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{ "abstract": "OBJECTIVE\nOur aim was to evaluate the general applicability, feasibility, and safety of robot-assisted radical prostatectomy (RARP) in Chinese renal allograft patients for prostate cancer removal.\n\n\nMETHODS\nA 62-year-old patient diagnosed as having biopsy-proven localized prostate cancer in March 2016 who had undergone renal transplant 12 years ago was studied. The preoperative prostate-specific antigen value was determined to be 11.82 ng/mL and the Gleason score was determined to be 3 + 3. The RARP was carried out using a transperitoneal and posterior approach with 5 ports in May 2016. The most important technique was ensuring that the transplanted kidney and ureter remained untouched during the surgery. Only the right obturator lymph nodes were dissected because the renal allograft was overlying the iliac vessels.\n\n\nRESULTS\nThe RARP was successfully concluded following 230 minutes with an estimated blood loss of 200 mL. There were no postoperative complications. Final pathology was T2cN0M0, Gleason 3 + 3. Following catheter removal, the patient was completely continent and was discharged with no change in serum creatinine or glomerular filtration rate levels. During a 21-month follow-up, unobstructed urination, no incontinence, no biochemical recurrence, and normal kidney function were observed.\n\n\nCONCLUSIONS\nRARP in Chinese renal allograft patients is a feasible method that can be accomplished with no injuries to the transplanted kidney or ureter and is achieved with favorable oncological and functional outcomes. In addition, post-kidney transplant male patients are recommended to have routine prostate-specific antigen screening for the early detection of prostate cancer.", "affiliations": "Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.;Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.;Department of Pediatrics, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.;Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.;Department of Urology, Jiangmen Hospital, Sun Yat-Sen University, Jiangmen, China.;Department of Urology, The Affiliated Hospital of Hainan Medical College, Haikou, Hainan, China.;Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.;Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.;Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.;Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.;Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.;Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.;Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address: chenw3@mail.sysu.edu.cn.", "authors": "Fang|Y|Y|;Chen|Z|Z|;Juan|L|L|;Feng|Z|Z|;Cao|J|J|;Zhou|B|B|;Huang|Y|Y|;Cen|J|J|;Lu|J|J|;Liang|Y|Y|;Wei|J|J|;Luo|J|J|;Chen|W|W|", "chemical_list": "D017430:Prostate-Specific Antigen", "country": "United States", "delete": false, "doi": "10.1016/j.transproceed.2018.09.015", "fulltext": null, "fulltext_license": null, "issn_linking": "0041-1345", "issue": "50(10)", "journal": "Transplantation proceedings", "keywords": null, "medline_ta": "Transplant Proc", "mesh_terms": "D002681:China; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D017430:Prostate-Specific Antigen; D011468:Prostatectomy; D011471:Prostatic Neoplasms; D065287:Robotic Surgical Procedures; D014184:Transplantation, Homologous", "nlm_unique_id": "0243532", "other_id": null, "pages": "3978-3983", "pmc": null, "pmid": "30577300", "pubdate": "2018-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Robot-Assisted Radical Prostatectomy in a Post-Kidney Transplant Patient: An Initial Case Report in China.", "title_normalized": "robot assisted radical prostatectomy in a post kidney transplant patient an initial case report in china" }

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"activesubstancename": "NIFEDIPINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "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": "NIFEDIPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", 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"drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.25 G, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "201403", "drugstartdateformat": "610", "drugstructuredosagenumb": "1.25", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.5 G, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Prostate cancer", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201603" } }, "primarysource": { "literaturereference": "FANG Y, CHEN Z, JUAN L, FENG Z, CAO J, ZHOU B ET AL.. ROBOT-ASSISTED RADICAL PROSTATECTOMY IN A POST-KIDNEY TRANSPLANT PATIENT: AN INITIAL CASE REPORT IN CHINA. TRANSPLANTATION PROCEEDINGS. 2018?50(10):3978-83", "literaturereference_normalized": "robot assisted radical prostatectomy in a post kidney transplant patient an initial case report in china", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20190120", "receivedate": "20190120", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15846250, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "CN-ACCORD-102952", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "VALSARTAN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "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": "VALSARTAN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "POST PROCEDURAL HYPOTHYROIDISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROXINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "091195", "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": "2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "NIFEDIPINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "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": "NIFEDIPINE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "065416", "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": ".5", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "065416", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.5 G", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201403", "drugstartdateformat": "610", "drugstructuredosagenumb": "1.25", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": null, "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": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Prostate cancer", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201603" } }, "primarysource": { "literaturereference": "FANG Y, CHEN Z, JUAN L, FENG Z, CAO J, ZHOU B ET AL. ROBOT-ASSISTED RADICAL PROSTATECTOMY IN A POST-KIDNEY TRANSPLANT PATIENT: AN INITIAL CASE REPORT IN CHINA. TRANSPLANTATION PROCEEDINGS. 2018? 50(10): 3978-3983. DOI:?10.1016/J.TRANSPROCEED.2018.09.015.", "literaturereference_normalized": "robot assisted radical prostatectomy in a post kidney transplant patient an initial case report in china", "qualification": "1", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20190123", "receivedate": "20190123", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15857203, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20190417" } ]

{ "abstract": "OBJECTIVE\nThe impact of chemotherapeutic sequelae on long-term quality of life (QoL) for survivors of malignant sacrococcygeal teratoma (SCT) is unknown. The incidence of chemotherapeutic toxicity in patients treated for malignant SCT and possible effects on the QoL were analyzed.\n\n\nMETHODS\nRetrospective chart review of patients ≥18 years treated for SCT in the Netherlands was performed. Present QoL was evaluated using the SF-36 questionnaire. The results of survivors of malignant SCT were compared to those of patients treated for benign SCT.\n\n\nRESULTS\nFifty-one of 76 traceable patients consented to participate. The results of 47 (92.2 %), 9 men and 38 women (median age 25.4 years, range 18.3-41.2), were analyzed. Eleven had been treated for malignancy; 63.6 % suffered from at least one chemotherapeutic sequel with hearing loss as the most common one. Results for both groups were similar on all but one SF-36 subcategory; those treated for malignant tumor scored significantly lower on the subcategory physical functioning (p = 0.02).\n\n\nCONCLUSIONS\nDespite the high incidence of chemotherapeutic sequelae among survivors of malignant SCT, their QoL does not differ from that of those treated for benign SCT. Even though their physical functioning is restricted, daily activities and psychosocial functioning of survivors of malignant SCT are not restricted.", "affiliations": "Department of Pediatric Surgery, Maastricht University Medical Center, Maastricht, The Netherlands.;Department of Pediatric Surgery, Maastricht University Medical Center, Maastricht, The Netherlands.;Department of Pediatric Oncology, Emma Children's Hospital, University Medical Center Amsterdam, Amsterdam, The Netherlands.;Department of Pediatric Surgery, University Medical Center Groningen, Groningen, The Netherlands.;Pediatric Surgical Center of Amsterdam (Emma Children's Hospital University Medical Center and VU Medical Center Amsterdam), Amsterdam, The Netherlands.;Department of Pediatric Surgery, University Medical Center Nijmegen, Nijmegen, The Netherlands.;Department of Pediatric Surgery, Sophia Children's Hospital, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.;Department of Pediatric Surgery, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.;Department of Pediatric Surgery, Maastricht University Medical Center, Maastricht, The Netherlands. e.vanheurn@amc.uva.nl.", "authors": "Kremer|Marijke E B|ME|;Derikx|Joep P M|JP|;Kremer|Leontien C M|LC|;van Baren|Robertine|R|;Heij|Hugo A|HA|;Wijnen|Marc H W A|MH|;Wijnen|René M H|RM|;van der Zee|David C|DC|;van Heurn|L W Ernest|LW|", "chemical_list": null, "country": "Germany", "delete": false, "doi": "10.1007/s00383-015-3842-5", "fulltext": null, "fulltext_license": null, "issn_linking": "0179-0358", "issue": "32(3)", "journal": "Pediatric surgery international", "keywords": "Chemotherapeutic sequelae; Malignant sacrococcygeal teratoma; Quality of life", "medline_ta": "Pediatr Surg Int", "mesh_terms": "D000293:Adolescent; D000328:Adult; D005260:Female; D006801:Humans; D008297:Male; D009426:Netherlands; D010386:Pelvic Neoplasms; D011788:Quality of Life; D012189:Retrospective Studies; D012445:Sacrococcygeal Region; D011795:Surveys and Questionnaires; D017741:Survivors; D013724:Teratoma; D016896:Treatment Outcome; D055815:Young Adult", "nlm_unique_id": "8609169", "other_id": null, "pages": "261-8", "pmc": null, "pmid": "26667016", "pubdate": "2016-03", "publication_types": "D016428:Journal Article", "references": "9293455;11150431;7690864;12610174;11763203;9817123;23432104;10206457;1403540;23045231;9473756;11283126;19417664;17560233;10811491;22248970;23583133;9498381;3439358;4843993;25746708;17058315;6789651;22459912", "title": "Evaluation of chemotherapeutic sequelae and quality of life in survivors of malignant sacrococcygeal teratoma.", "title_normalized": "evaluation of chemotherapeutic sequelae and quality of life in survivors of malignant sacrococcygeal teratoma" }

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null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "1983", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINBLASTINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "YOLK SAC TUMOUR SITE UNSPECIFIED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "1983", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINBLASTINE" } ], "patientagegroup": null, "patientonsetage": "2", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Deafness", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KREMER MEB, DERIKX JPM, KREMER LCM, VAN BAREN R, HEIJ HA, WIJNEN MHWA, ET AL.. EVALUATION OF CHEMOTHERAPEUTIC SEQUELAE AND QUALITY OF LIFE IN SURVIVORS OF MALIGNANT SACROCOCCYGEAL TERATOMA.. PEDIATR SURG INT.. 2016;32 (3):261-8", "literaturereference_normalized": "evaluation of chemotherapeutic sequelae and quality of life in survivors of malignant sacrococcygeal teratoma", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20160524", "receivedate": "20160524", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12398504, "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": "NL-TEVA-657182ISR", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "74656", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CONGENITAL TERATOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "1991", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "74284", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CONGENITAL TERATOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "1991", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IFOSFAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CONGENITAL TERATOMA", "drugintervaldosagedefinition": null, 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"patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Deafness", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dilatation ventricular", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Scoliosis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bundle