS. 2018?0:1?3.", "literaturereference_normalized": "acute retinal necrosis associated with herpes zoster vaccination", "qualification": "1", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20180821", "receivedate": "20180813", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15269557, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" }, { "companynumb": "AU-MYLANLABS-2021M1084483", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALACYCLOVIR HYDROCHLORIDE" }, "drugadditional": "2", "drugadministrationroute": "048", "drugauthorizationnumb": "078518", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 GRAM, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "Antiviral treatment", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALACYCLOVIR HYDROCHLORIDE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "GANCICLOVIR" }, "drugadditional": "2", "drugadministrationroute": null, "drugauthorizationnumb": "204560", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Injection", "drugdosagetext": "4 MG/0.1 ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "Antiviral treatment", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GANCICLOVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACYCLOVIR" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "019909", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Injection", "drugdosagetext": "7.5 MILLIGRAM/KILOGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "Antiviral treatment", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "7.5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACYCLOVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FOSCARNET" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Injection", "drugdosagetext": "2.4 MG/0.1 ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "Antiviral treatment", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOSCARNET" } ], "patientagegroup": null, "patientonsetage": "76", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Papillitis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Iridocyclitis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Visual acuity reduced", "reactionmeddraversionpt": "24.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "Menghini M, Raja V, Raiter J, Balaratnasingam C, Constable IJ. ACUTE RETINAL NECROSIS ASSOCIATED WITH HERPES ZOSTER VACCINATION. Retin-Cases-Brief-Rep 2021;15(2):166-168.", "literaturereference_normalized": "acute retinal necrosis associated with herpes zoster vaccination", "qualification": "1", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20211210", "receivedate": "20211116", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20075265, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 1, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" }, { "companynumb": "AU-SUN PHARMACEUTICAL INDUSTRIES LTD-2018R1-181245", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALACYCLOVIR HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "76588", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 GRAM, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "NECROTISING RETINITIS", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "8", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALACYCLOVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACYCLOVIR" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "7.5 MILLIGRAM/KILOGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL TREATMENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "7.5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACYCLOVIR." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FOSCARNET" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.4 MG/0.1 ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "NECROTISING RETINITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOSCARNET" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "GANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 MILLIGRAM/0.1 ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "NECROTISING RETINITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GANCICLOVIR." } ], "patientagegroup": null, "patientonsetage": "76", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MENGHINI M , RAJA V , RAITER J , BALARATNASINGAM C , CONSTABLE IJ. ACUTE RETINAL NECROSIS ASSOCIATED WITH HERPES ZOSTER VACCINATION. RETIN CASES BRIEF REP. 2018?JUL 25:1-3", "literaturereference_normalized": "acute retinal necrosis associated with herpes zoster vaccination", "qualification": "1", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20190218", "receivedate": "20180813", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15269235, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" } ]

{ "abstract": "Axillary artery blowout is a rare life- and limb-threatening condition. The traditional surgical approach of ligation and extra-anatomic bypass is associated with a high morbidity and mortality. We present a case report of a 65-year-old male with axillary artery hemorrhage secondary to an irradiated squamous cell cancer. We propose a staged hybrid approach for the treatment of this unusual clinical entity consisting of emergent stent grafting followed by planned elective extra-anatomic bypass, debridement, and a course of specific antimicrobial therapy.", "affiliations": "Division of Vascular Surgery, Department of Surgery, Duke University Medical Center, Durham, NC, USA.;Division of Vascular Surgery, Department of Surgery, Duke University Medical Center, Durham, NC, USA.", "authors": "Weissler|Elizabeth Hope|EH|https://orcid.org/0000-0002-8442-6150;Southerland|Kevin W|KW|", "chemical_list": "D000890:Anti-Infective Agents", "country": "United States", "delete": false, "doi": "10.1177/1538574419887306", "fulltext": null, "fulltext_license": null, "issn_linking": "1538-5744", "issue": "54(2)", "journal": "Vascular and endovascular surgery", "keywords": "hemorrhage; hybrid intervention; radiation damage; stent graft infection; upper extremity", "medline_ta": "Vasc Endovascular Surg", "mesh_terms": "D000368:Aged; D000890:Anti-Infective Agents; D001366:Axillary Artery; D001807:Blood Vessel Prosthesis; D019917:Blood Vessel Prosthesis Implantation; D002294:Carcinoma, Squamous Cell; D003646:Debridement; D057510:Endovascular Procedures; D006470:Hemorrhage; D006801:Humans; D008297:Male; D011832:Radiation Injuries; D018714:Radiotherapy, Adjuvant; D012878:Skin Neoplasms; D015607:Stents; D016896:Treatment Outcome", "nlm_unique_id": "101136421", "other_id": null, "pages": "172-174", "pmc": null, "pmid": "31714184", "pubdate": "2020-02", "publication_types": "D002363:Case Reports", "references": "18421037;28826996;30802582;24321265;29962258", "title": "A Hybrid Approach to Radiation-Induced Axillary Artery Hemorrhage.", "title_normalized": "a hybrid approach to radiation induced axillary artery hemorrhage" }

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{ "abstract": "A 18-year-old woman experienced abnormal and painful vaginal tissue loss while using an oral contraceptive. A pregnancy test was negative. Histopathological examination of the tissue showed a decidualised endometrium. We made the diagnosis of progesterone-induced membranous dysmenorrhoea.", "affiliations": "VU, School of Medical Sciences, Amsterdam.", "authors": "van Gaal|Nora|N|;van Krimpen|C Kees|CK|;Zwart|Christof A|CA|", "chemical_list": "D003276:Contraceptives, Oral; D011374:Progesterone", "country": "Netherlands", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0028-2162", "issue": "160()", "journal": "Nederlands tijdschrift voor geneeskunde", "keywords": null, "medline_ta": "Ned Tijdschr Geneeskd", "mesh_terms": "D000293:Adolescent; D003276:Contraceptives, Oral; D004717:Endometrium; D005260:Female; D006801:Humans; D017699:Pelvic Pain; D011374:Progesterone; D014621:Vagina", "nlm_unique_id": "0400770", "other_id": null, "pages": "A9515", "pmc": null, "pmid": "26840936", "pubdate": "2016", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "A young woman with abnormal vaginal tissue loss.", "title_normalized": "a young woman with abnormal vaginal tissue loss" }

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A YOUNG WOMAN WITH ABNORMAL VAGINAL TISSUE LOSS.. NEDERLANDS TIJDSCHRIFT VOOR GENEESKUNDE. 2016?160(6):A9515", "literaturereference_normalized": "a young woman with abnormal vaginal tissue loss", "qualification": "1", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20181116", "receivedate": "20180918", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15396897, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190204" }, { "companynumb": "NL-PFIZER INC-2018162835", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETHINYL ESTRADIOL\\LEVONORGESTREL" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "019192", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (150 UG/30 UG)", "drugenddate": null, "drugenddateformat": null, "drugindication": "CONTRACEPTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETHINYLESTRADIOL/LEVONORGESTREL" } ], "patientagegroup": null, "patientonsetage": "18", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Placental disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dysmenorrhoea", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VAN GAAL, N.. A YOUNG WOMAN WITH ABNORMAL VAGINAL TISSUE LOSS.. NEDERLANDS TIJDSCHRIFT VOOR GENEESKUNDE. 2016?160(6):A9515", "literaturereference_normalized": "a young woman with abnormal vaginal tissue loss", "qualification": "1", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20180613", "receivedate": "20180426", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14816836, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" }, { "companynumb": "NL-GLENMARK PHARMACEUTICALS-2018GMK034780", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETHINYL ESTRADIOL\\LEVONORGESTREL" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "091452", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CONTRACEPTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETHINYLESTRADIOL/LEVONORGESTREL" } ], "patientagegroup": null, "patientonsetage": "18", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Placental disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dysmenorrhoea", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VAN GAAL N, VAN KRIMPEN C C, ZWART C A.. A YOUNG WOMAN WITH ABNORMAL VAGINAL TISSUE LOSS.. NEDERLANDS TIJDSCHRIFT VOOR GENEESKUNDE. 2016?160 (6)", "literaturereference_normalized": "a young woman with abnormal vaginal tissue loss", "qualification": "1", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20180430", "receivedate": "20180430", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14826032, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" }, { "companynumb": "NL-MYLANLABS-2018M1030869", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETHINYL ESTRADIOL\\LEVONORGESTREL" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "091663", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CONTRACEPTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETHINYLESTRADIOL/LEVONORGESTREL" } ], "patientagegroup": null, "patientonsetage": "18", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dysmenorrhoea", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Placental disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VAN GAAL N, VAN KRIMPEN CC, ZWART CA.. A YOUNG WOMAN WITH ABNORMAL VAGINAL TISSUE LOSS.. NEDERLANDS TIJDSCHRIFT VOOR GENEESKUNDE. 2016?160(6):A9515", "literaturereference_normalized": "a young woman with abnormal vaginal tissue loss", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20180511", "receivedate": "20180510", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14873755, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" } ]

{ "abstract": "OBJECTIVE Intravenous nicardipine is commonly used for blood pressure reduction in patients with acute stroke. However, few studies have described its effects on cerebrovascular hemodynamics as measured by transcranial Doppler (TCD) waveform analysis and pulsatility index (PI). In this study, the authors report examples of a consistent but paradoxical finding associated with nicardipine that suggests intracranial vasoconstriction, contrary to what is expected from a vasodilator. METHODS The data presented are from a convenience sample of patients who underwent TCD monitoring before, after, or during nicardipine administration. In each case, TCD waveform morphologies and PIs were compared. RESULTS The TCD waveforms during nicardipine infusion are characterized by a prominent systolic peak and dicrotic notch. Systolic deceleration was more pronounced and PIs were significantly elevated in patients who were on nicardipine (p < 0.001). This finding was not evident when patients were not on nicardipine. CONCLUSIONS This study provides the first evidence of paradoxical intracranial vasoconstriction associated with intravenous nicardipine. In the authors' experience, this finding is consistently encountered in the vast majority of patients who are treated with intravenous nicardipine, and is contradictory to what is expected from a vasodilator. Future studies are needed to confirm this finding in larger populations and diverse clinical settings and to examine mechanisms that explain this phenomenon.", "affiliations": "Departments of1Neurosurgery and.;2Neurology, Cedars-Sinai Medical Center, Los Angeles, California; and.;2Neurology, Cedars-Sinai Medical Center, Los Angeles, California; and.;2Neurology, Cedars-Sinai Medical Center, Los Angeles, California; and.;Departments of1Neurosurgery and.;3Departments of Neurology and Neurosurgery, Icahn School of Medicine, New York, New York.;2Neurology, Cedars-Sinai Medical Center, Los Angeles, California; and.", "authors": "Lahiri|Shouri|S|;Nezhad|Mani|M|;Schlick|Konrad H|KH|;Rinsky|Brenda|B|;Rosengart|Axel|A|;Mayer|Stephan A|SA|;Lyden|Patrick D|PD|", "chemical_list": "D002121:Calcium Channel Blockers; D009529:Nicardipine", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0022-3085", "issue": "128(4)", "journal": "Journal of neurosurgery", "keywords": "Doppler; EDV = end-diastolic velocity; MCA = middle cerebral artery; MFV = mean flow velocity; PCoA = posterior communicating artery; PI = pulsatility index; PSV = peak systolic velocity; SAH = subarachnoid hemorrhage; TCD = transcranial Doppler; VA = vertebral artery; hemodynamics; nicardipine; pulsatility index; transcranial; ultrasonography; vascular disorders; vasoconstriction", "medline_ta": "J Neurosurg", "mesh_terms": "D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D017542:Aneurysm, Ruptured; D001783:Blood Flow Velocity; D002121:Calcium Channel Blockers; D002543:Cerebral Hemorrhage; D002560:Cerebrovascular Circulation; D005260:Female; D006339:Heart Rate; D006439:Hemodynamics; D006801:Humans; D002532:Intracranial Aneurysm; D008297:Male; D008875:Middle Aged; D009529:Nicardipine; D020521:Stroke; D017585:Ultrasonography, Doppler, Transcranial; D014661:Vasoconstriction", "nlm_unique_id": "0253357", "other_id": null, "pages": "1015-1019", "pmc": null, "pmid": "28430036", "pubdate": "2018-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Paradoxical cerebrovascular hemodynamic changes with nicardipine.", "title_normalized": "paradoxical cerebrovascular hemodynamic changes with nicardipine" }