branch block left", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Paraplegia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KREMER MEB, DERIKX JPM, KREMER LCM, VAN BAREN R, HEIJ HA, WIJNEN MHWA, ET AL. EVALUATION OF CHEMOTHERAPEUTIC SEQUELAE AND QUALITY OF LIFE IN SURVIVORS OF MALIGNANT SACROCOCCYGEAL TERATOMA. PEDIATR-SURG-INT 2016;32(3):261-268.", "literaturereference_normalized": "evaluation of chemotherapeutic sequelae and quality of life in survivors of malignant sacrococcygeal teratoma", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20160505", "receivedate": "20160505", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12338524, "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": "NL-FRESENIUS KABI-FK201602452", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "074735", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CONGENITAL TERATOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN (MANUFACTURER UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BLEOMYCIN SULFATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "065185", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CONGENITAL TERATOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BLEOMYCIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VINBLASTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "089515", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CONGENITAL TERATOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINBLASTINE (MANUFACTURER UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Deafness", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Obstructive airways disorder", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KREMER M,DERIKX J,KREMER L,BAREN R,HEIJ H,WIJNEN M. EVALUATION OF CHEMOTHERAPEUTIC SEQUELAE AND QUALITY OF LIFE IN SURVIVORS OF MALIGNANT SACROCOCCYGEAL TERATOMA. PEDIATR-SURG-INT 2016;32(3):261-268.", "literaturereference_normalized": "evaluation of chemotherapeutic sequelae and quality of life in survivors of malignant sacrococcygeal teratoma", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20160504", "receivedate": "20160504", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12334847, "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": "NL-MYLANLABS-2016M1016658", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, 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"drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINBLASTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CONGENITAL TERATOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "1991", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINBLASTINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Epiphysiolysis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Renal impairment", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Deafness", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KREMER MEB, DERIKX JPM, KREMER LCM, VAN BAREN R, HEIJ HA, WIJNEN MHWA, ET AL. EVALUATION OF CHEMOTHERAPEUTIC SEQUELAE AND QUALITY OF LIFE IN SURVIVORS OF MALIGNANT SACROCOCCYGEAL TERATOMA. PEDIATR-SURG-INT 2016;32(3):261-268.", "literaturereference_normalized": "evaluation of chemotherapeutic sequelae and quality of life in survivors of malignant sacrococcygeal teratoma", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20160421", "receivedate": "20160421", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12290228, "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": "NL-TEVA-657185ISR", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BLEOMYCIN SULFATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "65033", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CONGENITAL TERATOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "1988", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BLEOMYCIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINBLASTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CONGENITAL TERATOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "1988", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINBLASTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CONGENITAL TERATOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "1988", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Obstructive airways disorder", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Deafness", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KREMER MEB, DERIKX JPM, KREMER LCM, VAN BAREN R, HEIJ HA, WIJNEN MHWA, ET AL. EVALUATION OF CHEMOTHERAPEUTIC SEQUELAE AND QUALITY OF LIFE IN SURVIVORS OF MALIGNANT SACROCOCCYGEAL TERATOMA. PEDIATR-SURG-INT 2016;32(3):261-268.", "literaturereference_normalized": "evaluation of chemotherapeutic sequelae and quality of life in survivors of malignant sacrococcygeal teratoma", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20160506", "receivedate": "20160506", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12340829, "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": "NL-CORDEN PHARMA LATINA S.P.A.-NL-2016COR000158", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, 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null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "YOLK SAC TUMOUR SITE UNSPECIFIED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "1991", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IFOSFAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "YOLK SAC TUMOUR SITE UNSPECIFIED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "1991", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IFOSFAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINBLASTINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "YOLK SAC TUMOUR SITE UNSPECIFIED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BLEOMYCIN" } ], "patientagegroup": null, "patientonsetage": "2", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Deafness", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Renal impairment", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Epiphysiolysis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KREMER MEB, DERIKX JPM, KREMER LCM, VAN BAREN R, HEIJ HA, WIJNEN MHWA, ET AL.. EVALUATION OF CHEMOTHERAPEUTIC SEQUELAE AND QUALITY OF LIFE IN SURVIVORS OF MALIGNANT SACROCOCCYGEAL TERATOMA.. PEDIATR SURG INT.. 2016;32 (3):261-8", "literaturereference_normalized": "evaluation of chemotherapeutic sequelae and quality of life in survivors of malignant sacrococcygeal teratoma", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20160525", "receivedate": "20160525", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12401352, "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": "NL-FRESENIUS KABI-FK201602450", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "VINBLASTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "089515", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CONGENITAL TERATOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINBLASTINE (MANUFACTURER UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "IFOSFAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "076078", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CONGENITAL TERATOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IFOSFAMIDE (MANUFACTURER UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "074735", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CONGENITAL TERATOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN (MANUFACTURER UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "074983", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CONGENITAL TERATOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", 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"drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BLEOMYCIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Epiphysiolysis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Deafness", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Renal impairment", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KREMER M,DERIKX J,KREMER L,BAREN R,HEIJ H,WIJNEN M. EVALUATION OF CHEMOTHERAPEUTIC SEQUELAE AND QUALITY OF LIFE IN SURVIVORS OF MALIGNANT SACROCOCCYGEAL TERATOMA. PEDIATR-SURG-INT 2016;32(3):261-268.", "literaturereference_normalized": "evaluation of chemotherapeutic sequelae and quality of life in survivors of malignant sacrococcygeal teratoma", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20160504", "receivedate": "20160504", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12333512, "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": "NL-MYLANLABS-2016M1016659", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091062", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CONGENITAL TERATOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "1988", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINBLASTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CONGENITAL TERATOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "1988", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINBLASTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BLEOMYCIN SULFATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CONGENITAL TERATOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "1988", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BLEOMYCIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Obstructive airways disorder", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Deafness", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KREMER MEB, DERIKX JPM, KREMER LCM, VAN BAREN R, HEIJ HA, WIJNEN MHWA, ET AL. EVALUATION OF CHEMOTHERAPEUTIC SEQUELAE AND QUALITY OF LIFE IN SURVIVORS OF MALIGNANT SACROCOCCYGEAL TERATOMA. PEDIATR-SURG-INT 2016;32(3):261-268.", "literaturereference_normalized": "evaluation of chemotherapeutic sequelae and quality of life in survivors of malignant sacrococcygeal teratoma", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20160421", "receivedate": "20160421", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12292822, "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": "NL-CORDEN PHARMA LATINA S.P.A.-NL-2016COR000149", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "IFOSFAMIDE" }, 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null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTASES TO LUNG", "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": "IFOSFAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, 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null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "802", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Deafness", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dilatation ventricular", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Paraplegia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bundle branch block left", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Scoliosis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KREMER MEB, DERIKX JPM, KREMER LCM, VAN BAREN R, HEIJ HA, WIJNEN MHWA, ET AL.. EVALUATION OF CHEMOTHERAPEUTIC SEQUELAE AND QUALITY OF LIFE IN SURVIVORS OF MALIGNANT SACROCOCCYGEAL TERATOMA.. PEDIATR SURG INT.. 2016;32 (3):261-8", "literaturereference_normalized": "evaluation of chemotherapeutic sequelae and quality of life in survivors of malignant sacrococcygeal teratoma", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20160524", "receivedate": "20160524", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12398390, "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": "NL-FRESENIUS KABI-FK201602456", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BLEOMYCIN SULFATE" }, 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TERATOMA", "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": null, "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CONGENITAL TERATOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE (MANUFACTURER UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TENIPOSIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CONGENITAL TERATOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TENIPOSIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Deafness", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KREMER M,DERIKX J,KREMER L,BAREN R,HEIJ H,WIJNEN M. EVALUATION OF CHEMOTHERAPEUTIC SEQUELAE AND QUALITY OF LIFE IN SURVIVORS OF MALIGNANT SACROCOCCYGEAL TERATOMA. PEDIATR-SURG-INT 2016;32(3):261-268.", "literaturereference_normalized": "evaluation of chemotherapeutic sequelae and quality of life in survivors of malignant sacrococcygeal teratoma", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20160504", "receivedate": "20160504", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12333420, "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": "NL-HQ SPECIALTY-NL-2016INT000302", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IFOSFAMIDE." } ], "patientagegroup": null, "patientonsetage": "2", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Deafness", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Renal impairment", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Epiphysiolysis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KREMER MEB, DERIKX JPM, KREMER LCM, VAN BAREN R, HEIJ HA, WIJNEN MHWA, ET AL.. EVALUATION OF CHEMOTHERAPEUTIC SEQUELAE AND QUALITY OF LIFE IN SURVIVORS OF MALIGNANT SACROCOCCYGEAL TERATOMA.. PEDIATR SURG INT.. 2016;32 (3):261-8", "literaturereference_normalized": "evaluation of chemotherapeutic sequelae and quality of life in survivors of malignant sacrococcygeal teratoma", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20160523", "receivedate": "20160523", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12395240, "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": "NL-TEVA-657184ISR", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": null, 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"patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Renal impairment", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Deafness", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Epiphysiolysis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KREMER MEB, DERIKX JPM, KREMER LCM, VAN BAREN R, HEIJ HA, WIJNEN MHWA, ET AL. EVALUATION OF CHEMOTHERAPEUTIC SEQUELAE AND QUALITY OF LIFE IN SURVIVORS OF MALIGNANT SACROCOCCYGEAL TERATOMA. 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"literaturereference": "KREMER M, DERIKX J, KREMER L, VAN BAREN R, HEIJ H, WIJNEN M, WIJNEN R, VAN DER ZEE D, VAN HEURN L. EVALUATION OF CHEMOTHERAPEUTIC SEQUELAE AND QUALITY OF LIFE IN SURVIVORS OF MALIGNANT SACROCOCCYGEAL TERATOMA. PEDIATRIC SURGERY INTERNATIONAL. 2016 JAN 01;32:261-268.", "literaturereference_normalized": "evaluation of chemotherapeutic sequelae and quality of life in survivors of malignant sacrococcygeal teratoma", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20170629", "receivedate": "20170629", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13699615, "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": "NL-MYLANLABS-2016M1016655", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CISPLATIN" }, 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EVALUATION OF CHEMOTHERAPEUTIC SEQUELAE AND QUALITY OF LIFE IN SURVIVORS OF MALIGNANT SACROCOCCYGEAL TERATOMA. 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"drugstartdate": "1991", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BLEOMYCIN" } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "802", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dilatation ventricular", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Deafness", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Paraplegia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bundle branch block left", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Scoliosis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KREMER MEB, DERIKX JPM, KREMER LCM, VAN BAREN R, HEIJ HA, WIJNEN MHWA, ET AL.. EVALUATION OF CHEMOTHERAPEUTIC SEQUELAE AND QUALITY OF LIFE IN SURVIVORS OF MALIGNANT SACROCOCCYGEAL TERATOMA.. 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null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "1986", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BLEOMYCIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CONGENITAL TERATOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "1986", "drugstartdateformat": "602", 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EVALUATION OF CHEMOTHERAPEUTIC SEQUELAE AND QUALITY OF LIFE IN SURVIVORS OF MALIGNANT SACROCOCCYGEAL TERATOMA. PEDIATR-SURG-INT 2016;32(3):261-268.", "literaturereference_normalized": "evaluation of chemotherapeutic sequelae and quality of life in survivors of malignant sacrococcygeal teratoma", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20160421", "receivedate": "20160421", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12290201, "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": "NL-FRESENIUS KABI-FK201602455", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "VINBLASTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "089515", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CONGENITAL TERATOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINBLASTINE (MANUFACTURER UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BLEOMYCIN SULFATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "065185", "drugbatchnumb": null, "drugcharacterization": "1", 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"drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IFOSFAMIDE (MANUFACTURER UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Renal impairment", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Deafness", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KREMER M,DERIKX J,KREMER L,BAREN R,HEIJ H,WIJNEN M. EVALUATION OF CHEMOTHERAPEUTIC SEQUELAE AND QUALITY OF LIFE IN SURVIVORS OF MALIGNANT SACROCOCCYGEAL TERATOMA. PEDIATR-SURG-INT 2016;32(3):261-268.", "literaturereference_normalized": "evaluation of chemotherapeutic sequelae and quality of life in survivors of malignant sacrococcygeal teratoma", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20160504", "receivedate": "20160504", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12333691, "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": "NL-FRESENIUS KABI-FK201602436", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": 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"drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN (MANUFACTURER UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Bundle branch block left", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Paraplegia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Scoliosis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dilatation ventricular", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Deafness", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KREMER M,DERIKX J,KREMER L,BAREN R,HEIJ H,WIJNEN M. EVALUATION OF CHEMOTHERAPEUTIC SEQUELAE AND QUALITY OF LIFE IN SURVIVORS OF MALIGNANT SACROCOCCYGEAL TERATOMA. PEDIATR-SURG-INT 2016;32(3):261-268.", "literaturereference_normalized": "evaluation of chemotherapeutic sequelae and quality of life in survivors of malignant sacrococcygeal teratoma", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20160505", "receivedate": "20160505", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12337091, "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": "NL-TEVA-657187ISR", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINBLASTINE" }, "drugadditional": null, 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EVALUATION OF CHEMOTHERAPEUTIC SEQUELAE AND QUALITY OF LIFE IN SURVIVORS OF MALIGNANT SACROCOCCYGEAL TERATOMA. 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EVALUATION OF CHEMOTHERAPEUTIC SEQUELAE AND QUALITY OF LIFE IN SURVIVORS OF MALIGNANT SACROCOCCYGEAL TERATOMA. 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{ "abstract": "Amantadine intoxication occurred despite moderate renal dysfunction. This may have been affected by the use of donepezil, and we require careful attention to these combinations.", "affiliations": "Department of Clinical Pharmaceutics and Pharmacy Practice Tohoku Medical and Pharmaceutical University Sendai Japan.;Department of Pharmacy Tohoku Medical and Pharmaceutical University Hospital Sendai Japan.;Department of Pharmacy Tohoku Medical and Pharmaceutical University Hospital Sendai Japan.;Department of Clinical Pharmaceutics and Pharmacy Practice Tohoku Medical and Pharmaceutical University Sendai Japan.;Division of Neurology Tohoku Medical and Pharmaceutical University Hospital Sendai Japan.;Division of Neurology Tohoku Medical and Pharmaceutical University Hospital Sendai Japan.;Division of Psychiatry Tohoku Medical and Pharmaceutical University Sendai Japan.;Department of Clinical Pharmaceutics and Pharmacy Practice Tohoku Medical and Pharmaceutical University Sendai Japan.", "authors": "Okada|Kouji|K|https://orcid.org/0000-0001-7191-2857;Uno|Takashi|T|;Utsumi|Miho|M|;Usui|Kensuke|K|;Nakamura|Masashi|M|;Nakashima|Ichiro|I|;Suzuki|Eiji|E|;Watanabe|Yoshiteru|Y|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1002/ccr3.2803", "fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904 John Wiley and Sons Inc. Hoboken \n\n10.1002/ccr3.2803\nCCR32803\nCase Report\nCase Reports\nAmantadine intoxication despite moderate renal dysfunction: A case of combined use with donepezil\nOKADA et al.Okada Kouji https://orcid.org/0000-0001-7191-2857\n1\n\n2\n Uno Takashi \n2\n Utsumi Miho \n2\n Usui Kensuke \n1\n\n2\n Nakamura Masashi \n3\n Nakashima Ichiro \n3\n Suzuki Eiji \n4\n Watanabe Yoshiteru \n1\n\n2\n \n1 \nDepartment of Clinical Pharmaceutics and Pharmacy Practice\nTohoku Medical and Pharmaceutical University\nSendai\nJapan\n\n\n2 \nDepartment of Pharmacy\nTohoku Medical and Pharmaceutical University Hospital\nSendai\nJapan\n\n\n3 \nDivision of Neurology\nTohoku Medical and Pharmaceutical University Hospital\nSendai\nJapan\n\n\n4 \nDivision of Psychiatry\nTohoku Medical and Pharmaceutical University\nSendai\nJapan\n\nCorrespondence\n\nKouji Okada, Department of Clinical Pharmaceutics and Pharmacy Practice, Tohoku Medical and Pharmaceutical University, 1‐12‐1 Fukumuro, Miyagino‐ku, Sendai, Miyagi 983‐8512, Japan.\n\nEmail: kokada@tohoku-mpu.ac.jp\n\n16 3 2020 \n6 2020 \n8 6 10.1002/ccr3.v8.61053 1056\n11 2 2020 26 2 2020 27 2 2020 © 2020 The Authors. Clinical Case Reports published by John Wiley & Sons LtdThis is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nAmantadine intoxication occurred despite moderate renal dysfunction. This may have been affected by the use of donepezil, and we require careful attention to these combinations.\n\nAmantadine intoxication occurred despite moderate renal dysfunction. This may have been affected by the use of donepezil, and we require careful attention to these combinations.\n\n\namantadinecerebral infarctiondonepezilintoxicationinvoluntary movementmoderate renal dysfunction source-schema-version-number2.0cover-dateJune 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.8.4 mode:remove_FC converted:19.06.2020\n\n\nOkada \nK \n, \nUno \nT \n, \nUtsumi \nM \n, et al. Amantadine intoxication despite moderate renal dysfunction: A case of combined use with donepezil\n. Clin Case Rep . 2020 ;8 :1053 –1056\n. 10.1002/ccr3.2803\n==== Body\n1 INTRODUCTION\nAdministration of amantadine and donepezil to improve patient with Alzheimer‐type dementia and cerebral infarction led to involuntary movements. Amantadine blood concentration reached a toxic level (3647 ng/mL). It is necessary to carefully monitor patients with even moderate renal dysfunction, who receive combinations of amantadine and drugs, such as donepezil.\n\nAmantadine acts on dopaminergic neurons and is used to treat symptoms of Parkinson's disease.1 This drug also alleviates the decrease in spontaneity due to late effects of cerebral infarction,2 and it is approved for this purpose in Japan. As elimination is primarily achieved through renal clearance, half‐life of amantadine is longer in patients with renal dysfunction.3 The renal clearance of amantadine can exceed creatinine clearance (Ccr), suggesting that tubular secretion can play a role in elimination. Hence, amantadine doses must be reduced in patients with renal dysfunction to avoid toxicity.4 So far, amantadine intoxication has only been reported in patients with renal failure.5, 6, 7 However, the aim of this study is to report our clinical experience with a patient who developed toxic symptoms due to an increase in blood amantadine concentration during the combined use of donepezil, while being diagnosed with cerebral infarction and moderate renal dysfunction.\n\n2 CASE HISTORY\nThe patient was an 80‐year‐old woman. Her medical history consisted of arrhythmia that had developed 16 years ago, Alzheimer's disease 4 years ago, and a fracture in the right femoral neck 2 years ago. Due to motor aphasia and right hemiparesis, she was admitted to our hospital and diagnosed with cerebral infarction. Findings upon admission included height 152.0 cm, weight 52.2 kg, blood pressure 149/59 mm Hg, pulse 89 beats per minute, temperature 36.5°C, and SpO2 93%‐95% (room air). Medicines that were brought were canceled on admission.