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PARADOXICAL CEREBROVASCULAR HEMODYNAMIC CHANGES WITH NICARDIPINE. 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PARADOXICAL CEREBROVASCULAR HEMODYNAMIC CHANGES WITH NICARDIPINE. JOURNAL OF NEUROSURGERY. 2018 APR?128(4):1015-1019.", "literaturereference_normalized": "paradoxical cerebrovascular hemodynamic changes with nicardipine", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200511", "receivedate": "20200511", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17768417, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200714" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-269437", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "NICARDIPINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "078405", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BLOOD PRESSURE MANAGEMENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NICARDIPINE" } ], "patientagegroup": null, "patientonsetage": "46", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cerebral vasoconstriction", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemodynamic instability", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LAHIRI S, NEZHAD M, SCHLICK KH, RINSKY B, ROSENGART A, MAYER SA, ET AL. PARADOXICAL CEREBROVASCULAR HEMODYNAMIC CHANGES WITH NICARDIPINE. J NEUROSURG. 2018?APR 128:1015-1019", "literaturereference_normalized": "paradoxical cerebrovascular hemodynamic changes with nicardipine", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201215", "receivedate": "20201215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18617347, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210114" }, { "companynumb": "US-BAXTER-2020BAX009873", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "NICARDIPINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "041", "drugauthorizationnumb": "019734", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BLOOD PRESSURE INCREASED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARDENE" } ], "patientagegroup": null, "patientonsetage": "57", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cerebral vasoconstriction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Paradoxical drug reaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "LAHIRI S, NEZHAD M, SCHLICK K, RINSKY B, ROSENGART A, MAYER S, LYDEN P. 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PARADOXICAL CEREBROVASCULAR HEMODYNAMIC CHANGES WITH NICARDIPINE. 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PARADOXICAL CEREBROVASCULAR HEMODYNAMIC CHANGES WITH NICARDIPINE. 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PARADOXICAL CEREBROVASCULAR HEMODYNAMIC CHANGES WITH NICARDIPINE. 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PARADOXICAL CEREBROVASCULAR HEMODYNAMIC CHANGES WITH NICARDIPINE. J NEUROSURG. 2018?APR 128:1015-1019", "literaturereference_normalized": "paradoxical cerebrovascular hemodynamic changes with nicardipine", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201215", "receivedate": "20201215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18617346, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210114" }, { "companynumb": "US-BAXTER-2020BAX009869", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "NICARDIPINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "041", "drugauthorizationnumb": "019734", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BLOOD PRESSURE INCREASED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARDENE" } ], "patientagegroup": null, "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Paradoxical drug reaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cerebral vasoconstriction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "LAHIRI S, NEZHAD M, SCHLICK K, RINSKY B, ROSENGART A, MAYER S, LYDEN P. PARADOXICAL CEREBROVASCULAR HEMODYNAMIC CHANGES WITH NICARDIPINE. JOURNAL OF NEUROSURGERY. 2018 APR?128(4):1015-1019.", "literaturereference_normalized": "paradoxical cerebrovascular hemodynamic changes with nicardipine", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200511", "receivedate": "20200511", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17768396, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200714" }, { "companynumb": "US-MYLANLABS-2019M1095199", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "NICARDIPINE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "090664", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BLOOD PRESSURE MEASUREMENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NICARDIPINE" } ], "patientagegroup": null, "patientonsetage": "46", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cerebral vasoconstriction", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Paradoxical drug reaction", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LAHIRI S, NEZHAD M, SCHLICK KH, RINSKY B, ROSENGART A, MAYER SA, ET AL. PARADOXICAL CEREBROVASCULAR HEMODYNAMIC CHANGES WITH NICARDIPINE. 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PARADOXICAL CEREBROVASCULAR HEMODYNAMIC CHANGES WITH NICARDIPINE. 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PARADOXICAL CEREBROVASCULAR HEMODYNAMIC CHANGES WITH NICARDIPINE. JOURNAL OF NEUROSURGERY? DOI: 10.3171/2016.11.JNS161992. 2018?128(4):1015-1019.", "literaturereference_normalized": "paradoxical cerebrovascular hemodynamic changes with nicardipine", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200511", "receivedate": "20200511", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17765419, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200714" }, { "companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-20-02182", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "NICARDIPINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "02276", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BLOOD PRESSURE INCREASED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NICARDIPINE" } ], "patientagegroup": null, "patientonsetage": "66", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cerebral vasoconstriction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LAHIRI S, NEZHAD M, SCHLICK K, RINSKY B, ROSENGART A, MAYER S, LYDEN P. PARADOXICAL CEREBROVASCULAR HEMODYNAMIC CHANGES WITH NICARDIPINE? DOI: 10.3171/2016.11.JNS161992.. JOURNAL OF NEUROSURGERY. 2018?128(4):1015-1019.", "literaturereference_normalized": "paradoxical cerebrovascular hemodynamic changes with nicardipine", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200512", "receivedate": "20200512", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17768772, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200714" }, { "companynumb": "US-MYLANLABS-2019M1095202", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "NICARDIPINE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "090664", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BLOOD PRESSURE MANAGEMENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NICARDIPINE" } ], "patientagegroup": null, "patientonsetage": "30", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cerebral vasoconstriction", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Paradoxical drug reaction", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LAHIRI S, NEZHAD M, SCHLICK KH, RINSKY B, ROSENGART A, MAYER SA, ET AL. PARADOXICAL CEREBROVASCULAR HEMODYNAMIC CHANGES WITH NICARDIPINE. J-NEUROSURG 2018?128(4):1015-1019.", "literaturereference_normalized": "paradoxical cerebrovascular hemodynamic changes with nicardipine", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20191014", "receivedate": "20191014", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16914040, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-223459", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "NICARDIPINE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "078405", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BLOOD PRESSURE MANAGEMENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NICARDIPINE" } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cerebral vasoconstriction", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemodynamic instability", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LAHIRI S, NEZHAD M, SCHLICK KH, RINSKY B, ROSENGART A, MAYER SA, ET AL. PARADOXICAL CEREBROVASCULAR HEMODYNAMIC CHANGES WITH NICARDIPINE. 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PARADOXICAL CEREBROVASCULAR HEMODYNAMIC CHANGES WITH NICARDIPINE. JOURNAL OF NEUROSURGERY. 2018 APR?128(4):1015-1019.", "literaturereference_normalized": "paradoxical cerebrovascular hemodynamic changes with nicardipine", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200511", "receivedate": "20200511", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17768420, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200714" }, { "companynumb": "US-MYLANLABS-2019M1095204", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "NICARDIPINE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "090664", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BLOOD PRESSURE MANAGEMENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NICARDIPINE" } ], "patientagegroup": null, "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Paradoxical drug reaction", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cerebral vasoconstriction", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LAHIRI S, NEZHAD M, SCHLICK KH, RINSKY B, ROSENGART A, MAYER SA, ET AL. PARADOXICAL CEREBROVASCULAR HEMODYNAMIC CHANGES WITH NICARDIPINE. J-NEUROSURG 2018?128(4):1015-1019.", "literaturereference_normalized": "paradoxical cerebrovascular hemodynamic changes with nicardipine", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20191014", "receivedate": "20191014", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16914030, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "US-BAXTER-2020BAX009874", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "NICARDIPINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "041", "drugauthorizationnumb": "019734", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BLOOD PRESSURE INCREASED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARDENE" } ], "patientagegroup": null, "patientonsetage": "30", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cerebral vasoconstriction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Paradoxical drug reaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "LAHIRI S, NEZHAD M, SCHLICK K, RINSKY B, ROSENGART A, MAYER S, LYDEN P. PARADOXICAL CEREBROVASCULAR HEMODYNAMIC CHANGES WITH NICARDIPINE. 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PARADOXICAL CEREBROVASCULAR HEMODYNAMIC CHANGES WITH NICARDIPINE. 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PARADOXICAL CEREBROVASCULAR HEMODYNAMIC CHANGES WITH NICARDIPINE. J-NEUROSURG 2018?128(4):1015-1019.", "literaturereference_normalized": "paradoxical cerebrovascular hemodynamic changes with nicardipine", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20191014", "receivedate": "20191014", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16914045, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-20-02181", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "NICARDIPINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "022276", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BLOOD PRESSURE INCREASED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NICARDIPINE" } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cerebral vasoconstriction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LAHIRI S, NEZHAD M, SCHLICK K, RINSKY B, ROSENGART A, MAYER S, LYDEN P. PARADOXICAL CEREBROVASCULAR HEMODYNAMIC CHANGES WITH NICARDIPINE. JOURNAL OF NEUROSURGERY? DOI: 10.3171/2016.11.JNS161992. 2018?128 (4):1015-1019.", "literaturereference_normalized": "paradoxical cerebrovascular hemodynamic changes with nicardipine", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200512", "receivedate": "20200512", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17769651, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200714" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-269433", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "NICARDIPINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "078405", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BLOOD PRESSURE MANAGEMENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NICARDIPINE" } ], "patientagegroup": null, "patientonsetage": "66", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemodynamic instability", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cerebral vasoconstriction", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LAHIRI S, NEZHAD M, SCHLICK KH, RINSKY B, ROSENGART A, MAYER SA, ET AL. PARADOXICAL CEREBROVASCULAR HEMODYNAMIC CHANGES WITH NICARDIPINE. J NEUROSURG. 2018?APR 128:1015-1019", "literaturereference_normalized": "paradoxical cerebrovascular hemodynamic changes with nicardipine", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201215", "receivedate": "20201215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18618111, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210114" }, { "companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-20-02180", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "NICARDIPINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "02276", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BLOOD PRESSURE MEASUREMENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NICARDIPINE" } ], "patientagegroup": null, "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cerebral vasoconstriction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LAHIRI S, NEZHAD M, SCHLICK K, RINSKY B, ROSENGART A, MAYER S, LYDEN P. PARADOXICAL CEREBROVASCULAR HEMODYNAMIC CHANGES WITH NICARDIPINE. JOURNAL OF NEUROSURGERY? DOI: 10.3171/2016.11.JNS161992.. 2018?128(4):1015-1019.", "literaturereference_normalized": "paradoxical cerebrovascular hemodynamic changes with nicardipine", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200512", "receivedate": "20200512", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17769263, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200714" }, { "companynumb": "US-BAXTER-2020BAX009871", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "NICARDIPINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "041", "drugauthorizationnumb": "019734", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "ON POST-HEMORRHAGE DAY 2", "drugenddate": null, "drugenddateformat": null, "drugindication": "BLOOD PRESSURE INADEQUATELY CONTROLLED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARDENE" } ], "patientagegroup": null, "patientonsetage": "66", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Paradoxical drug reaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cerebral vasoconstriction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "LAHIRI S, NEZHAD M, SCHLICK K, RINSKY B, ROSENGART A, MAYER S, LYDEN P. PARADOXICAL CEREBROVASCULAR HEMODYNAMIC CHANGES WITH NICARDIPINE. JOURNAL OF NEUROSURGERY. 2018 APR?128(4):1015-1019.", "literaturereference_normalized": "paradoxical cerebrovascular hemodynamic changes with nicardipine", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200511", "receivedate": "20200511", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17768413, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200714" } ]

{ "abstract": "BACKGROUND\nPoisoning in toddlers and infants is almost always unintentional due to their exploratory behavior, which is different from adults. The prevalence and background of childhood poisoning in Qatar is still unknown. The aim of this study is to explore the extent of childhood poisoning in Qatar and, specifically, to describe the frequency of poisoning as a cause of Accident & Emergency (A&E) admission, the demographic profile of affected patients, the circumstances leading to exposure, and the specific agents involved in poisoning among children under age 14 in our setting.\n\n\nMETHODS\nThis study was a cross-sectional survey of children up to 14 years old utilizing retrospective data between October 2009 and October 2012. The data were collected from the childhood poisoning case registry and patient medical records at the Accident and Emergency (A&E) Unit of all the Hamad Medical Corporation hospitals. Pharmacists reviewed all the handwritten medical records. Data written on the data collection form were transferred into excel and later into SPSS version 21. The data were analyzed using frequencies and percentages, and a chi-square test was used for categorical variables.\n\n\nRESULTS\nOut of 1179 registered poisoning cases listed in the registry, only 794 cases (67.3%) were usable and included in the final analysis. A&E admissions for unintentional poisoning for children accounted for 0.22% of all A&E admissions from 2009 to 12. The majority of poisoning cases happened among children between 1 and 5 years old (n = 704, 59.7%). Cases were more frequent among non-Qatari than Qatari children (39.4% vs. 28.5%). Most cases occurred in the living room (28.2%) and typically took place in the afternoon (29.2%). Analgesic and antipyretic medicines were the most common agents ingested by children (n = 194, 36.9%), specifically paracetamol (n = 140, 26.6%).\n\n\nCONCLUSIONS\nCases of unintentional poisoning are higher among children aged 1 to 5 years, males and non-Qatari. Most cases occurred in the living room and typically took place in the afternoon. The most common type of poison ingested by children was medicines, i.e., analgesics and antipyretics, specifically paracetamol.", "affiliations": "Drug Information Unit, Pharmacy Department, Al Wakra Hospital, Al Wakra, Qatar. AAhmed21@hmc.org.qa.;Drug Information Unit, Pharmacy Department, Al Wakra Hospital, Al Wakra, Qatar. Aaljamal@hmc.org.qa.;College of Pharmacy, Qatar University, Al Tarfa, P.O. Box 2713, Doha, Qatar. mohamedizham@qu.edu.qa.;Paediatric Emergency, Al Wakra Hospital, Al Wakra, Qatar. Kalawi@hmc.org.qa.;Paediatric Emergency, Al Wakra Hospital, Al Wakra, Qatar. Ksalameh@hmc.org.qa.;Pharmacy Department, Women Hospital, Al Wakra, Qatar. Sabuzaineh@hmc.org.qa.;Pharmacy Department, Al Wakra Hospital, Al Wakra, Qatar. Fadheir@sidra.org.", "authors": "Ahmed|Abdelrahman|A|;AlJamal|Ashraf Nazmi|AN|;Mohamed Ibrahim|Mohamed Izham|MI|;Salameh|Khalil|K|;AlYafei|Khalid|K|;Zaineh|Samah Abu|SA|;Adheir|Fathea Salama S S|FS|", "chemical_list": "D000700:Analgesics; D058633:Antipyretics", "country": "England", "delete": false, "doi": "10.1186/s12887-015-0423-7", "fulltext": "\n==== Front\nBMC PediatrBMC PediatrBMC Pediatrics1471-2431BioMed Central London 42310.1186/s12887-015-0423-7Research ArticlePoisoning emergency visits among children: a 3-year retrospective study in Qatar Ahmed Abdelrahman AAhmed21@hmc.org.qa AlJamal Ashraf Nazmi Aaljamal@hmc.org.qa Mohamed Ibrahim Mohamed Izham (+974) 4403 5580mohamedizham@qu.edu.qa Salameh Khalil Kalawi@hmc.org.qa AlYafei Khalid Ksalameh@hmc.org.qa Zaineh Samah Abu Sabuzaineh@hmc.org.qa Adheir Fathea Salama S S Fadheir@sidra.org Drug Information Unit, Pharmacy Department, Al Wakra Hospital, Al Wakra, Qatar College of Pharmacy, Qatar University, Al Tarfa, P.O. Box 2713, Doha, Qatar Paediatric Emergency, Al Wakra Hospital, Al Wakra, Qatar Pharmacy Department, Women Hospital, Al Wakra, Qatar Pharmacy Department, Al Wakra Hospital, Al Wakra, Qatar 28 8 2015 28 8 2015 2015 15 10427 3 2015 18 8 2015 © Ahmed et al. 2015\nOpen Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nPoisoning in toddlers and infants is almost always unintentional due to their exploratory behavior, which is different from adults. The prevalence and background of childhood poisoning in Qatar is still unknown. The aim of this study is to explore the extent of childhood poisoning in Qatar and, specifically, to describe the frequency of poisoning as a cause of Accident & Emergency (A&E) admission, the demographic profile of affected patients, the circumstances leading to exposure, and the specific agents involved in poisoning among children under age 14 in our setting.\n\nMethods\nThis study was a cross-sectional survey of children up to 14 years old utilizing retrospective data between October 2009 and October 2012. The data were collected from the childhood poisoning case registry and patient medical records at the Accident and Emergency (A&E) Unit of all the Hamad Medical Corporation hospitals. Pharmacists reviewed all the handwritten medical records. Data written on the data collection form were transferred into excel and later into SPSS version 21. The data were analyzed using frequencies and percentages, and a chi-square test was used for categorical variables.\n\nResults\nOut of 1179 registered poisoning cases listed in the registry, only 794 cases (67.3 %) were usable and included in the final analysis. A&E admissions for unintentional poisoning for children accounted for 0.22 % of all A&E admissions from 2009 to 12. The majority of poisoning cases happened among children between 1 and 5 years old (n = 704, 59.7 %). Cases were more frequent among non-Qatari than Qatari children (39.4 % vs. 28.5 %). Most cases occurred in the living room (28.2 %) and typically took place in the afternoon (29.2 %). Analgesic and antipyretic medicines were the most common agents ingested by children (n = 194, 36.9 %), specifically paracetamol (n = 140, 26.6 %).\n\nConclusions\nCases of unintentional poisoning are higher among children aged 1 to 5 years, males and non-Qatari. Most cases occurred in the living room and typically took place in the afternoon. The most common type of poison ingested by children was medicines, i.e., analgesics and antipyretics, specifically paracetamol.\n\nKeywords\nAccident & emergency visitsChildrenGovernment hospitalPoisoningQatarissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nPoisoning refers to an injury resulting from exposure to an exogenous substance that causes cellular injury or death. Poisons can be inhaled, ingested, injected or absorbed. Poisoning may also be acquired in utero. The exposure may be acute or chronic, and the clinical presentation varies accordingly. The factors determining the severity of poisoning and its outcomes in a child are interrelated. These include the type of poison, the dose, the formulation, the route of exposure, the age of the child, the presence of other poisons, the state of nutrition of the child, and the presence of other diseases or injuries [1, 2]. According to the World Health Organization (WHO) and the United Nations Children’s Fund (UNICEF), poisoning in childhood is common because children are curious and explore their world with all their senses, including taste [1]. Most of the time they are at home, and the home and its environments can be an unsafe place in which poisonous substances are unintentionally ingested.\n\nPoisoning is a significant global public health problem. The extent of the problem is different from 1 country to the other. In 16 high-income and middle-income countries, poisoning is the fourth biggest cause of unintentional injury after road traffic injuries, fires and drowning [1]. Further, according to data from the WHO, an estimated 350 000 people died from unintentional poisoning in 2002. In 2004, acute poisoning caused more than 45 000 deaths in children and youth less than 20 years of age. It is the second most common cause of injury resulting in the hospitalization of children under the age of five years [1].\n\nWhile accidental poisoning occurs most often in the previously mentioned age group, less than 1 % of poisoning cases in children are serious. The most common agents involved are over-the-counter (OTC) medications, prescription medications, household products, paraffin/kerosene, pesticides, poisonous plants and animal or insect bites [2]. Identifying those at risk at an early stage remains a challenge. Education of the general public and the provision of childproof containers for household chemicals and medicines play a key role in prevention [3]. The time interval between the exposure to poison and the appearance of clinical symptoms presents an important window of opportunity. During this period, it is important to minimize absorption by removing or neutralizing the poison (in the case of ingestion) or by administering agents that prevent damage to the organs.\n\nAccording to a report from the WHO [1], fatal poisoning rates in low-income and middle-income countries are four times that of high-income countries. Africa and low-income and middle-income countries in Europe and the Western Pacific Regions have the highest rates. Common poisoning agents in high-income countries include pharmaceuticals, household products (e.g., bleach and cleaning agents), pesticides, poisonous plants and bites from insects and animals. Common poisoning agents in low-income and middle-income countries are fuels such as paraffin and kerosene, pharmaceuticals and cleaning agents. In some countries, poisoning death rates are highest in children less than one year old, while non-fatal poisonings appear to be more common among children aged 1 to 4 years. Studies from both low-income and high-income countries suggest that poisonings and their management are costly.\n\nA lack of adult supervision at home leads to some 500 cases of poisoning among children in Qatar every year, caused by the consumption of substances such as medicines, cosmetics or chemicals [4]. According to this report, approximately 40,000 children are injured yearly due to several reasons including poisoning and are rushed to emergency units for medical attention; alarmingly, 85 % of these events occur at home. As a result, there is an increasing pressure on the emergency facilities of the Hamad Medical Corporation (HMC) to meet the demands for hospital care. These accidents are preventable because the main reasons for such incidents are a lack of knowledge, a lack of awareness and a lack of adult supervision. Further, it is reported that most poisoning events involve medicines, household products and cosmetics, but no study has verified this claim. If we are to make progress in reducing childhood injury from pharmaceutical and chemical poisoning, we need to better understand the epidemic. A study assessing the medications that are the most consequential—those that contribute the most emergency department (ED) visits, hospitalization, and harm, is needed.\n\nAlthough it is a global phenomenon, poisoning among children has unique epidemiological attributes depending on socio-economic demographics. Therefore, there is a need for a study in this part of the world to understand the unique epidemiological characteristics in Qatar to effectively address the problem of childhood poisoning.\n\nThe aim of this study is to explore the extent of childhood poisoning in Qatar. Specifically, the primary objectives of this study are to describe the frequency of poisoning as a cause of A&E admission, the demographic profile of affected patients, the circumstances leading to exposure, and the specific agents involved in poisoning among children less than 14 years old in our setting.