\n\nThe time course of drug administration and symptoms are illustrated in Figure 1, and the transition of laboratory values and vital signs are summarized in Table 1. On the day after hospitalization, the patient received heparin sodium, edaravone, and fluid replacements. On the 13th day, right hemiparesis was still persistent. In addition to hemiparesis, her decreased spontaneity due to the late effects of cerebral infarction diminished her oral intake. Therefore, she received simultaneous administration of amantadine (150 mg/d for the loss of spontaneity with the late effects of cerebral infarction) and apixaban via a nasogastric tube. Furthermore, because there was not much improvement in her spontaneity and mobility due to Alzheimer's dementia, 3 mg/d of donepezil was administered on the 16th day, followed by 5 mg/d donepezil on the 24th day. On the 27th day, involuntary movements (stiffening and tremor) started appearing. On the 30th day, tremors were observed across the entire body when the patient was being addressed or touched, which were presumed to be Gegenhalten. We also suspected that the tremors were extrapyramidal symptoms and, hence, stopped the administration of donepezil. On the 34th day, as fever and tachycardia had developed, chest X‐ray and blood tests were performed; no infections, such as pneumonia, were found. On the 35th day, involuntary movements and fever increased, which we suspected to be due to amantadine intoxication. Hence, the administration of amantadine was discontinued. On the 36th day, we added carvedilol for the treatment of tachycardia. Blood concentration of amantadine was measured, which was found to be at a toxic level (3647 ng/mL). Creatine kinase was within the normal range, and no malignant syndromes were found. On the 37th day, clonazepam was initiated due to the persistence of the myoclonus‐like involuntary movement. On the 40th day, both stimulated systemic hypertonia and involuntary movement seemed to improve. On the 49th day, the toxic symptoms disappeared and the patient was discharged from the hospital.\n\nFigure 1 Time course of drug administered and symptoms\n\nTable 1 Summary of laboratory values and vital signs from day 1‐day 47, where “day” refers to time after hospitalization\n\n \tDay 1\tDay 13\tDay 27\tDay 36\tDay 47\t\nLaboratory data\t\nWBC\t×103/µL\t5.8\t4.6\t5.1\t7.8\t4.4\t\nHgb\tg/dL\t15.3\t13.9\t13.1\t11.7\t12.2\t\nPLT\t×104/µL\t16.2\t29.1\t27.8\t24.4\t38.2\t\nAST\tU/L\t12\t9\t20\t16\t17\t\nALT\tU/L\t4\t5\t40\t22\t23\t\nLDH\tU/L\t150\t210\t256\t235\t218\t\nCK\tU/L\t15\t–\t–\t47\t–\t\nScr\tmg/dL\t0.81\t0.61\t0.65\t0.65\t0.56\t\nBUN\tmg/dL\t13\t21\t20\t30\t20\t\nCcr\tmL/min\t43\t58\t54\t54\t63\t\nAlb\tg/dL\t3.9\t2.9\t3.1\t3.2\t2.6\t\nNa\tmEq/L\t137\t–\t132\t132\t138\t\nK\tmEq/L\t4.6\t–\t4.5\t4.0\t4.5\t\nCl\tmEq/L\t100\t–\t96\t96\t105\t\nCRP\tmg/dL\t0.03\t1.47\t0.93\t1.65\t1.22\t\nVital sign\t\nSpO2\t%\t93‐98\t95\t98\t85‐96\t96‐97\t\nPR\tbpm\t89‐105\t85‐90\t55\t110‐133\t100\t\nSBP\tmm Hg\t132‐149\t114‐136\t118\t128‐130\t125\t\nDBP\tmm Hg\t59‐88\t60‐73\t64\t66‐84\t68\t\nNote\n“day” means days of after hospitalization.\n\nAbbreviations: Alb, albumin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Ccr, creatinine clearance; CK, creatine kinase; Cl, serum chloride; CRP, C‐reactive protein; DBP, diastolic blood pressure; Hgb, haemoglobin; K, serum potassium; LDH, lactate dehydrogenase; Na, serum sodium; PLT, platelet count; PR, pulse rate; SBP, systolic blood pressure; Scr, serum creatinine; SpO2, blood oxygen saturation; WBC, white blood cell count.\n\nJohn Wiley & Sons, Ltd3 DISCUSSION\nWe experienced a case of amantadine intoxication despite the presence of only moderate renal dysfunction. Previous reports indicate that toxic symptoms are observed if amantadine blood concentration exceeds 3000 ng/mL.8 In our case, we found that amantadine had reached toxic levels. We suspect that individual differences in the ability to excrete the drug and/or the effects of combined use of donepezil caused amantadine intoxication in this case.\n\nNishikawa et al (2009) also reported that plasma amantadine concentration exhibited a significant negative correlation with Ccr. And a 4‐fold range in blood concentration was noted when 100 mg/d of amantadine was administered to patients with normal renal function.8 The dosage of amantadine in the package insert for the late effect of cerebral infarction was \"100‐150 mg/d divided into 2‐3 doses.\" The dosage of amantadine was within the standard dose range; however, it may have been an overdose for our patient. Other reports also describe the use of amantadine intoxication to improve the spontaneity of patients with moderate renal dysfunction.9 As most of amantadine is excreted into urine in the unchanged form, individual differences in the ability to excrete the drug are the cause of fluctuation in the blood amantadine levels. A report described how amantadine intoxication at 150 mg/d in a patient with moderate renal dysfunction could be controlled by the re‐administration of amantadine at 50 mg/d initially and then gradually increasing the dosage.9\n\n\nThe potency of the drug interaction between amantadine and donepezil should be studied, as amantadine intoxication symptoms were found to occur while using donepezil. Donepezil is effective in reducing involuntary movements due to Alzheimer's dementia,10 which was also observed in this case. Amantadine is known as a drug having a large ratio of tubular secretion to the renal clearance (from the information in the package insert). Memantine, an N‐methyl‐d‐aspartate receptor inhibitor with a structure similar to amantadine, is a substrate of the organic cation transporter 2 (OCT2) and the multidrug and toxin extrusion protein 1 (MATE1).11 OCT2 is primarily a renal uptake transporter that is expressed on the basolateral (blood) side of the proximal tubule cells. MATE1 is an apically expressed poly‐specific proton antiporter that mediates renal efflux of diverse substrates that are primarily organic cations. Donepezil inhibits both OCT212 and MATE1.13 We hypothesize that the combined use of amantadine and donepezil led to competition in transport of amantadine through OCT2 and MATE1 leading to inhibition of its excretion and a consequent increase in its blood concentration. Although pharmacokinetics data are not available for the combination of amantadine and donepezil, there are several reports on memantine, which has a structure and activity similar to those of amantadine. An in vivo study reported that the combination of donepezil and memantine decreased clearance of memantine and hence increased its blood concentration and its area under the curve.14 However, no significant pharmacokinetic interaction was observed in a co‐administration study of donepezil and memantine conducted on healthy human subjects.15 Moreover, meta‐analyses have also investigated the combined efficacy and safety of donepezil and memantine for Alzheimer‐type dementia.16 Currently, the effect of the combination of memantine and donepezil is not considered a clinical problem. However, to the best of our knowledge, there are no reports on the direct evaluation of the effects of the combination of amantadine and donepezil. Drug interactions related to renal transporters are becoming clear, but there are many obscurity points. And these drug interactions are still not well recognized in clinical practice.17 In fact, the package insert does not contain any information about drug interactions between amantadine and donepezil. In this report, we presume amantadine intoxication because of their interaction through renal transporter inhibition although the mode of action will need further investigation.\n\n4 CONCLUSIONS\nAmantadine is excreted renally at a high rate in the form of the unchanged drug. In this case, amantadine concentrations in the blood increased to toxic levels despite moderate renal dysfunction. It is necessary to carefully monitor the patient for toxic symptoms caused by amantadine, especially in patients receiving a combination of amantadine and drugs such as donepezil.\n\nCONFLICT OF INTEREST\nWe declare no conflict of interest.\n\nAUTHOR CONTRIBUTIONS\nKO: designed the study, analyzed and interpretation of data, and wrote the manuscript. TU and MU: provided pharmaceutical care to patient, collected data, and were involved in manuscript drafting and editing. KU: contributed to case interpretation and was involved in manuscript drafting and editing. MN and IN: provided clinical care to patient and were involved in manuscript drafting and editing. ES and YW: were involved in manuscript drafting and editing and contributed to supervision. All authors approved the final version of the manuscript 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\nACKNOWLEDGMENTS\nThe authors thank Dr M. Nagai (Ehime University, School of Medicine Hospital) for his technical assistance in determining the concentration of amantadine in the blood.\n==== Refs\nREFERENCES\n1 \n\nSchwab \nRS \n, \nEngland \nJr\nAC \n, \nPoskanzer \nDC \n, \nYoung \nRR \n. Amantadine in the treatment of Parkinson's disease\n. JAMA . 1969 ;208 :1168 ‐1170\n.5818715 \n2 \n\nYamada \nK \n, \nTanabe \nH \n, \nYoshino \nK \n, et al. Clinical effect of Symmetrel for decreased willingness and spontaneity resulting from cerebral infarction\n. J Med . 1990 ;24 :853 ‐869\n.\n3 \n\nHoradam \nVW \n, \nSharp \nJG \n, \nSmilack \nJD \n, et al. Pharmacokinetics of amantadine hydrochloride in subjects with normal and impaired renal function\n. Ann Intern Med . 1981 ;94 :454 ‐458\n.7212501 \n4 \n\nWu \nMJ \n, \nIng \nTS \n, \nSoung \nLS \n, \nDaugirdas \nJT \n, \nHano \nJE \n, \nGandhi \nVC \n. Amantadine hydrochloride pharmacokinetics in patients with impaired renal function\n. Clin Nephrol . 1982 ;17 :19 ‐23\n.7035042 \n5 \n\nStrong \nDK \n, \nEisenstat \nDD \n, \nBryson \nSM \n, \nSitar \nDS \n, \nArbus \nGS \n. Amantadine neurotoxicity in a pediatric patient with renal insufficiency\n. DICP . 1991 ;25 :1175 ‐1177\n.1763530 \n6 \n\nMacchio \nGJ \n, \nIto \nV \n, \nSahgal \nV \n. Amantadine‐induced coma\n. Arch Phys Med Rehabil . 1993 ;74 :1119 ‐1120\n.8215867 \n7 \n\nNakata \nM \n, \nIto \nS \n, \nShirai \nW \n, \nHattori \nT \n. Severe reversible neurological complications following amantadine treatment in three elderly patients with renal insufficiency\n. Eur Neurol . 2006 ;56 :59 ‐61\n.16921246 \n8 \n\nNishikawa \nN \n, \nNagai \nM \n, \nMoritoyo \nT \n, \nYabe \nH \n, \nNomoto \nM \n. Plasma amantadine concentrations in patients with Parkinson's disease\n. Parkinsonism Relat Disord . 2009 ;15 :351 ‐353\n.18823813 \n9 \n\nKunieda \nK \n, \nShigematsu \nT \n, \nFujishima \nI \n. Case reports describing amantadine intoxication in a rehabilitation hospital\n. Prog Rehabil Med . 2017 ;2 :20170017 .\n10 \n\nGauthier \nS \n, \nFeldman \nH \n, \nHecker \nJ \n, et al. Emir B; Donepezil MSAD Study Investigators Group. Efficacy of donepezil on behavioral symptoms in patients with moderate to severe Alzheimer's disease\n. Int Psychogeriatr . 2002 ;14 :389 ‐404\n.12670060 \n11 \n\nMüller \nF \n, \nWeitz \nD \n, \nDerdau \nV \n, et al. Contribution of MATE1 to renal secretion of the NMDA receptor antagonist memantine\n. Mol Pharm . 2017 ;14 :2991 ‐2998\n.28708400 \n12 \n\nHacker \nK \n, \nMaas \nR \n, \nKornhuber \nJ \n, \nFromm \nMF \n, \nZolk \nO \n. Substrate‐dependent inhibition of the human organic cation transporter OCT2: a comparison of metformin with experimental substrates\n. PLoS ONE . 2015 ;10 :e0136451.26327616 \n13 \n\nMartínez‐Guerrero \nLJ \n, \nMorales \nM \n, \nEkins \nS \n, \nWright \nSH \n. Lack of influence of substrate on ligand interaction with the human multidrug and toxin extruder, MATE1\n. Mol Pharmacol . 2016 ;90 :254 ‐264\n.27418674 \n14 \n\nHassan \nMG \n, \nIkeda \nR \n, \nWada \nM \n, et al. Interaction study of acetylcholinesterase inhibitors on pharmacokinetics of memantine in rat plasma by HPLC‐fluorescence method\n. Biomed Chromatogr . 2013 ;27 :1685 ‐1689\n.23861199 \n15 \n\nPericlou \nAP \n, \nVentura \nD \n, \nSherman \nT \n, \nRao \nN \n, \nAbramowitz \nWT \n. Lack of pharmacokinetic or pharmacodynamic interaction between memantine and donepezil\n. Ann Pharmacother . 2004 ;38 :1389 ‐1394\n.15266045 \n16 \n\nChen \nR \n, \nChan \nPT \n, \nChu \nH \n, et al. Treatment effects between monotherapy of donepezil versus combination with memantine for Alzheimer disease: a meta‐analysis\n. PLoS ONE . 2017 ;12 :e0183586.28827830 \n17 \n\nIvanyuk \nA \n, \nLivio \nF \n, \nBiollaz \nJ \n, \nBuclin \nT \n. Renal drug transporters and drug interactions\n. Clin Pharmacokinet . 2017 ;56 :825 ‐892\n.28210973\n\n", "fulltext_license": "CC BY", "issn_linking": "2050-0904", "issue": "8(6)", "journal": "Clinical case reports", "keywords": "amantadine; cerebral infarction; donepezil; intoxication; involuntary movement; moderate renal dysfunction", "medline_ta": "Clin Case Rep", "mesh_terms": null, "nlm_unique_id": "101620385", "other_id": null, "pages": "1053-1056", "pmc": null, "pmid": "32577263", "pubdate": "2020-06", "publication_types": "D002363:Case Reports", "references": "28708400;7212501;5818715;8215867;28827830;15266045;7035042;12670060;27418674;18823813;16921246;1763530;26327616;28210973;23861199", "title": "Amantadine intoxication despite moderate renal dysfunction: A case of combined use with donepezil.", "title_normalized": "amantadine intoxication despite moderate renal dysfunction a case of combined use with donepezil" }