\n\nMethods\nStudy design\nThis research is a cross-sectional descriptive study utilizing retrospective data. The study was led by the drug information pharmacists at Al-Wakra Hospital, Al-Wakra, Qatar.\n\nEthics consideration\nThis study was conducted according to the government regulations and institutional research policies and procedures in Qatar. The study protocol was approved by the Hamad Medical Ethics Committee (Research Proposal No: 12253/10). The need for subject informed consent was waived by Hamad Medical Ethics Committee.\n\nStudy location and period\nThe data and information from October 2009 to October 2012 were collected from the A&E Unit of all hospitals managed under the Hamad Medical Corporation (HMC).\n\nThe Hamad Medical Corporation is the principal public healthcare provider for the State of Qatar. In addition to three general hospitals (Al Khor Hospital, Al Wakra Hospital and The Cuban Hospital), HMC also manages five specialist hospitals (Hamad General Hospital, Women Hospital, Women’s Hospital, the National Center for Cancer Care and Research and Heart Hospital) that care for patients with the most prevalent conditions including cancer and heart conditions, and they provide specialist treatment and rehabilitation for women and children. HMC also operates the national Ambulance Service and a home healthcare service [5].\n\nPopulation and sampling\nThe target population for the study was all children aged 14 years or younger presenting with poisoning at any HMC A&E during the study period. The information about the study population was gathered from the childhood poisoning case registry in the A&E unit. The study excluded intentional poisoning cases if mentioned in the case registry; these cases are few due to cultural practices and beliefs. This study only examined unintentional poisoning cases.\n\nData collection procedure\nThe data were collected from hospital medical records. Pharmacists reviewed all the handwritten medical records. All of the required information was extracted and transferred onto a data collection form. The data collection form was developed and pretested before it was used. The collected information included patient demographic profiles (i.e., age, gender and nationality), the type of poison, the time of arrival at the hospital after exposure, the time of exposure, the season when the event occurred, the length of the hospital stay, the storage condition of the poison, the medical intervention and the outcome of the unintentional poisoning.\n\nData management and analysis\nData recorded on the data collection form were transferred into an excel program, and then later into SPSS version 21. The data were analyzed descriptively using frequencies and percentages. A chi-square test was used for categorical data with an alpha level of 0.05.\n\nResults\nOf the 1179 registered poisoning cases listed in the registry, only 794 cases (67.3 %) were usable and included in the final analysis. The rest of the records were excluded due to the unavailability of medical records or missing data. A&E admissions for unintentional poisoning for children accounted for 0.22 % of all A&E admissions from 2009 to 2012.\n\nThe following Table presents the number of emergency cases during the study period (Table 1).Table 1 Total number of registered cases from 2009 to 2012\n\nDiagnosis in general\tFrequency (%)\t\nRespiratory disorder\t470402 (86.4)\t\nCommon cold\t25750 (4.7)\t\nGastrointestinal disorder\t17889 (3.3)\t\nSkin disorders\t16019 (2.9)\t\nEye and Ear disorder\t6717 (1.2)\t\nTrauma\t5599 (1.0)\t\nPoisoning\t1179 (0.3)\t\nNeurological disorder\t794 (0.2)\t\nTotal\t544,349\t\n\n\nThe total number of A&E visits (for children aged 14 and younger) that occurred during the study period was 544,349. Based on data availability, the statistics indicated that there were 259,584 (54.2 %) male cases compared to 219,020 (45.8 %) female cases; and Qatari children comprised 163,963 cases (33.9 %) compared to 320,240 cases (66.1 %) among non-Qatari children.\n\nTable 2 illustrates the association between the child age groups and gender and nationality. No significant association was found.Table 2 The association between age groups of admitted children with gender and nationality\n\n\tAge group\t\t\t\nCharacteristics\t(1–5)\t(6–9)\t(10–14)\tTotal\t\np value\t\n\t\nn (%)\t\nn (%)\t\nn (%)\t\t\t\nGender\t\t\t\t\t\t\n Male:\t385 (88.7)\t40 (9.2)\t9 (2.1)\t434\t0.95 (NS)\t\n Female:\t320 (89.1)\t31 (8.6)\t8 (2.3)\t359\t\t\nNationality\t\t\t\t\t\t\n Qatari:\t298 (88.7)\t30 (8.9)\t8 (2.4)\t336\t0.99 (NS)\t\n Non-Qatari:\t406 (88.6)\t41 (9.0)\t11 (2.4)\t458\t\t\n\n\nThe findings in Table 3 demonstrate that for most of the poisoning cases, the time of exposure before visiting the A&E department is less than 1 h. (54.2 %). Most of the cases happened in the living room (28.2 %), followed by in the kitchen (15.5 %). Poisoning cases usually occurred in the afternoon (29.2 %), followed by the evening (24.3 %). In terms of identifying whether poisoning cases are seasonal, cases occurred more frequently between June and August, during which the number of cases was only slightly higher than other periods. For the majority of cases, the patients were hospitalized between 1–4.9 h (35.2 %) and 67.0 % of the patients were discharged. Further findings showed that the most common route of exposure is oral (66.7 %, n = 786). The most common type of poisons experienced by children was medicine (72.6 %), and the most common type of non-medicine related poisons was household items (14.9 %). The non-medicine types of poisons were Clorox (51 cases), mice poisoning (30 cases), Dettol (28 cases), detergent (10 cases), acetone (7 cases), boric acid (7 cases), and other agents/substances.Table 3 Poison-related information and type of poisoning management\n\nItems\t\tFrequency (%)\t\nTime of exposure before visiting the A&E Department\tLess than 1\t639 (80.5)\t\n1 to less than 2\t154 (19.4)\t\n2 to 3\t1 (0.1)\t\nMore than 3\tNil\t\nPoisoning place\tLiving room\t333 (42.2)\t\nKitchen\t183 (23.1)\t\nSchool\t1 (0.1)\t\nOthers\t273 (34.6)\t\nTime of exposure\tMorning\t157 (20.0)\t\nAfternoon\t344 (43.7)\t\nEvening\t286 (35.3)\t\nMonths (Seasons) of exposure\tDecember-February (Winter)\t177 (22.4)\t\nMarch-May (Spring)\t204 (25.8)\t\nJune-August (Summer)\t211 (26.7)\t\nSeptember-November (Fall)\t199 (25.1)\t\nType of poisons\tMedicines\t530 (72.6)\t\nNon-medicine\t200 (27.4)\t\nNon-medication poisons (n = 200)\tHousehold items\t176 (88.0)\t\nInsecticide\t24 (12.0)\t\nType of management\tChelating agent i.e., charcoal\t506 (64.2)\t\nEmesis\tNil\t\nAntidotes\tNil\t\nAcetylcystine\t5 (0.6)\t\nObservation\t278 (35.2)\t\nLength of hospital stay\tLess than 1 h.\t49 (6.2)\t\n1 to 4.9 h\t415 (52.3)\t\n5 to 9.9 h\t282 (35.6)\t\nMore or equal to 10 h\t47 (5.9)\t\nOutcome of the management\tPatient was discharged\t790 (99.5)\t\nPatient was referred\t4 (0.5)\t\nNote: Total frequency is not equal to 794 due missing data\n\n\n\nTable 3 also presents the type of management provided to the patients. In the majority of cases, the children were managed using a chelating agent i.e., charcoal (42.9 %), in 23.6 % of the cases, the children were put under observation and 67 % of the patients were discharged from the A&E. The rest were admitted for inpatient hospitalization.\n\nThe information on the type of medicines commonly ingested by children is indicated in Table 4 below. Analgesic and antipyretic medicines are the most common agents ingested by children (n = 194, 36.9 %), followed by antihypertensive agents (n = 55, 10.5 %), then antihistamines (n = 42, 8.0 %); paracetamol is the most common medicine (n = 140, 26.6 %) ingested by children. The source of poison, in order of frequency, was from the original container (n = 609, 51.7 %), a food container (n = 2, 0.2 %), a soda bottle (n = 1, 0.1 %), and a juice bottle (n = 1, 0.1 %). The poisons were obtained from the refrigerator in 13.3 % (n = 157) of cases (Table 3).Table 4 The association between age groups of children and classes of medicines ingested\n\n\tAge group\t\t\nMedicines class\t(1–5)\t(6–9)\t(10–14)\tTotal\t\n\t\nn (%)\t\nn (%)\t\nn (%)\t\t\nAnalgesic and antipyretic (n = 194)\t148 (76.3)\t37 (19.1)\t9 (4.6)\t194\t\nAntihypertensive (n = 55)\t53 (96.4)\t2 (3.6)\t0 (0)\t55\t\nAntihistamines & cough mixture (n = 42)\t35 (83.3)\t6 (14.3)\t1 (2.4)\t42\t\nVitamins and minerals (n = 42)\t38 (90.5)\t3 (7.1)\t1 (2.4)\t42\t\nAntihyperglycemic (n = 23)\t21 (91.3)\t2 (8.7)\t0 (0)\t23\t\nAnticonvulsant (n = 21)\t17 (80.9)\t2 (9.5)\t2 (9.5)\t21\t\nHormones (n = 24)\t20 (83.3)\t3 (12.5)\t1 (4.2)\t24\t\nAntibiotics (n = 6)\t6 (100)\t0 (0)\t0 (0)\t6\t\nMisc. (n = 123)\t115 (93.5)\t8 (6.5)\t0 (0)\t123\t\n\n\nDiscussion\nThis study aims to explore the extent of childhood poisoning in Qatar. Specifically, the primary objectives of this study are to describe the frequency of poisoning as a cause of A&E admission, the demographic profile of affected patients, the circumstances leading to exposure, and the specific agents involved in poisoning among children younger than 14 years old in our setting.\n\nAccording to McGregor et al. [6], Poison Control Centers in the United States received more than 2.4 million reports of toxin exposures in 2003. Most exposures involved oral ingestion and occurred in the home, and more than 80 % were unintentional. Children younger than six years accounted for 51 % of the exposures. Of these, 38 % involved children three years of age or younger. Most ingestions involved nontoxic substances and were managed at home [6]. A report by the WHO indicated that there are strong associations between injuries and a child’s age, the developmental stage of a child, how he/she interacts with the world and activities undertaken [1]. The results for Qatar are somewhat similar to those of other countries: the majority of poisoning cases occurred among children between 1 and 5 years old, and male patients had slightly higher rates of poisoning than females. A study of Victorian public hospitalization in Australia reported that hospital admissions for injury, i.e., unintentional poisoning for children less than 5 years old, accounted for 16.8 % of all hospital admissions [7]. The hospitalization rates and frequencies were higher for males compared to females; and mostly occurred at ages 1 and 2. The NSU Briefing on Childhood Poisoning in Australia indicated that an estimated 14,339 young children were hospitalized as a result of poisoning from 1999–2000 to 2003–2004 [8]. The rates of hospitalized poisoning injury were highest among patients two years of age (males = 366 and females = 338 poisoning admissions per 100,000 population). Studies by Lam [2], Reith et al. [9] and Morrison et al. [10] indicated that children 0-4 years of age were most frequently hospitalized due to poisoning [2, 9, 10].\n\nAccording to Meyer et al. [11], unintentional household poisoning in Germany always occurred in toddlers and infants due to their behaviors, which supports our research results [11]. Although a significant reduction of poison cases in advanced countries has been achieved, children are still exposed to toxic agents. The products most accessible to children, as seen from our research and compared to other studies, are primarily medication and secondarily cleaning products and cosmetics. This exposure reflects the availability and accessibility of the products due to the lack of safe storage devices and product disposal practices. Cleaning products should be kept or stored on high shelves. In addition, there should be increased awareness among family members regarding this issue. The relevant authority, such as the Qatar Ministry of Health and municipal councils in collaboration with consumer groups, should assess the effectiveness of child resistant product packaging for household items.\n\nA study called the CHIRPP (the Canadian Hospital Injury Reporting and Prevention Program) conducted in an accident and emergency department in the Sick Child Hospital in Canada reflects that injuries commonly occur in a child’s own home, particularly at the age of 0-4 years [12]. The majority of such cases presented with the ingestion of a foreign body. The CHIRPP is a valuable source of information on patterns of childhood injury that may be used to develop, implement and evaluate child injury prevention activity. Slightly over half of the cases were boys, and seasonal variation was observed with most cases occurring during vacation time and at home.\n\nThis study found that in most of the poisoning cases, the time of exposure before visiting the A&E department is less than 1 h., and most of the cases happened in the living room, followed by the kitchen, both of which are in the home. There is no clear difference between months or seasons within a year. The reports by Hoy et al. [7], Cripps and Steel [8] and Morrison et al. [10] also indicated that the most common place for the poisoning of younger children in Australia was in the home; they also mentioned adjacent grounds, but this was not reported in our study [7, 8, 10].\n\nIn the majority of cases, the children were managed using a chelating agent. The majority of patients were hospitalized for between 1–4.9 h and were then discharged. Hoy et al. [7] reported that 97 % of admissions due to poisoning are shorter than three days’ duration [7].\n\nDue to the nature and environment of the country, non-pharmaceutical poisoning admissions in children from noxious bites from arthropods such as spiders, bees and wasps were not observed, in contrast to the cases reported in countries such as India [13]. The poisoning cases observed in Qatar thus differ from poisoning events in other countries.