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"reactionmeddrapt": "Drug level increased", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Extrapyramidal disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myoclonus", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OKADA K, UNO T, UTSUMI M, USUI K, NAKAMURA M, NAKASHIMA I, ET AL. AMANTADINE INTOXICATION DESPITE MODERATE RENAL DYSFUNCTION: A CASE OF COMBINED USE WITH DONEPEZIL. CLIN CASE REP. 2020 MAR 16?8(6):1053?1056.", "literaturereference_normalized": "amantadine intoxication despite moderate renal dysfunction a case of combined use with donepezil", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200709", "receivedate": "20200709", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17998474, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" }, { "companynumb": "JP-UPSHER-SMITH LABORATORIES, LLC-2020USL00176", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMANTADINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "076186", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "CEREBRAL INFARCTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMANTADINE HYDROCHLORIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEMENTIA ALZHEIMER^S TYPE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": null, "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "52.2", "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OKADA K, UNO T, UTSUMI M, ET AL.. AMANTADINE INTOXICATION DESPITE MODERATE RENAL DYSFUNCTION: A CASE OF COMBINED USE WITH DONEPEZIL. CLIN CASE REP. 2020", "literaturereference_normalized": "amantadine intoxication despite moderate renal dysfunction a case of combined use with donepezil", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200406", "receivedate": "20200406", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17629704, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200713" }, { "companynumb": "JP-TEVA-2020-JP-1799816", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMANTADINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPOKINESIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMANTADINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "090425", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 MILLIGRAM DAILY; ADMINISTERED ON THE 16TH DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEMENTIA ALZHEIMER^S TYPE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "VIA A NASOGASTRIC TUBE", "drugenddate": null, "drugenddateformat": null, "drugindication": "CEREBRAL INFARCTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "090425", "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MILLIGRAM DAILY; ADMINISTERED ON THE 24TH DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEMENTIA ALZHEIMER^S TYPE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "EDARAVONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CEREBRAL INFARCTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EDARAVONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CEREBRAL INFARCTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN SODIUM." } ], "patientagegroup": "6", "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "52.2", "reaction": [ { "reactionmeddrapt": "Hypertonia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dyskinesia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OKADA K, UNO T, UTSUMI M, USUI K, NAKAMURA M, NAKASHIMA I, ET AL. AMANTADINE INTOXICATION DESPITE MODERATE RENAL DYSFUNCTION: A CASE OF COMBINED USE WITH DONEPEZIL. CLIN?CASE?REP 2020?8(6):1053?1056.", "literaturereference_normalized": "amantadine intoxication despite moderate renal dysfunction a case of combined use with donepezil", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210628", "receivedate": "20200714", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18019817, "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-PRINSTON PHARMACEUTICAL INC.-2020PRN00101", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "200292", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "200292", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEMENTIA ALZHEIMER^S TYPE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMANTADINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "CEREBRAL INFARCTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMANTADINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": null, "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "52.2", "reaction": [ { "reactionmeddrapt": "Myoclonus", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tremor", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OKADA K, UNO T, UTSUMI M, ET AL.. AMANTADINE INTOXICATION DESPITE MODERATE RENAL DYSFUNCTION: A CASE OF COMBINED USE WITH DONEPEZIL. CLIN CASE REP. 2020", "literaturereference_normalized": "amantadine intoxication despite moderate renal dysfunction a case of combined use with donepezil", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200331", "receivedate": "20200331", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17605277, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200409" }, { "companynumb": "JP-ADAMAS PHARMA, LLC-2020ADA00826", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMANTADINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "208944", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "CEREBRAL INFARCTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMANTADINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, 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"drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL." } ], "patientagegroup": null, "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "52.2", "reaction": [ { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tremor", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypertonia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hyperkinesia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Accidental overdose", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OKADA K, UNO T, UTSUMI M, ET AL.. AMANTADINE INTOXICATION DESPITE MODERATE RENAL DYSFUNCTION: A CASE OF COMBINED USE WITH DONEPEZIL. CLIN CASE REP. 2020", "literaturereference_normalized": "amantadine intoxication despite moderate renal dysfunction a case of combined use with donepezil", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200407", "receivedate": "20200407", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17639078, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200713" }, { "companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-252564", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CEREBRAL INFARCTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMANTADINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MILLIGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "CEREBRAL INFARCTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMANTADINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "90493", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 MILLIGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "CEREBRAL INFARCTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "90493", "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MILLIGRAM, DAILY", "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": "DONEPEZIL." } ], "patientagegroup": null, "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "52.2", "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OKADA K, UNO T, UTSUMI M, USUI K, NAKAMURA M, NAKASHIMA I, ET AL. AMANTADINE INTOXICATION DESPITE MODERATE RENAL DYSFUNCTION: A CASE OF COMBINED USE WITH DONEPEZIL. CLIN CASE REP. 2020?8(6):1053?1056", "literaturereference_normalized": "amantadine intoxication despite moderate renal dysfunction a case of combined use with donepezil", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200710", "receivedate": "20200710", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18002396, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "JP-UNICHEM PHARMACEUTICALS (USA) INC-UCM202003-000423", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "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": "HEMIPARESIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "EDARAVONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEMIPARESIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EDARAVONE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "203656", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ON 16TH DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEMENTIA ALZHEIMER^S TYPE", 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"drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "203656", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ON 24TH DAY", "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": "DONEPEZIL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMANTADINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MOVEMENT DISORDER", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMANTADINE." } ], "patientagegroup": "6", "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "52.2", "reaction": [ { "reactionmeddrapt": "Dyskinesia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypertonia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tremor", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Musculoskeletal stiffness", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OKADA K, ?UNO T, ?UTSUM M, USUI K, NAKAMURA M, NAKASHIMA I. AMANTADINE INTOXICATION DESPITE MODERATE RENAL DYSFUNCTION: A CASE OF COMBINED USE WITH DONEPEZIL. CLIN CASE REP. 2020?. DOI:10.1002/CCR3.2803", "literaturereference_normalized": "amantadine intoxication despite moderate renal dysfunction a case of combined use with donepezil", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "JP", "receiptdate": "20200406", "receivedate": "20200406", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17631456, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200713" }, { "companynumb": "JP-STRIDES ARCOLAB LIMITED-2020SP007842", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MILLIGRAM PER DAY ON THE 24TH DAY", "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": "DONEPEZIL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AMANTADINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "209035", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MILLIGRAM PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "CEREBRAL INFARCTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMANTADINE HYDROCHLORIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "EDARAVONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, 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null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 MILLIGRAM PER DAY ON THE 16TH DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEMENTIA ALZHEIMER^S TYPE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL." } ], "patientagegroup": null, "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "52.2", "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myoclonus", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Musculoskeletal stiffness", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tremor", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OKADA K, UNO T, UTSUMI M, USUI K, NAKAMURA M, NAKASHIMA I, ET AL.. AMANTADINE INTOXICATION DESPITE MODERATE RENAL DYSFUNCTION: A CASE OF COMBINED USE WITH DONEPEZIL. CLINICAL CASE REPORTS. 