\n\nSeventy three per cent of poisoning hospitalizations in an Australian study were due to the ingestion of drugs, medications, or biological substances [7]. The remainder were mostly due to exposure to domestic chemicals. In our study, analgesic and antipyretic medicines are the most common agents ingested by the children, and paracetamol is the most common medicine ingested by children. The most common type of non-medicine related poisons was household items and the source of poison was from the original container. Cripps and Steel [8] and Reith et al. [9] also reported that paracetamol was the most common pharmaceutical poisoning diagnosed in one and two year old Australian children [8, 9]. Thus, paracetamol is commonly involved in childhood poisoning. Lam [2] also reported that analgesics are the most frequently associated medication involved in childhood poisoning [2]. A study by Bond et al. [14] indicated that children’s self-exposure to prescription products dominated the health care impact of the visits and the rate of admissions, and it caused significant injuries [14]. The greatest resource use and morbidity followed self-ingestion of prescription products, particularly opioids, sedative-hypnotics, and cardiovascular agents. Unlike Qatar and other countries, kerosene and snakebites were the most common agents in India, where kerosene has remained the single largest contributor to childhood poisoning [13].\n\nThe studies described above show that the issue of medication poisoning in children is still a concern and is not improving. Past preventive efforts have proved to be inadequate. More children are exposed, seen in an A&E, admitted, and injured each year. According to Budnitz et al. (2012) [3], despite childproof caps and safety warnings, the number of accidental drug poisonings among young children has increased over the years. This is because prescription drug use by both adults and children is on the rise, and there are simply more bottles of pills in the home that can potentially be accessed by curious children [3, 15]. In other studies, the greatest increases are observed from prescription pharmaceuticals, particularly opioid analgesics, sedative-hypnotics, and cardiovascular medications. In our study, such cases are still few. New efforts must be directed at these important conditions. Educational efforts are important but are unlikely to achieve significant improvements alone. Education interventions should the readdress home storage of all medications, the repackaging of medications, particularly chronic medications, and the fact that older siblings may not be as careful as parents when opening containers or taking medications, in addition to targeting nannies and other caretakers. A study conducted by the Pittsburgh Poison Centre concluded that “a large percentage of the adult population are potential poisoning victims due to their inability to read and comprehend label instructions” [16]. Storage devices and child-resistant closures may need improvement. Additionally, mechanical barriers to ingestion such as blister packs may be required for more substances.\n\nIt is clearly that children between the ages of 1–5 years old are the most vulnerable to poisoning. Further, this study also indicated that poisoning from household items and insecticides occurred only among children between the ages of 1–5 years old. The results of this research have multiple applications that may help in reducing the level of unintentional poisoning incidents and in better utilizing internal hospital resources for other areas of concern by: (1) developing public awareness programs and increasing the level of community awareness about the main causes of unintentional poisoning; (2) providing a key for eliminating the common causes of unintentional poisoning cases in future studies; (3) preventing potential children mortality due to unintentional poisoning; (4) enhancing emergency response plans to reduce exposure time to poisoning based on the root cause identified; and (5) enhancing community knowledge on emergency response actions in the event of unintentional poisonings.\n\nStudy strengths and limitations\nThis was the first study in Qatar and in public hospitals. This study included all hospitals under the HMC. The findings of this study, which were based on a large sample size, will be used to design an intervention study focusing on educational strategies. However, this study suffers several limitations including missing data and the unavailability of some medical records. In addition, the pharmacists experienced difficulties when extracting information from the medical records due to the illegible handwriting of the physicians. The authors did not included a review by a doctor of all illegible medical records.\n\nThis study is a retrospective review of hospital records, and therefore subject to several additional limitations that should be noted explicitly. For example, not all cases of poisoning in childhood in Qatar are brought to an A&E, and this may introduce a systematic error. Further, not all cases of poisoning may have been identified as such in the records. The authors could not confirm whether the included cases were identified from admission diagnoses, discharge (final diagnoses), or both. Some cases may have been missed or misclassified by clinicians. This study was also not able to determine the proportion of cases that presented to various healthcare institutions under the HMC organization.\n\nRecommendations\nThere are several specific and general suggestions related to practice, policy and future research that various stakeholders should further consideration:i. The parameters related to poisoning cases in the A&E unit should be properly and completely documented;\n\nii. Hospitals should establish a database for poisoning cases and information should be captured once parents or children arrive at the A&E department;\n\niii. It is important to introduce new regulations to cover emergency substances such as dietary supplements, herbal preparations, and traditional remedies;\n\niv. Social disparity issues must be addressed and included in prevention programs because the poisoning of children is related to the social and economic status of the children;\n\nv. A study of the impact of education on the prevalence and incidence of childhood poisoning is needed;\n\nvi. The Qatar National Poison Prevention & Control Center (Q-NPPCC) should be set up and with a toll-free number 24 h a day and 7 days a week;\n\nvii. Trained doctors, pharmacists and nurses in clinical toxicology are needed to develop hospital poison teams; and\n\nviii. Clinical toxicology should be directed toward the further development of clinic and basic science research.\n\n\n\nConclusions\nUnintentional poisoning cases were higher among non-Qatari male children aged 1 to 5 years old. Most of the cases occurred in the living room. Poisoning cases usually occurred in the afternoon and evening. The most common type of poison experienced by children was medicine, and exposure was commonly oral. Analgesics and antipyretics were the most common class of medicines ingested by children in Qatar. Paracetamol was the most common medicine ingested by children.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nAA, ANA, KS, KA, SAZ, FSSSA and MIMI made significant contributions to the study and manuscript preparation. All authors contributed to the conception and design of the study, and the acquisition of the data. AA, ANA and MIMI further analyzed and interpreted the data and drafted and revised the manuscript. All authors have read, reviewed and approved the manuscript for publication.\n\nAcknowledgement\nThe research team would like to thank the HMC Medical Research Center for approving the Research Protocol #12253/13.\n==== Refs\nReferences\n1. WHO-UNICEF. Children and poisoning: world report on child injury prevention. World Health Organization. 2008. [http://www.who.int/violence_injury_prevention/child/injury/world_report/en/, date accessed: March 15, 2014]\n2. Lam LT Childhood and adolescence poisoning in NSW, Australia: an analysis of age, sex, geographic, and poison types Inj Prev 2003 9 338 342 10.1136/ip.9.4.338 14693896 \n3. Budnitz DS Lovegrove MC The last mile: taking the final steps in preventing pediatric pharmaceutical poisonings J Pediatr 2012 160 2 190 192 10.1016/j.jpeds.2011.09.020 22056349 \n4. Saleem F. The Peninsular, 2013; [http://thepeninsulaqatar.com/news/qatar/220492/carelessness-causes-over-500-child-poisoning-cases-a-year]\n5. Hamad Medical Corporation. [www.hmc.org.qa]\n6. McGregor T Parkar M Rao S Evaluation and management of common childhood poisonings Am Fam Physician 2009 79 5 397 403 19275069 \n7. Hoy JL Day L Tibballs J Ozanne-Smith J Unintentional poisoning hospitalisations among young children in Victoria Inj Prev 1999 5 31 5 10.1136/ip.5.1.31 10323567 \n8. Cripps R, Steel D. Childhood poisoning in Australia. AIHW National Injury Surveillance Unit, Research Centre for Injury Studies, Flinders University, South Australia, 2006. [http://www.nisu.flinders.edu.au/pubs/reports/2006/injcat90.pdf]\n9. Reith DM Pitt WR Hockey R Childhood poisoning in Queensland: an analysis of presentation and admission rates J Peadiatr Child Health 2001 37 446 50 10.1046/j.1440-1754.2001.00666.x \n10. Morrison A Stone D Doraiswamy N Ramsay L Injury surveillance in an accident and emergency department: A year in the life of CHIRPP Arch Dis Child 1999 80 533 10.1136/adc.80.6.533 10332002 \n11. Meyer S Eddleston M Bailey B Desel H Gottschling S Gortner L Unintentional household poisoning in children Klin Padiatr 2007 219 254 270 10.1055/s-2007-972567 17763291 \n12. Canadian Hospitals Injury Reporting and Prevention Program (CHIRPP). Public Health Agency of Canada. [http://www.phac-aspc.gc.ca/injury-bles/chirpp/index-eng.php, date accessed: March 30, 2014]\n13. Rathore S Verma AK Pandey A Kumar S Pediatric poisoning trend in Lucknow district, India J Forensic Res 2013 4 1 \n14. Bond GR Woodward RW Ho M The growing impact of pediatric pharmaceutical poisoning J Pediatr 2012 160 2 265 270 10.1016/j.jpeds.2011.07.042 21920539 \n15. Budnitz DS Lovegrove MC Rose KO Adherence to label and device recommendations for over-the-counter pediatric liquid medications Pediatrics 2014 133 2 e283 90 10.1542/peds.2013-2362 24394683 \n16. Mrvos R Dean BS Krenzelok EP Illiteracy: a contributing factor to poisoning Vet Hum Toxicol 1993 35 466 8 8249274\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2431", "issue": "15()", "journal": "BMC pediatrics", "keywords": null, "medline_ta": "BMC Pediatr", "mesh_terms": "D000293:Adolescent; D000700:Analgesics; D058633:Antipyretics; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D004636:Emergency Service, Hospital; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D011041:Poisoning; D015995:Prevalence; D011780:Qatar; D012189:Retrospective Studies", "nlm_unique_id": "100967804", "other_id": null, "pages": "104", "pmc": null, "pmid": "26315670", "pubdate": "2015-08-28", "publication_types": "D016428:Journal Article", "references": "22056349;10323567;21920539;19275069;11885707;10332002;24394683;8249274;14693896;17763291", "title": "Poisoning emergency visits among children: a 3-year retrospective study in Qatar.", "title_normalized": "poisoning emergency visits among children a 3 year retrospective study in qatar" }

[ { "companynumb": "QA-JNJFOC-20150905483", "fulfillexpeditecriteria": "1", "occurcountry": "QA", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "019872", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACCIDENTAL EXPOSURE TO PRODUCT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PARACETAMOL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "019872", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PARACETAMOL" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "IBRAHIM MI, AHMAED A, ALJAMAL AN, SALAMEH K, ALYAFEI K, ZAINEH SA, ET AL. POISONING EMERGENCY VISITS AMONG CHILDREN: A 3-YEAR RETROSPECTIVE STUDY IN QATAR.. BMC PEDIATRICS 28-AUG-2015;15 (1):104.", "literaturereference_normalized": "poisoning emergency visits among children a 3 year retrospective study in qatar", "qualification": "3", "reportercountry": "QA" }, "primarysourcecountry": "QA", "receiptdate": "20150922", "receivedate": "20150922", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11537158, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20151125" } ]

{ "abstract": "BACKGROUND\nPegfilgrastim, a long-acting granulocyte-colony-stimulating factor used to prevent neutropenia, is not indicated for administration within 24 h of completion of chemotherapy. The safety of administering pegfilgrastim in gastrointestinal cancer chemotherapy regimens containing continuous intravenous infusion of 5-fluorouracil (5-FUCI) on the day of completion of 5-fluorouracil has not been adequately studied.\n\n\nMETHODS\nAn institutional review board-approved retrospective analysis of patients with a gastrointestinal malignancy receiving pegfilgrastim on the final day of 5-FUCI was conducted. The primary end point was to determine the incidence of grade 3 and grade 4 neutropenia and febrile neutropenia when pegfilgrastim was administered on the final day of 5-FUCI. The secondary endpoint was to determine rate of dose reductions and treatment delays.\n\n\nRESULTS\nA total of 300 patients were reviewed from January 2010 to May 2017. The most common cancers were colorectal (25%) and pancreatic (60%), with 77% of patients having late stage disease. The risk of a patient developing grade 3 neutropenia was 0.010 (95% CI 0.002-0.029) and grade 4 neutropenia was 0.007 (95% CI 0.001-0.024). The risk of febrile neutropenia was 0.007 (95% CI 0.001-0.024). The risks of treatment delay and treatment reduction were 0.013 (95% CI 0.004-0.034) and 0.010 (95% CI 0.002-0.029), respectively.\n\n\nCONCLUSIONS\nThe low risk of grade 3 and grade 4 neutropenia, febrile neutropenia, as well as dose delays and/or reduction suggests that pegfilgrastim can be administered on the final day of 5-FUCI. Limitations of this study were that it was retrospective in nature and was conducted at a single institution.", "affiliations": "Emory Winship Cancer Institute, Emory University, Atlanta, GA, USA.;Georgia Cancer Center for Excellence at Grady Healthcare, Atlanta, GA, USA.;Rollins School of Public Health, Emory University, Atlanta, GA, USA.;Emory Winship Cancer Institute, Emory University, Atlanta, GA, USA.", "authors": "Draper|Amber S|AS|https://orcid.org/0000-0001-7172-205X;Lafollette|Jennifer|J|;Kim|Chaejin|C|;Wu|Christina S|CS|", "chemical_list": "C455861:pegfilgrastim; D011092:Polyethylene Glycols; D000069585:Filgrastim; D005472:Fluorouracil", "country": "England", "delete": false, "doi": "10.1177/1078155220945771", "fulltext": null, "fulltext_license": null, "issn_linking": "1078-1552", "issue": "27(5)", "journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners", "keywords": "5-FU; Pegfilgrastim; fluorouracil; neutropenia", "medline_ta": "J Oncol Pharm Pract", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D000069585:Filgrastim; D005472:Fluorouracil; D005770:Gastrointestinal Neoplasms; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009503:Neutropenia; D011092:Polyethylene Glycols; D012189:Retrospective Studies", "nlm_unique_id": "9511372", "other_id": null, "pages": "1159-1164", "pmc": null, "pmid": "32762293", "pubdate": "2021-07", "publication_types": "D023362:Evaluation Study; D016428:Journal Article", "references": null, "title": "Retrospective study evaluating the safety of administering pegfilgrastim on the final day of 5-fluorouracil continuous intravenous infusion.", "title_normalized": "retrospective study evaluating the safety of administering pegfilgrastim on the final day of 5 fluorouracil continuous intravenous infusion" }

[ { "companynumb": "US-AMGEN-USASP2020129915", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK EVERY 14 DAYS CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROINTESTINAL CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "5 FU" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PEGFILGRASTIM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "125031", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "UNK EVERY 14 DAYS (ON THE FINAL DAY OF 5 FU)", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PEGFILGRASTIM" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Febrile neutropenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Unevaluable event", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Inappropriate schedule of product administration", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KIM C. RETROSPECTIVE STUDY EVALUATING THE SAFETY OF ADMINISTERING PEGFILGRASTIM ON THE FINAL DAY OF 5?FLUOROURACIL CONTINUOUS INTRAVENOUS INFUSION. JOURNAL OF ONCOLOGY PHARMACY PRACTICE. 2020?1?6", "literaturereference_normalized": "retrospective study evaluating the safety of administering pegfilgrastim on the final day of 5 fluorouracil continuous intravenous infusion", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200819", "receivedate": "20200819", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18167542, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]

{ "abstract": "This study aims to explore how patients with metastatic gastrointestinal stromal tumour (GIST) experience the adverse effects of treatment, as expressed by the individuals themselves.\nA qualitative, phenomenological and hermeneutic design was applied. Twenty patients with metastatic GIST participated in the study. In-depth and semi-structured interviews were conducted and then analysed by means of an inductive thematic analysis.\nThe majority of participants reported experiencing a changed life after being diagnosed with metastatic GIST and commencing systemic medical treatment. More than half of them described partially debilitating self-reported side effects and complaints that had a detrimental impact on their lives. The life-prolonging tyrosine kinase inhibitor treatment prompted the participants to adapt to 'a new normal'. Several participants also emphasised having an ambivalent relationship with the pill, although most looked upon it as 'a friend' because it kept them alive. Paradoxically, while the participants struggled with the side effects of treatment as well as the consequences of living with a chronic cancer, half of them considered themselves to be healthy and, thus, to not actually be cancer patients.\nWe observed a gap between the biomedical perspective on disease that health professionals typically adopt and the individual experiences of patients living with metastatic GIST. For those patients who are living in limbo between having metastatic cancer and offered an effective treatment, a holistic view of health on the part of their healthcare providers seems crucial. A vital goal should hence be to improve communication between healthcare professionals and GIST patients so as to secure an individualised follow-up with guidance on coping with, and adapting to, their new normal.Trial registration The study was approved by the data protection officer of the Oslo University Hospital (Approval Number 2016/15358).", "affiliations": "1Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, P.O. Box 5960, Nydalen, 0424 Oslo, Norway.;1Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, P.O. Box 5960, Nydalen, 0424 Oslo, Norway.;3Department of Health and Care Sciences, Faculty of Health Sciences, UiT The Arctic University of Norway, Hansine Hansens veg 18, 9019 Tromsø, Norway.;2Department of Interdisciplinary Health Sciences, Institute of Health and Society, University of Oslo, Postboks 1089, Blindern, 0317 Oslo, Norway.;1Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, P.O. Box 5960, Nydalen, 0424 Oslo, Norway.", "authors": "Fauske|Lena|L|;Hompland|Ivar|I|;Lorem|Geir|G|;Bondevik|Hilde|H|;Bruland|Øyvind S|ØS|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1186/s13569-019-0116-3", "fulltext": "\n==== Front\nClin Sarcoma ResClin Sarcoma ResClinical Sarcoma Research2045-3329BioMed Central London 11610.1186/s13569-019-0116-3ResearchPerspectives on treatment side effects in patients with metastatic gastrointestinal stromal tumour: a qualitative study Fauske Lena +47 02770lena.fauske@ous-hf.no 12Hompland Ivar ivahom@uos-hf.no 1Lorem Geir geir.lorem@uit.no 3Bondevik Hilde hilde.bondevik@medisin.uio.no 2Bruland Øyvind S. osb@ous-hf.no 141 0000 0004 0389 8485grid.55325.34Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, P.O. Box 5960, Nydalen, 0424 Oslo, Norway 2 0000 0004 1936 8921grid.5510.1Department of Interdisciplinary Health Sciences, Institute of Health and Society, University of Oslo, Postboks 1089, Blindern, 0317 Oslo, Norway 3 0000000122595234grid.10919.30Department of Health and Care Sciences, Faculty of Health Sciences, UiT The Arctic University of Norway, Hansine Hansens veg 18, 9019 Tromsø, Norway 4 0000 0004 1936 8921grid.5510.1Institute of Clinical Medicine, University of Oslo, Oslo, Norway 30 4 2019 30 4 2019 2019 9 69 11 2018 17 4 2019 © The Author(s) 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nThis study aims to explore how patients with metastatic gastrointestinal stromal tumour (GIST) experience the adverse effects of treatment, as expressed by the individuals themselves.\n\nMethods\nA qualitative, phenomenological and hermeneutic design was applied. Twenty patients with metastatic GIST participated in the study. In-depth and semi-structured interviews were conducted and then analysed by means of an inductive thematic analysis.\n\nResults\nThe majority of participants reported experiencing a changed life after being diagnosed with metastatic GIST and commencing systemic medical treatment. More than half of them described partially debilitating self-reported side effects and complaints that had a detrimental impact on their lives. The life-prolonging tyrosine kinase inhibitor treatment prompted the participants to adapt to ‘a new normal’. Several participants also emphasised having an ambivalent relationship with the pill, although most looked upon it as ‘a friend’ because it kept them alive. Paradoxically, while the participants struggled with the side effects of treatment as well as the consequences of living with a chronic cancer, half of them considered themselves to be healthy and, thus, to not actually be cancer patients.\n\nConclusions\nWe observed a gap between the biomedical perspective on disease that health professionals typically adopt and the individual experiences of patients living with metastatic GIST. For those patients who are living in limbo between having metastatic cancer and offered an effective treatment, a holistic view of health on the part of their healthcare providers seems crucial. A vital goal should hence be to improve communication between healthcare professionals and GIST patients so as to secure an individualised follow-up with guidance on coping with, and adapting to, their new normal.\n\nTrial registration The study was approved by the data protection officer of the Oslo University Hospital (Approval Number 2016/15358)\n\nElectronic supplementary material\nThe online version of this article (10.1186/s13569-019-0116-3) contains supplementary material, which is available to authorized users.\n\nKeywords\nGastrointestinal stromal tumour (GIST)Metastatic cancerSide effectsQualitative researchLily Constance and Karl Ingolf Larssons LegacyCRF/18004Fauske Lena issue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nRecent progress in the field of medical oncology has increasingly rendered cancer a chronic disease, with metastatic gastrointestinal stromal tumours (GIST) being a prime example of this phenomenon. Due to the seminal discovery of KIT mutations in cases of GIST [1], alongside the subsequent introduction of the tyrosine kinase inhibitor (TKI) imatinib [2, 3], metastatic GIST has changed from being a highly aggressive type of cancer that caused the death of almost all patients within the first year of diagnosis [4] to being a chronic cancer with a median overall survival rate of approximately 7 years [5]. Indeed, imatinib and the other TKIs that have been introduced as effective treatments for metastatic GISTs induce long-term remission in the majority of patients and, for some, even result in an extended life expectancy of decades [5, 6]. However, although imatinib has revolutionised the treatment of metastatic GIST, most patients will eventually experience drug resistance [3]. This is particularly true in cases of treatment with second- [7] and third-line TKIs.\n\nImatinib is taken orally on a daily basis, and it is considered to be moderately to well tolerated, at least when compared to conventional chemotherapy [8]. Although severe adverse effects are uncommon, virtually all patients treated with imatinib report some side effects, with the most frequent being anaemia, periorbital oedema and watery eyes, diarrhoea, muscle cramps (typically in the hands and legs), fatigue and nausea [3, 9].\n\nIn addition to the well-known medical side effects of imatinib, several practical and psychosocial challenges may influence the daily lives of patients, although the extent to which this is the case has not yet been well studied. For instance, as most patients with metastatic GIST eventually will succumb to their disease [6, 10], the fear of disease progression is undeniably a challenge for patients and their families [11].\n\nFurther, in one study, the prevalence of severe fatigue among 61 GIST patients who were receiving TKI treatment was found to be significantly higher (30%) when compared to the matched healthy controls (15%) [12]. The fatigued patients reported a lower quality of life (QoL) as well as increased impairment in all the functional domains, including psychological distress and physical functioning. Another study described the extended lifetime that results from the TKI treatment of GIST as being akin to a Sword of Damocles [11]. The patients reported a good global QoL, although the majority also reported a considerable fear of disease progression. They experienced significantly higher levels of psychological distress, functional impairments and difficulty making plans for the future [11].\n\nBeing ill as a result of a serious disease not only affects a part of an individual’s body or an organ, but also impacts his/her practical, social, intellectual and emotional needs. To the best of our knowledge, only one study concerning GIST that had a qualitative design (mixed methods) has previously been conducted [13]. That study emphasised that patients with metastatic GIST shared similar emotional journeys. The patients were found to experience five stages of disease management, namely crisis, hope, adaptation, ‘new normal’ and uncertainty. This entire process was found to have a detrimental impact on their lives [13].\n\nIn the current study, our aim was to explore how patients with metastatic GIST experience both living with their disease and the adverse effects of its treatment. By adopting a qualitative method involving a phenomenological approach that utilised an explanatory design, we aimed to better understand how patients voice their experiences.\n\nMethods\nThis study adopts a psychosocial and sociocultural perspective on health and illness in order to identify the reasons behind the experienced phenomena, as expressed by the participants themselves. In line with the study’s methodological framework and research questions, we have applied a phenomenological experience-based and hermeneutics interpretation-based approach to disease and illness [14, 15]. Phenomenological research aims to investigate individual human experiences (phenomena) as they manifest in both daily life and specific situations [16], while hermeneutics relates to the methods developed for achieving an understanding and interpretation of phenomena in a comprehensible manner [17]. Here, comprehension develops through the entire process, and it is based on the participant’s and the researcher’s pre-understandings, as well as on the historical and cultural contexts.