2020?8(6):1053?1056", "literaturereference_normalized": "amantadine intoxication despite moderate renal dysfunction a case of combined use with donepezil", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200713", "receivedate": "20200713", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18012449, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" }, { "companynumb": "JP-BION-008835", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMANTADINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "078720", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ABULIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMANTADINE HYDROCHLORIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "EDARAVONE" }, "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": "EDARAVONE" }, { "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, 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"drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ON THE 16TH DAY FOLLOWED BY 5 MG/D DONEPEZIL ON THE 24TH DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEMENTIA ALZHEIMER^S TYPE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL/DONEPEZIL HYDROCHLORIDE" } ], "patientagegroup": "6", "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "52.2", "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Extrapyramidal disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Myoclonus", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug level increased", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dyskinesia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Musculoskeletal stiffness", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tremor", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Paratonia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OKADA K, UNO T, UTSUMI M, USUI K, NAKAMURA M, NAKASHIMA I, ET AL. AMANTADINE INTOXICATION DESPITE MODERATE RENAL DYSFUNCTION: A CASE OF COMBINED USE WITH DONEPEZIL. CLIN CASE REP. 2020 MAR 16?8(6):1053?1056.", "literaturereference_normalized": "amantadine intoxication despite moderate renal dysfunction a case of combined use with donepezil", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200709", "receivedate": "20200709", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17999742, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" }, { "companynumb": "JP-STRIDES ARCOLAB LIMITED-2020SP008063", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "AMANTADINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "209035", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MILLIGRAM, PER DAY ON DAY 101.", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMANTADINE HYDROCHLORIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AMANTADINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "209035", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MILLIGRAM, PER DAY ON DAY 56.", "drugenddate": null, "drugenddateformat": null, "drugindication": "REHABILITATION THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMANTADINE HYDROCHLORIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AMANTADINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "209035", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MILLIGRAM, PER DAY, ON DAY 49.", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPOKINESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMANTADINE HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Renal impairment", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypophagia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myoclonus", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hallucination", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OKADA K, UNO T, UTSUMI M, ET AL.. AMANTADINE INTOXICATION DESPITE MODERATE RENAL DYSFUNCTION: A CASE OF COMBINED USE WITH DONEPEZIL.. CLIN CASE REP.. 2020?8:1053?1056", "literaturereference_normalized": "amantadine intoxication despite moderate renal dysfunction a case of combined use with donepezil", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200717", "receivedate": "20200717", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18037242, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" }, { "companynumb": "JP-CPL-001713", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": "1", "drugadministrationroute": null, 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AMANTADINE INTOXICATION DESPITE MODERATE RENAL DYSFUNCTION: A CASE OF COMBINED USE WITH DONEPEZIL. CLINICAL CASE REPORTS. 2020.", "literaturereference_normalized": "amantadine intoxication despite moderate renal dysfunction a case of combined use with donepezil", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200418", "receivedate": "20200408", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17642920, "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": "JP-JUBILANT CADISTA PHARMACEUTICALS-2020JUB00112", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEMENTIA ALZHEIMER^S TYPE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMANTADINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "210403", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "CEREBRAL INFARCTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMANTADINE HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "52.2", "reaction": [ { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Myoclonus", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OKADA K, UNO T, UTSUMI M, ET AL.. AMANTADINE INTOXICATION DESPITE MODERATE RENAL DYSFUNCTION: A CASE OF COMBINED USE WITH DONEPEZIL. CLIN CASE REP. 2020", "literaturereference_normalized": "amantadine intoxication despite moderate renal dysfunction a case of combined use with donepezil", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200403", "receivedate": "20200403", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17624340, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200713" }, { "companynumb": "NVSC2020JP187596", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMANTADINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": 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null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMANTADINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 MG, QD, 16TH DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEMENTIA ALZHEIMER^S TYPE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUROLOGICAL SYMPTOM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" } ], "patientagegroup": null, "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "52.2", "reaction": [ { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dyskinesia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OKADA K, UNO T, UTSUMI M, USUI K, NAKAMURA M, NAKASHIMA I ET AL.. AMANTADINE INTOXICATION DESPITE MODERATE RENAL DYSFUNCTION: A CASE OF COMBINED USE WITH DONEPEZIL. CLINICAL CASE REPORTS. 2020?8:1053?6", "literaturereference_normalized": "amantadine intoxication despite moderate renal dysfunction a case of combined use with donepezil", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200707", "receivedate": "20200704", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17981065, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "JP-ACCORD-178405", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "201335", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ON THE 24TH DAY, AFTER BREAKFAST (7DAYS), DISSOLVING TABLET", "drugenddate": "20180707", "drugenddateformat": "102", "drugindication": "DEMENTIA ALZHEIMER^S TYPE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20180626", "drugstartdateformat": "102", "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL/DONEPEZIL HYDROCHLORIDE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMANTADINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CEREBRAL INFARCTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMANTADINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "201335", "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ON THE 24TH DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ABULIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "EDARAVONE" }, "drugadditional": "3", "drugadministrationroute": "045", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "FORMULATION UNKNOWN", "drugdosagetext": "NASOGASTRIC TUBE", "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": "EDARAVONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "3", "drugadministrationroute": "045", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "FORMULATION UNKNOWN", "drugdosagetext": "NASOGASTRIC TUBE", "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": "APIXABAN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "201335", "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ON THE 16TH DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEMENTIA ALZHEIMER^S TYPE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": "3", "drugadministrationroute": "045", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "FORMULATION UNKNOWN", "drugdosagetext": "NASOGASTRIC TUBE", "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" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMANTADINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "GRANULES", "drugdosagetext": "AFTER MEALS", "drugenddate": "20180718", "drugenddateformat": "102", "drugindication": "ABULIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20180626", "drugstartdateformat": "102", "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMANTADINE." } ], "patientagegroup": null, "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "52.2", "reaction": [ { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Musculoskeletal stiffness", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Myoclonus", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug level increased", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Extrapyramidal disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dyskinesia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Paratonia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20180626" } }, "primarysource": { "literaturereference": "OKADA K, UNO T, UTSUMI M, USUI K, NAKAMURA M, NAKASHIMA I ET AL. AMANTADINE INTOXICATION DESPITE MODERATE RENAL DYSFUNCTION: A CASE OF COMBINED USE WITH DONEPEZIL. CLINICAL CASE REPORTS. 2020.", "literaturereference_normalized": "amantadine intoxication despite moderate renal dysfunction a case of combined use with donepezil", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200707", "receivedate": "20200408", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17645701, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201102" }, { "companynumb": "JP-DEXPHARM-20200619", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DEMENTIA ALZHEIMER^S TYPE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL NON DEXCEL PRODUCT" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "APIXABAN" }, "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": "APIXABAN" }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DEMENTIA ALZHEIMER^S TYPE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL NON DEXCEL PRODUCT" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMANTADINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CEREBRAL INFARCTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMANTADINE." } ], "patientagegroup": "6", "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "52.2", "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Musculoskeletal stiffness", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tremor", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Paratonia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dyskinesia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OKADA K, UNO T, UTSUMI M, USUI K, NAKAMURA M, NAKASHIMA I ET AL. AMANTADINE INTOXICATION DESPITE MODERATE RENAL DYSFUNCTION: A CASE OF COMBINED USE WITH DONEPEZIL. CLINICAL CASE REPORTS. 2020", "literaturereference_normalized": "amantadine intoxication despite moderate renal dysfunction a case of combined use with donepezil", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200721", "receivedate": "20200721", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 18050851, "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": "The diagnosis of serum sickness-like reaction (SSLR) is typically based on clinical findings. Histopathologic examination is often deferred, as these eruptions commonly present in young children, and often to primary care providers. A PubMed literature search revealed only five existing cases of SSLR which describe cutaneous histopathologic features. We report two cases of SSLR, one each to bupropion and cefazolin. Skin biopsy findings in both cases showed a neutrophil-predominant urticarial pattern resembling neutrophilic urticaria or neutrophilic urticarial dermatosis. We also provide a summary of the histopathologic findings that can help support a diagnosis of SSLR.", "affiliations": "Department of Dermatology, University of Minnesota, Minneapolis, MN, USA.;Department of Dermatology, University of Minnesota, Minneapolis, MN, USA.", "authors": "Nguyen|Cuong V|CV|;Miller|Daniel D|DD|", "chemical_list": "D000900:Anti-Bacterial Agents; D018687:Antidepressive Agents, Second-Generation; D016642:Bupropion; D002437:Cefazolin", "country": "United States", "delete": false, "doi": "10.1111/cup.12863", "fulltext": null, "fulltext_license": null, "issn_linking": "0303-6987", "issue": "44(2)", "journal": "Journal of cutaneous pathology", "keywords": "bupropion; cefazolin; cutaneous drug reaction; neutrophilic dermatoses; serum sickness-like reaction", "medline_ta": "J Cutan Pathol", "mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D018687:Antidepressive Agents, Second-Generation; D016642:Bupropion; D002437:Cefazolin; D003875:Drug Eruptions; D006801:Humans; D008297:Male; D009504:Neutrophils; D012713:Serum Sickness; D014581:Urticaria; D055815:Young Adult", "nlm_unique_id": "0425124", "other_id": null, "pages": "177-182", "pmc": null, "pmid": "27862184", "pubdate": "2017-02", "publication_types": "D002363:Case Reports", "references": null, "title": "Serum sickness-like drug reaction: two cases with a neutrophilic urticarial pattern.", "title_normalized": "serum sickness like drug reaction two cases with a neutrophilic urticarial pattern" }

[ { "companynumb": "US-APOTEX-2017AP020236", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "076143", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "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": "BUPROPION HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "24", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Serum sickness-like reaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "NGUYEN CV, MILLER DD. SERUM SICKNESS-LIKE DRUG REACTION: TWO CASES WITH A NEUTROPHILIC URTICARIAL PATTERN. J CUTAN PATHOL. 2017;44:177-182", "literaturereference_normalized": "serum sickness like drug reaction two cases with a neutrophilic urticarial pattern", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20171026", "receivedate": "20171026", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14127990, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180321" }, { "companynumb": "PHHY2017US133102", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CEFAZOLIN" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "62831", "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": "CEFAZOLIN" } ], "patientagegroup": null, "patientonsetage": "74", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Face oedema", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Papule", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Urticaria", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Ecchymosis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Arthralgia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Eyelid oedema", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Serum sickness-like reaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pruritus", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Skin discolouration", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "NGUYEN CV, MILLER DD.. SERUM SICKNESS-LIKE DRUG REACTION: TWO CASES WITH A NEUTROPHILIC URTICARIAL PATTERN. JOURNAL OF CUTANEOUS PATHOLOGY. 2017;44(2):177-82", "literaturereference_normalized": "serum sickness like drug reaction two cases with a neutrophilic urticarial pattern", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170914", "receivedate": "20170914", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13968733, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171128" } ]

{ "abstract": "The occurrence of ascites after Renal Transplant (RT) is infrequent, and may be a consequence of surgical or medical complications. Case report: 61 year-old, male, history of arterial hypertension, tongue carcinoma and alcoholic habits 12-20g/day. He had chronic kidney disease secondary to autosomal dominant polycystic kidney disease, without hepatic polycystic disease. He underwent cadaver donor RT in September 2017. He had delayed graft function by surgically corrected renal artery stenosis. He was admitted in January 2018 for ascites de novo, with no response to diuretics. HE had visible abdominal collateral circulation. Graft dysfunction, adequate tacrolinemia, Innocent urinary sediment, mild anemia, without thrombocytopenia. Serum albumin 4.0g / dL. Normal hepatic biochemistry. Peritoneal fluid with transudate characteristics and serum albumin gradient > 1.1. Ultrasound showed hepatomegaly, permeable vascular axes, without splenomegaly. Mycophenolate mofetil was suspended, with reduced remaining immunosuppression. He maintained refractory ascites: excluded infectious, metabolic, autoimmune and neoplastic etiologies. No nephrotic proteinuria and no heart failure. MRI: micronodules compatible with bile cysts. Upper Digestive Tract Endoscopy did not show gastroesophageal varicose veins. Normal abdominal lymphoscintigraphy. He underwent exploratory laparoscopy with liver biopsy: incomplete septal cirrhosis of probable vascular etiology some dilated bile ducts. He maintained progressive RT dysfunction and restarted hemodialysis. The proposed direct measurement of portal pressure was delayed by ascites resolution. There was further recovery of the graft function. Discussion: Incomplete septal cirrhosis is an uncommon cause of non-cirrhotic portal hypertension. Its definition is not well known, morphological and pathophysiological. We have not found published cases of post-RT ascites secondary to this pathology, described as possibly associated with drugs, immune alterations, infections, hypercoagulability and genetic predisposition.", "affiliations": "Serviço de Nefrologia do Centro Hospitalar de Trás-os-Montes e Alto Douro, Vila Real, Portugal.;Serviço de Nefrologia e Transplantação Renal do Centro Hospitalar do Porto, Porto, Portugal.;Serviço de Nefrologia e Transplantação Renal do Centro Hospitalar do Porto, Porto, Portugal.;Serviço de Nefrologia e Transplantação Renal do Centro Hospitalar do Porto, Porto, Portugal.;Serviço de Nefrologia e Transplantação Renal do Centro Hospitalar do Porto, Porto, Portugal.;Serviço de Nefrologia e Transplantação Renal do Centro Hospitalar do Porto, Porto, Portugal.;Serviço de Nefrologia e Transplantação Renal do Centro Hospitalar do Porto, Porto, Portugal.;Serviço de Nefrologia e Transplantação Renal do Centro Hospitalar do Porto, Porto, Portugal.;Serviço de Gastroenterologia do Centro Hospitalar do Porto, Porto, Portugal.;Serviço de Anatomia Patológica do Centro Hospitalar do Porto, Porto, Portugal.;Serviço de Nefrologia e Transplantação Renal do Centro Hospitalar do Porto, Porto, Portugal.", "authors": "Eusébio|Catarina Pereira|CP|https://orcid.org/0000-0002-4055-7116;Correia|Sofia|S|;Silva|Filipa|F|;Almeida|Manuela|M|;Pedroso|Sofia|S|;Martins|La Salete|S|;Diais|Leonídio|L|;Queirós|José|J|;Pessegueiro|Helena|H|;Vizcaíno|Ramon|R|;Henriques|António Castro|AC|", "chemical_list": null, "country": "Brazil", "delete": false, "doi": "10.1590/2175-8239-JBN-2018-0175", "fulltext": "\n==== Front\nJ Bras NefrolJ Bras NefroljbnJornal Brasileiro de Nefrologia0101-28002175-8239Sociedade Brasileira de Nefrologia 10.1590/2175-8239-JBN-2018-0175Case ReportsRefractory ascites and graft dysfunction in early renal transplantation Ascite refratária e disfunção do enxerto no pós-transplante renal precoce http://orcid.org/0000-0002-4055-7116Eusébio Catarina Pereira 1Correia Sofia 2Silva Filipa 2Almeida Manuela 2Pedroso Sofia 2Martins La Salete 2Diais Leonídio 2Queirós José 2Pessegueiro Helena 3Vizcaíno Ramon 4Henriques António Castro 2\n1 Serviço de Nefrologia do Centro Hospitalar de Trás-os-Montes e Alto Douro, Vila Real, Portugal.\n2 Serviço de Nefrologia e Transplantação Renal do Centro Hospitalar do Porto, Porto, Portugal.\n3 Serviço de Gastroenterologia do Centro Hospitalar do Porto, Porto, Portugal.\n4 Serviço de Anatomia Patológica do Centro Hospitalar do Porto, Porto, Portugal.Correspondence to: Catarina Pereira Eusébio. E-mail: catarina.ip.eusebio@gmail.com18 3 2019 Oct-Dec 2019 41 4 570 574 14 8 2018 31 1 2019 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.Abstract\nThe occurrence of ascites after Renal Transplant (RT) is infrequent, and may be a consequence of surgical or medical complications. Case report: 61 year-old, male, history of arterial hypertension, tongue carcinoma and alcoholic habits 12-20g/day. He had chronic kidney disease secondary to autosomal dominant polycystic kidney disease, without hepatic polycystic disease. He underwent cadaver donor RT in September 2017. He had delayed graft function by surgically corrected renal artery stenosis. He was admitted in January 2018 for ascites de novo, with no response to diuretics. HE had visible abdominal collateral circulation. Graft dysfunction, adequate tacrolinemia, Innocent urinary sediment, mild anemia, without thrombocytopenia. Serum albumin 4.0g / dL. Normal hepatic biochemistry. Peritoneal fluid with transudate characteristics and serum albumin gradient > 1.1. Ultrasound showed hepatomegaly, permeable vascular axes, without splenomegaly. Mycophenolate mofetil was suspended, with reduced remaining immunosuppression. He maintained refractory ascites: excluded infectious, metabolic, autoimmune and neoplastic etiologies. No nephrotic proteinuria and no heart failure. MRI: micronodules compatible with bile cysts. Upper Digestive Tract Endoscopy did not show gastroesophageal varicose veins. Normal abdominal lymphoscintigraphy. He underwent exploratory laparoscopy with liver biopsy: incomplete septal cirrhosis of probable vascular etiology some dilated bile ducts. He maintained progressive RT dysfunction and restarted hemodialysis. The proposed direct measurement of portal pressure was delayed by ascites resolution. There was further recovery of the graft function. Discussion: Incomplete septal cirrhosis is an uncommon cause of non-cirrhotic portal hypertension. Its definition is not well known, morphological and pathophysiological. We have not found published cases of post-RT ascites secondary to this pathology, described as possibly associated with drugs, immune alterations, infections, hypercoagulability and genetic predisposition.\n\nResumo\nA ocorrência de ascite no pós-Transplante Renal (TR) é infrequente, podendo ser consequência de complicações cirúrgicas ou médicas. Caso clínico: 61 anos, masculino, antecedentes de hipertensão arterial, carcinoma da língua e hábitos alcoólicos 12-20g/dia. Doença renal crônica secundária à doença renal poliquística autossômica dominante, sem poliquistose hepática. Submetido a TR de doador cadáver em setembro de 2017. Atraso na função de enxerto por estenose da artéria renal, corrigida cirurgicamente. Internado em janeiro de 2018 por ascite de novo, sem resposta a diuréticos. Circulação colateral abdominal visível. Disfunção do enxerto, tacrolinemia adequada. Sedimento urinário inocente. Anemia ligeira, sem trombocitopenia. Albumina sérica 4,0g/dL. Bioquímica hepática normal. Líquido peritoneal com características de transudado e gradiente sero-ascítico de albumina > 1,1. Ecografia com hepatomegalia, eixos vasculares permeáveis, sem esplenomegalia. Suspendeu micofenolato mofetil, reduziu restante imunossupressão. Manteve ascite refratária: excluídas etiologias infecciosas, metabólicas, autoimunes e neoplásicas. Sem proteinúria nefrótica e sem insuficiência cardíaca. RM: micronódulos compatíveis com quistos biliares. EDA sem varizes gastroesofágicas. Linfocintigrafia abdominal normal. Submetido a laparoscopia exploradora com biópsia hepática: cirrose septal incompleta de provável etiologia vascular, alguns ductos biliares dilatados. Manteve disfunção progressiva do TR, reiniciou hemodiálise. Proposta medição direta da pressão portal, protelada por resolução da ascite. Recuperação posterior da função de enxerto. Discussão: A cirrose septal incompleta é uma causa incomum de hipertensão portal não cirrótica. A sua definição é morfológica e a fisiopatologia, pouco conhecida. Não encontramos publicados casos de ascite pós-TR secundária a esta patologia, descrita como possivelmente associada a fármacos, alterações imunitárias, infecções, hipercoagulabilidade e predisposição genética.\n\nKeywords:\nKidney TransplantationAscitesFibrosisPharmaceutical Preparations.Palavras-chave:\nTransplante de RimAsciteFibrosePreparações Farmacêuticas.\n==== Body\nIntroduction\nThe term \"ascites\" refers to a pathological buildup of fluid in the peritoneal cavity. It is associated with symptoms and changes in the physical examination when the volume is greater than 1.5 L, with smaller volumes being diagnosed through image studies.1\n,\n2 In its etiology, conditions that directly involve the peritoneum (infection, neoplasia) may be a consequence of changes in another organ, or systemic changes. In the West, cirrhosis is the main cause of ascites (75%), followed by peritoneal neoplasia (12%), heart failure (5%) or peritoneal tuberculosis (2%).3 Ascites can also be classified as associated with portal hypertension (such as liver cirrhosis, heart failure or Budd-Chiari syndrome) or not associated with portal hypertension (peritonitis or peritoneal metastases).4 Another etiology, uncommon in Western countries, is idiopathic non-cirrhotic portal hypertension, and it is rarely considered in the differential diagnoses.5 Little is known about the pathophysiology of this entity, which is defined by the presence of clinical signs and symptoms of portal hypertension in the absence of known cirrhosis or liver disease.6\n\n\nIn a patient with ascites as its initial clinical condition, one should perform a detailed clinical history and physical examination as well as analytical and image assesments.2 Diagnostic paracentesis is the test that alone offers more information and should be performed early.1 A serum albumin (SA) greater than 1.1 g/dL has 97% diagnostic accuracy for ascites secondary to portal hypertension.2\n,\n3\n\n\nThe occurrence of ascites in the post-renal transplantation is rare and may occur with either preserved graft function or in situations of its dysfunction.4 There are reports of cases associated with problems such as rejection, graft decapsulation, urinary or vascular leakage, lymphocytosis, transudation, or infection.7\n,\n8 In rare cases, ascites and hepatotoxicity is associated with immunosuppressive drugs such as mycophenolate mofetil, azathioprine and sirolimus.7\n,\n9\n,\n10 Nephrogenic ascites should also be considered in cases of advanced or terminal renal dysfunction. Its pathophysiology is unknown, but it is assumed that there is an increase in the permeability of the peritoneal membrane with consequent exudation, characterized by SA less than 1.1 g/dL.11\n\n\nClinical case\nA 61-year-old male, with a history of arterial hypertension, tongue carcinoma, had been submitted to partial glossectomy 8 years earlier. He had inactive smoking habits and alcoholic habits of about 12-20 g/day. Personal and family history of chronic renal disease secondary to dominant Autosomal Polycystic Kidney Disease, with no hepatic impairment diagnosed. He was in hemodialysis for four years, without adversities. He underwent nephrectomy of the right kidney in preparation for renal transplantation (RT). No known history of blood transfusion or hypersensitizing events. He underwent RT from a cadaver donor four months before the current situation, with three HLA Class I and one Class II incompatibilities, without anti-doping antibodies. Donor and recipient with previously acquired immunity to CMV (IgG positive for both serologies).