\n\nPatients\nPatients with metastatic GIST who were treated at the Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital (NRH OUH), were included in this qualitative study. They were identified from the prospective sarcoma registry at the NRH OUH and their clinical data were extracted from that database. The inclusion criteria were: (i) confirmed metastatic GIST, (ii) receiving treatment with TKIs for at least 2 years prior to inclusion in the study and (iii) stable disease, which was defined as no change in the administration of the TKI. The study cohort consisted of 20 patients, 11 women and nine men, with a median age of 61 years (range 36–85). They all did write and speak Norwegian and were all undergoing regular follow-up at our sarcoma outpatient clinics. In the results section, the participants are identified by their gender and age. Demographic and clinical information concerning the participants is presented in Table 1. Twelve of the participants received the conventional 400 mg dose of imatinib, four had reduction of the dose to 200 mg due to adverse events, whereas two had dose escalation up to 800 mg due to disease progression on 400 mg. Two participants received sunitinib.Table 1 Baseline demographic and clinical data concerning the study cohort\n\nTotal number of patients\t20\t\nAge (years)a\t61 (36–85)\t\nSex\t\n Female\t11 (55)\t\n Male\t9 (45)\t\nRelationship status\t\n Married\t9 (45)\t\n Cohabiting\t3 (15)\t\n Single\t8 (40)\t\nChildren\t\n Yes\t16 (80)\t\n No\t4 (20)\t\nTime since primary diagnosis (years)a\t8 (2–22)\t\nTime receiving systemic treatment (years)a\t6 (2–15)\t\nPrimary tumour localisation\t\n Stomach\t12 (60)\t\n Small bowel\t7 (35)\t\n Rectum\t1 (5)\t\nKIT/PDGFRA mutations\t\n KIT exon 11\t11 (55)\t\n KIT exon 9\t3 (15)\t\n KIT exon 13\t1 (5)\t\n PDGFRA exon 18\t1 (5)\t\n PDGFRA exon 12\t1 (5)\t\n Not detected\t3 (15)\t\nMetastatic site\t\n Liver\t10 (50)\t\n Peritoneal\t8 (40)\t\n Liver and peritoneal\t2 (10)\t\nMetastasis at diagnosis\t\n Yes\t10 (50)\t\n No\t10 (50)\t\nPrevious adjuvant imatinib treatment (12–36 months)\t\n Yes\t5 (25)\t\n No\t15 (75)\t\nSystemic treatment in a metastatic setting\t\n Imatinib\t18 (90)\t\n Sunitinib\t2 (10)\t\nNumber of surgeries (including surgery to the primary tumour)\t\n No surgery\t1 (5)\t\n 1\t10 (50)\t\n 2\t8 (40)\t\n 5\t1 (5)\t\nRadiotherapy\t\n Yes\t2 (10)\t\n No\t18 (90)\t\nThe values given in parentheses are percentages unless otherwise indicated, avalues are the median (range)\n\nPDGFRA platelet-derived growth factor α-gene\n\n\n\n\nProcedure\nThe recruitment of participants was performed by the treating oncologists at the NRH OUH. The first author provided detailed information regarding all the relevant aspects of study participation and also conducted the interviews. The average length of the interviews was 45 min (16 to 82 min). Sixteen interviews were conducted in relation to a previously scheduled routine clinical follow-up appointment at the NRH OUH, while four were conducted in the participants’ home. The interviews followed a semi-structured guide and they were conducted on a face-to-face basis. The interviews were transcribed verbatim by a medical secretary. The interview guide invited the participants to narrate their whole story from the time of diagnosis to the present day, and it included the following main topics: How do the disease and its treatment affect your daily life? How is your relationship with the pill? Do you consider yourself to be healthy or ill? (Additional file 1). All the collected information was stored confidentially, and thematic analyses were conducted on anonymised transcripts.\n\nThe study was approved by the data protection officer of the NRH OUH (Approval Number 2016/15358), and written informed consent was obtained from all participants prior to beginning the study.\n\nData analysis\nA thematic analysis is a qualitative approach that has been widely applied across the social, behavioural and applied health sciences [18]. The purpose of this method is to identify patterns of meaning across a dataset in order to answer the research question being addressed. The patterns are identified through a process of data familiarisation and data coding, as well as through theme development and revision. In this study, the entire dataset was coded in detail (i.e. a thorough, inclusive and extensive coding approach) by hand by the first author, as well as partly by the third and fourth authors. The codes were then divided into themes and concepts. The emergent themes formed the core of the analysis, and they were reflected upon in accordance with the study’s objectives and also compared with the existing literature and theory [18]. Throughout the entire process of analysis, the researcher regularly returned to the original data to check the themes and quotes, as well as to ensure that the meaning had not been lost during either interpretation or translation [19].\n\nResults\nThe majority of participants reported experiencing a changed life after being diagnosed with a GIST and beginning systemic treatment. The crucial life-prolonging TKI treatment had side effects that influenced their daily lives in negative and challenging ways, which caused the participants to adapt to ‘a new normal’. Several participants emphasised that they had an ambivalent relationship with the pill, although most looked upon it as ‘a friend’ because it kept them alive. Paradoxically, while the patients struggled with both the side effects of treatment and the consequences of living with a chronic cancer, half of them considered themselves to be healthy and, thus, to not actually be cancer patients. We identified two dominant themes, namely self-reported adverse treatment effects and the paradoxical self.\n\nSelf-reported adverse treatment effects\nThe participants reported varying degrees of self-reported side effects stemming from imatinib and sunitinib, although their subjective experiences of those side effects and their everyday consequences were similar in many ways. In addition to the side effects of taking daily medication, several participants pointed out that the gastrointestinal surgery had also resulted in challenges, such as abdominal pain, dumping syndrome or food intolerance.\n\nThe majority of participants mentioned the well-known side effects of imatinib, such as oedema, especially periorbital oedema, nausea, diarrhoea, muscle cramps, muscle aches, joint pain, tiredness and exhaustion. Many also reported experiencing an increased need for sleep, cognitive challenges, reduced sexual desire, as well as poor stress tolerance around the intake of the pill. Furthermore, some mentioned alcohol and certain food intolerances, itching, insomnia and neuropathy, among other less common side effects (Fig. 1).Fig. 1 Self-reported subjective side effects\n\n\n\n\nBased on their stories, the participants were divided into three groups. In the first group were four participants who had few self-reported side effects and complaints, which had only a minor influence on their everyday life, and who lived almost as they did before. In the second group were five participants who had some self-reported side effects and complaints, which meant that they experienced limitations and the need to adjust, although their everyday life was reasonably satisfactory. In the third group were 11 participants who reported extensive, partially debilitating, self-reported side effects and complaints that had a detrimental influence on their lives.\n\nAs mentioned above, more than half of the participants reported that the experienced side effects had a considerable negative impact on their daily lives. For instance, one woman (age 52) experienced the effect of a daily dose of 400 mg of imatinib as terrible:‘I had cramps in all the muscles all over my body […] and with a lot of oedema in my face and legs [...] I lost two litres of fluid every morning. [...] I also got enlarged breasts […] they went up roughly one size a year. [...] And I needed a lot of sleep too, I felt fatigued.’\n\n\n\n\nShe also stated that the medicine reduced her wellbeing, although it did have a positive side: ‘It’s awful that there are so many side effects, but then I think it has helped me.’ She reduced her dose to 200 mg after a few years, which led to fewer side effects and a better life. Several others reported that reducing the medication dose led to a reduction in complaints. Further, the side effects were found to change over time, for example, nausea and cramps might decrease, while tiredness might increase. One male participant (47) said:‘As time has passed, I’ve noticed that I’m a bit weaker in my whole body, more tired especially, so I go to bed a bit earlier than usual. It seems to be a feeling like the one I normally have when getting the flu [...], then you feel a bit shivery, in fact it’s a kind of normal state. But I think it has come on gradually, I don’t think it was like that in the beginning, during the first few years.’\n\n\n\n\nFurthermore, several participants stated that their tiredness had become more pronounced after they had been taking imatinib for some years.\n\nMany participants reported having become used to the side effects and having learned to adapt their lives accordingly. However, this was not the case for the two participants who were on a higher dose (800 mg daily). They reported many side effects, several of which were exhausting, debilitating and had a profound negative effect on their lives. For instance, one woman (49) stated that the medicine had such strong side effects that she lost all her energy, had a lot of cramps, felt cold and tired all the time, and did not dare to meet people, so she just stayed indoors. ‘My skin... swollen mucous membranes […] people could hardly recognise me, I developed a huge face, you could hardly see my eyes. […] It just developed and got worse and worse and worse.’ She stressed that she had been unprepared for such changes: “I didn’t think that this medicine would completely knock me out.’\n\nSunitinib is the first choice of alternative treatment when resistance to imatinib occurs [8]. The two participants who took sunitinib described more and stronger side effects from that drug when compared to what they experienced when they took imatinib. Both reported that tiredness and exhaustion were more of a challenge than before. One male participant (52) described pain in his skin and mucous membranes:‘And physically, I can feel the side effect that I call sunburn under the skin. […] I get strong side effects if I drink alcohol. I’ve stopped liking coffee, tea and hot drinks because my tongue’s very sensitive. […] I don’t drink so many fizzy drinks now because getting those bubbles on my tongue is like getting barbed wire on my tongue. It’s a real drag, the sore feeling in my skin and hands, and inside all over my body, and in my mouth and mucous membranes, and it hurts just to clean my teeth. It really hurts. So, my dental hygiene isn’t so good now. Just try to brush your teeth with a steel brush. […] And the toothpaste tastes like strong whiskey. […] When I use sunitinib, all those side effects are very powerful.’\n\n\n\n\nMany participants mentioned the rapid effect of treatment after starting imatinib, with the pain related to the disease being reduced after just a few days. They were grateful that there was a pill that could reverse the disease, or at least keep it under control, so that they could live with metastatic GIST. However, both the imatinib and sunitinib patients stated that there were two sides to the coin: ‘It’s both a friend and an enemy - without it I have no life. That’s simple maths,’ said a male participant (52). He also said that the pill was a daily reminder that he had a serious illness, which he otherwise tried not to focus on. It extended his life for several more years, but it also led to him experiencing many side effects and challenges. The majority of participants looked upon the pill as a friend because it kept them alive, although they emphasised a certain level of ambivalence in relation to it due to all the side effects. Despite the latter, none of the participants had ever considered stopping taking the drug.\n\nThe paradoxical self\nDespite having metastatic GISTs, many of the participants did not think of themselves as being cancer patients in their everyday lives. Nevertheless, they emphasised how their daily dose of medicine and its side effects regularly reminded them of their condition. However, they continued to feel healthy in their daily lives and, most of the time, they hence did not think about their cancer. For instance, a young man (36), whose side effects were so minimal that he could continue to work, stated:‘Basically, I consider myself to be healthy, but obviously I’ve started to understand now, in the last six months, or the last year, that I’m still having treatment, so it’s a kind of in-between thing in a way. But in my day-to-day life, I’m healthy. [...] As long as I can do the things I like doing, I’m content.’\n\n\n\n\nBeing healthy was often not voiced as being related to a lack of illness, but rather to doing things that were important to the participants. One man (73) said, ‘I consider myself to be healthy. I really do. Because I want to do things, I like being outdoors, in the woods, picking berries and so on, that’s what I’ve done all my life.’ Being healthy was related to being able to live a normal life. The participants wanted to make the best of their lives and to not focus on cancer. One woman (74) said, ‘I’m basically healthy. So, I try to live as normally as I possibly can.’ Even some of those participants who did view themselves as cancer patients did not generally talk about their disease. One woman (51) who experienced many side effects of imatinib said:‘That’s life. […] But the most important thing is to make an effort and to try to live as normally as possible in spite of … [cancer]. […] Having a job, that’s really important. Don’t just sit at home thinking and brooding, but do everything you used to do. […] Maybe you’ll need some extra breaks, well, just take them then.’\n\n\n\n\nSeveral participants mentioned having made a conscious choice not to focus on their illness and all the associated negatives. One woman (52) stressed, “Yes, I changed my focus. Of course, sometimes I feel a bit down and then I just sit down at home and cry a few tears. And then I think “change your focus”. I prefer just to think I am not ill.’ An elderly woman (85) with a serious exhaustion problem said, “When I feel a depression coming on and I’m very tired and I’ve got no energy, then I say, “You have no right to feel like this, you’ve just got no right”. And then it passes.’ Some participants pointed out that categorising themselves as healthy despite their cancer did not necessarily mean that they were repressing the disease; instead, it related to the role they wanted to play. One woman (51) who experienced severe side effects stressed that she did not want to consider herself to be ill: ‘No, so I see myself as healthy. Because I don’t want to be ill.’ Several others pointed out that they managed to focus on the healthy and normal aspects of their life, which enabled them to live positively despite the cancer and the side effects of treatment.\n\nDiscussion\nThis study examined patients’ experiences living with GIST and undergoing TKI treatment, as well as how the experienced adverse effects significantly challenged their daily lives. The predominant patient narrative concerned living with treatment and how it was established as part of ‘a new normal’. More than half of the participants in the current study described how extensive, partially debilitating, self-reported side effects and complaints had a detrimental influence on their lives. Interestingly, none of the participants questioned their medical treatment. The reason for this might be that the participants considered the life-prolonging effect of TKI treatment to outweigh the adverse effects. Our interpretation of a paradoxical self may relate to the fact that participants who were dependent on life-prolonging cancer treatment and who experienced adverse effects still considered themselves to be healthy. However, their experiences with imatinib or sunitinib, as treatments for metastatic GISTs, altered their self-identity and what good health meant to them. Many participants emphasised that being healthy and normal meant being able to still do what they could do before, for example, going to work or being busy with something that was enjoyable or important to them.\n\nBy conducting in-depth interviews with patients living with metastatic GIST, we found that more than half of them told a story that did not comply with the prevailing biomedical comprehension of the imatinib toxicity profile. Their subjective experience with side effects of treatment had significant physical, practical and social consequences for their everyday life. Hence, we observed a gap between the biomedical perspective on disease that health professionals typically adopt and the individual lived experiences of patients with metastatic GIST. Understandably, the biomedical approach of health professionals and the pharmaceutical industry alike is more concerned with the objective medical side effects of a treatment than with its overall impact on patients’ daily lives. The biomedical model could be described as reductive and, thus, criticised for being too narrow. It is a model that primarily focuses on cure or extended survival but it says next to nothing about how disease affects the more practical, relational or existential aspects of life as experienced by the patients themselves, nor does it consider the psychosocial resources that patients need to cope with in their daily life. Research has shown that physicians tend to underestimate their patients’ health status [20] and to consider that side effects must be medical and life-threatening in order to be regarded as harmful. However, patients may blame ‘the pill’ for symptoms or challenges that are not necessarily related to their medication. For example, one patient reported being less happy as a side effect of imatinib. Whether this lack of happiness is a side effect, a consequence of the stressful situation of living with a chronic cancer or some other issue remains uncertain. As pointed out by Poort et al., fatigue is disabling and not only associated with current TKI use, but also with psychological distress and physical functioning [12]. Nevertheless, we hypothesise that challenging and debilitating side effects, as experienced by patients with metastatic GIST, may not be noticed and given appropriate attention. During follow up, it seems important that the oncologist develops a comprehensive picture of what it means for the patients to live with metastatic GIST. The subjective and psychosocial consequences of the treatment should be captured, and communication on how to deal with this should be an essential part. However, it is not necessarily the oncologist who should be responsible for the supportive care. Cancer nurses, other health care professionals and peers might play important roles. Improved communication might help the patients to better cope with the side effects that negatively impact their everyday life. Further research on how daily practical and psychosocial life is affected by the subjective side effects of cancer treatment, as well as how best help to patients to overcome those daily challenges, is hence warranted. Also, actively exploring dose reduction of imatinib tailored to the patients’ side effect and disease control, as well as interventions like cognitive behavioural therapies, might be justified.\n\nThe majority of our participants described ‘a new normal’ involving new preconditions whereby they experienced challenges, such as tiredness and fatigue, as well as a reduction in work capacity and social life, when compared to their ‘old normal’. From a psychosocial perspective, serious disease can be understood as a biographical disruption and a serious incident in a person’s life. Their previous life story is disrupted, as is their identity [14, 21]. Our participants described how illness had broken into their daily life and altered their life experiences. This experience of ‘otherness’ can lead to a sense of standing out negatively from the perceived norm, as well as to a reduced social life [21]. Most of our participants were very keen to lead a life as normal as possible. Attempting to continue with the activities and social relationships that correspond to their pre-disease life is a feature of the biographical disruption seen in chronically ill people. However, their sense of normality had to be changed and adapted to the new constraints in their life. This appeared particularly evident when the participants expressed the wish to return to the roles they had before the disease struck [21]. Existing in a world of disease can be a challenging situation. Striving for normality in the form of a new normal can, for chronic GIST patients, represent a means of coping with physical and existential challenges and distancing oneself from the disease. It is hence vitally important that sufficient attention is being paid to this issue during the follow-up of such patients.\n\nThe fact that several of our participants emphasised that they considered themselves to be healthy, despite having metastatic cancer and experiencing side effects of the associated treatment, could be related to questions such as ‘what is health and when is a person healthy?’ An individual’s ability to cope and to achieve vital goals is more important than whether that individual is defined as healthy or ill. In fact, the articular-holistic health concept stresses that health must be linked to action and function [22]. This view contradicts the prevailing notion of health as the absence of disease. In addition to being able to achieve vital goals and maintain everyday activity, health involves one’s ability to accomplish education and to work, to lead an active and social life, to have the opportunity to form close relationships and to establish a family, that is, living a normal life. In line with the findings of this study, this may be of particular relevance to those living with metastatic GISTs and, therefore, fighting everyday challenges.\n\nHealth is a way of being in the world. It is concerned with being in a meaningful relationship with others [23]. It has been emphasised that one cannot divide health into only somatic and psychological issues, since health is part of a being’s completeness (the whole of being), where we find our own well-being in the world in which we live. The prevailing paradigm in modern medicine has a unilateral focus on science and technology that may counteract the possibility to see the whole person, including that person’s health challenges and opportunities [23]. For chronic GIST patients, this means that cancer treatment is a prerequisite for extended survival, although it may not be sufficient.\n\nThis study did have certain limitations. As with most qualitative studies, the small sample size limits its generalisability. Nevertheless, the obtained narratives are rich and full of nuanced examples. In qualitative research, one does not seek representative data, but rather aims to illuminate the phenomena that participants experience from their own perspectives.\n\nConclusions\nAdvances in cancer research that result in new treatments will, over the next few decades, probably result in more patients with different cancer diagnoses living in a chronic phase, which means that they cannot be cured, although they will remain in stable remission for several years. This should prompt more attention and research concerning how daily practical and psychosocial life is affected in patients with metastatic cancer who are in long-term remission. In this regard, metastatic GIST could serve as a model disease due to the high response rate and relatively long expected survival in these patients. Our findings indicate that, for those patients who are living in limbo between having metastatic cancer and receiving effective treatment, a holistic view of health on the part of healthcare providers is crucial. One vital goal should be to improve communication between healthcare professionals and cancer patients in order to secure a comprehensive follow-up with guidance on how to cope with, and adapt to, their new normal.\n\nAdditional file\n\nAdditional file 1. Interview schedule.\n\n \n\n\nAbbreviations\nGISTgastrointestinal stromal tumour\n\nNRH OUHNorwegian Radium Hospital, Oslo University Hospital\n\nTKItyrosine kinase inhibitors\n\nQoLquality of life\n\nAuthors’ contributions\nLF conducted the interviews and the study analyses, drafted the manuscript and performed the final editing of the manuscript. All the other authors assisted in conducting the study, contributed significantly to the scientific/intellectual content and provided critical revisions to the draft manuscript. ØB had the initial idea and, together with IH, recruited the participants. IH, HB and GL partly analysed the data. All the authors meet the criteria for authorship in accordance with the authorship standards of the International Committee of Medical Journal Editors (ICMJE) Recommendations for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals (https://www.ICMJE.org). All authors read and approved the final manuscript.\n\n\nAcknowledgements\nThe authors are grateful to the participants for their kind and crucial contribution to this study. They also wish to acknowledge Erik Skjeggestad for his valuable comments.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAvailability of data and materials\nThe dataset supporting the conclusions of this article is included within the article.\n\nConsent to publish\nWritten informed consent for the publication of their clinical details was obtained from all the participants.\n\nEthics approval and consent to participate\nThe study was approved by the data protection officer of the NRH OUH (Approval Number 2016/15358), since the public use data do not contain any variables that could identify an individual subject, either directly or indirectly. Informed consent was obtained from all the participants in this study.\n\nFunding\nThe study received financial support from Lilly Constance and Karl Ingolf Larssons Stiftelse (Grant CRF/18004). The funders played no role in the collection of data, the interpretation of the results or the writing of the manuscript.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Hirota S Isozaki K Moriyama Y Hashimoto K Nishida T Ishiguro S Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors Science. 1998 279 5350 577 580 10.1126/science.279.5350.577 9438854 \n2. Joensuu H Roberts PJ Sarlomo-Rikala M Andersson LC Tervahartiala P Tuveson D Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor N Engl J Med. 2001 344 14 1052 1056 10.1056/NEJM200104053441404 11287975 \n3. Demetri GD von Mehren M Blanke CD Van den Abbeele AD Eisenberg B Roberts PJ Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors N Engl J Med. 2002 347 7 472 480 10.1056/NEJMoa020461 12181401 \n4. 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Gadamer H-G The enigma of health: the art of healing in a scientific age 1996 Stanford Stanford University Press\n\n", "fulltext_license": "CC BY", "issn_linking": "2045-3329", "issue": "9()", "journal": "Clinical sarcoma research", "keywords": "Gastrointestinal stromal tumour (GIST); Metastatic cancer; Qualitative research; Side effects", "medline_ta": "Clin Sarcoma Res", "mesh_terms": null, "nlm_unique_id": "101577890", "other_id": null, "pages": "6", "pmc": null, "pmid": "31061697", "pubdate": "2019", "publication_types": "D016428:Journal Article", "references": "10260456;10636102;11287975;12181401;15451219;16955344;17046465;19920223;21107913;22536061;25734906;26687836;27233141;28362562;28557540;30188977;9438854", "title": "Perspectives on treatment side effects in patients with metastatic gastrointestinal stromal tumour: a qualitative study.", "title_normalized": "perspectives on treatment side effects in patients with metastatic gastrointestinal stromal tumour a qualitative study" }

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