\n\nHe underwent induction immunosuppression with Basiliximab, tacrolimus, mycophenolate mofetil (MMF) and methylprednisolone. His delayed graft function by renal artery stenosis was surgically corrected in the immediate post-RT. At the time, he had high serum creatinine (CrS) 2.6 mg/dL. No need for transfusion of erythrocyte concentrate in the post-RT period. She maintained outpatient follow-up, with basal CrS of 2.6-2.8 mg/dL. He had been regularly medicated with tacrolimus, prednisolone, mycophenolate mofetil, pantoprazole, furosemide, amlodipine, carvedilol, lisinopril, tamsulosin, folic acid, B vitamins and erythropoietin analogue. He was hospitalized as a result of ascites again, progressive aggravation, without response to an increase in diuretic therapy. He had no dyspnea, no orthopnea, had visible abdominal collateral circulation and a slight peripheral edema on physical examination, with no other noticeable changes. Analytically, the graft function worsened (CrS 4.5 mg/dL), with adequate tacrolimus levels (Tacrolimus 8.9 ng/mL). Light anemia (Hb 10.7 g/dL), no thrombocytopenia (platelets 154,000). Serum albumin 4.0 g/dL, LDH 266 U/L. Unchanged hepatic biochemistry (TGO 24 U/L, TGP 15 U/L, GGT 32 U/L, alkaline phosphatase 55 U/L, total bilirubin 0.25 mg/dL); normal coagulation panel. Innocent urinary sediment, with a P/CrU ratio of 0.33. The patient was submitted to diagnostic and evacuation paracentesis, with peritoneal fluid drainage (PF), with a slightly milky aspect but no diagnostic cellularity of peritonitis, with biochemical transudate characteristics (total protein and LDH), SA > 1.1 g/dL and triglycerides in the upper limit of normality (210 mg/dL, the upper limit being 200 mg/dL), which could justify the macroscopic appearance of PF. Abdominal ultrasound showed hepatomegaly (16.3 cm; patient height 165 cm), with liver with regular contours and increased parenchyma echogenicity, pervious vascular axes and no splenomegaly. He suspended MMF and reduced the remaining immunosuppression. He maintained refractory ascites, requiring frequent evacuation paracentesis and drainage higher than 3 L (administered i.v. albumin when ≥ 5 L).\n\nGraft dysfunction was interpreted in the context of effective intravascular volume depletion by losses to the third space and marked increase of intra-abdominal pressure (high volume ascites under tension), which is corroborated by the transient improvement in graft function, objectified immediately after performing evacuation paracenteses (CrS minimum 3.1 mg/dL). The results of the PF microbiological, mycological and mycobacteriological exams were negative. Viral hepatitis and HIV serologies were negative. He had negative alpha-fetoprotein, copper, ceruloplasmin, alpha-1-antitrypsin and hepatic autoimmunity markers. His ferritin was slightly increased (467 mg/dL). He also had peripheral blood flow cytometry and normal PF. He showed negative stool parasitological examination. His contrast CT scan revealed scattered millimetric hypervascular hepatic nodules and small simple biliary cysts. His MRI with hepato-specific contrast showed multiple micronodules with features suggestive of biliary cysts. His upper gastrointestinal endoscopy showed no gastroesophageal varices. His abdominal lymphoscintigraphy had no changes, and his transthoracic echocardiogram showed no relevant changes.\n\nWe discussed this case at a multidisciplinary team meeting: due to the lack of diagnostic data, exploratory laparoscopy was suggested. Intraoperatively, the liver had a nodular macroscopic appearance. In the same surgical procedure, we performed a surgical wedge biopsy. The anatomopathological exam revealed incomplete septal cirrhosis of probable vascular etiology (veno-occlusive disease) and dilated bile ducts in some portal spaces (Figures 1 and 2). The patient evolved with progressive RT dysfunction and required regular hemodialysis. In a later gastroenterology consultation, a direct measurement of portal pressure was proposed, with a view to the eventual placement of a transjugular intrahepatic portal-systemic shunt, which was, however, delayed because of the complete ascites resolution. Given the favorable evolution, the hypercoagulability disorder study was also not performed. After one month on regular dialysis, the patient recovered graft function and maintained stable RT function, with CrS 1.9mg/dL, under double immunosuppression (tacrolimus and prednisolone). At 6 months of follow-up, the ascites did not recur.\n\n\nFigure 1 Liver histology. Reticulin staining 100x. Fibrous septa are observed which incompletely resemble a nodule.\n\n\n\n\nFigure 2 Liver histology. Masson trichrome 200x. We see central lobular vein with changes suggestive of veno-occlusive disease.\n\n\n\nDiscussion\nThe term incomplete septal cirrhosis (ISC) was first introduced by Popper in 1966.12 Liver biopsy studies revealed a ISC frequency of 0.74-1.4%.13 Histologically, it is characterized by of hepatic parenchyma nodularity, vascularized septa, reticulin buildup between hyperplastic parenchyma zones, sinusoidal dilatation and hepatocyte hyperplasia.14 One of the pathophysiological mechanisms suggested was the existence of obliterative portal venopathy, with consequent heterogeneity in the hepatic parenchyma portal irrigation.\n\nISC is one of the histological presentation patterns of idiopathic non-cirrhotic portal hypertension (INCPH), and it is considered by several authors as a stage of disease manifestation.12\n,\n15 The international nomenclature of INCPH is ambiguous. In Asia, where it is most frequent, it is known as non-cirrhotic portal fibrosis (India) and idiopathic portal hypertension (Japan). In the West, it has been dubbed hepatorenal sclerosis, idiopathic portal hypertension, incomplete septal cirrhosis, and nodular regenerative hyperplasia.15\n\n\nThe main etiologies proposed for INCPH are: infectious (bacterial infections of the gastrointestinal tract and umbilical pyemia with repeated septic embolization for portal circulation, schistosomiasis and HIV); (systemic sclerosis, systemic lupus erythematosus, hypogammaglobulinemia); exposure to drugs and toxins (arsenic, azathioprine); prothrombotic states.16 Still, there are rare forms of genetic and familial predisposition described.14\n,\n15\n\n\nThe diagnostic criteria for INCPH are the presence of a clinical sign of portal hypertension (splenomegaly/hyperpesplenism, esophageal varicose veins, ascites, increase in the hepatic venous pressure gradient or presence of portal venous collaterals), after cirrhosis, vascular thrombosis of the portal and hepatic veins, and conditions that may be associated with chronic liver disease (infectious, autoimmune, metabolic, etc.).15\n,\n17\n\n\nIn the clinical case described here, the appearance of ascites seems to be temporally related to RT. Therefore, late surgical complications were excluded by imaging exams. The PF biochemical analysis revealed a SA > 1.1 g/dL, which is suggestive of portal hypertension and is corroborated by the presence of exuberant collateral venous circulation in the abdominal wall, and hepatomegaly. Although splenomegaly and esophageal varices did not coexist, the clinical picture, at the time of diagnosis, showed little evolution time, which may justify the absence of these findings. A SA > 1.1 g/dL makes unlikely etiologies such as ascites secondary to infectious, nephrogenic or neoplastic peritonitis, which were also investigated and ruled out. The intra-abdominal vascular axes thrombosis, hepatic cirrhosis or liver disease (metabolic, autoimmune and viral), as well as heart failure or nephrotic syndrome that could justify the clinical picture.\n\nThe authors thus reached the histological diagnosis of incomplete septal cirrhosis after exploratory laparoscopy and surgical liver biopsy. The main causes that are thought to be associated with this entity were described above and also mostly excluded during the diagnostic investigation. However, it remains the hypothesis that the ISC, in the case of our patient, may be associated with the pharmacological exposure to the MMF. There is only one reported case of refractory ascites in the literature, after kidney-pancreas transplantation, which association with mycophenolic acid was confirmed after ascites resurgence of with its reintroduction. However, in this case, no liver biopsy was performed.9\n\n\nVeno-occlusive disease, which has been described as a possible etiology of hepatic septal cirrhosis. In our clinical case, it is characterized by loss of sinusoidal wall integrity and obliterative venulitis, and has been widely described as associated with myeloablative regimens used in hematopoietic cell transplantation. However, it has also been described as secondary to other chemotherapy, radiotherapy, teas/herbal products and other pharmacological therapies, among which the antimetabolite drug Azathioprine is highlighted, with interest in our case.18\n,\n19\n\n\nIn our patient, after one month in a regular hemodialysis program, we achieved ascites resolution and graft function recovery. After 6 months of follow-up, with double immunosuppression (prednisolone and tacrolimus [low tacrolinemia, 5-6 ng/mL]), the patient had no evidence of ascites relapse, confirmed by imaging, which is more in favor of the possible association between MMF, refractory ascites and incomplete septal cirrhosis/ INCPH, described in this clinical case.\n==== Refs\nReferences\n1 Sood R Ascites: Diagnosis and Management J Indian Acad Clin Med 2004 5 81 89 \n2 Tsochatzis EA Gerbes AL Diagnosis and treatment of ascites J Hepatol 2017 67 184 185 10.1016/j.jhep.2017.01.011 28119010 \n3 Garcia-Tsao G Ascites Dooley JS Lok ASF Burroughs AK Heathcote MB Sherlock's Diseases of the Liver and Biliary System 2011 12th ed Hoboken Backwell 210 233 \n4 Markov M Van Thiel DH Nadir A Ascites and kidney transplantation: case report and critical appraisal of the literature Dig Dis Sci 2007 52 3383 3388 10.1007/s10620-006-9727-7 17410444 \n5 Hübscher SG Pathology of non-cirrhotic portal hypertension and incomplete septal cirrhosis Diagn Histopathol 2011 17 530 538 10.1016/j.mpdhp.2011.10.003 \n6 Ibarrola C Colina F Clinicopathological features of nine cases of non-cirrhotic portal hypertension: current definitions and criteria are inadequate Histopathology 2003 42 251 264 12605645 \n7 Castro G Freitas C Beirão I Rocha G Henriques AC Cabrita A Chylous ascites in a renal transplant recipient under sirolimus (rapamycin) treatment Transplant Proc 2008 40 1756 1758 10.1016/j.transproceed.2008.02.074 18589188 \n8 Kawaguchi S Nohara T Shima T Matsuyama S Nose C Yamahana J Massive Ascites in a Renal Transplant Patient after Laparoscopic Fenestration of a Lymphocele Case Rep Transplant 2016 2016 7491627 10.1155/2016/7491627 27891288 \n9 Weber NT Sigaroudi A Ritter A Boss A Lehmann K Goodman D Intractable ascites associated with mycophenolate in a simultaneous kidney-pancreas transplant patient: a case report BMC Nephrol 2017 18 360 360 10.1186/s12882-017-0757-5 29233098 \n10 Gane E Portmann B Saxena R Wong P Ramage J Williams R Nodular regenerative hyperplasia of the liver graft after liver transplantation Hepatology 1994 20 88 94 8020909 \n11 Han SH Reynolds TB Fong TL Nephrogenic ascites. Analysis of 16 cases and review of the literature Medicine (Baltimore) 1998 77 233 245 9715728 \n12 Bernard PH Le Bail B Cransac M Barcina MG Carles J Balabaud C Progression from idiopathic portal hypertension to incomplete septal cirrhosis with liver failure requiring liver transplantation J Hepatol 1995 22 495 499 7665869 \n13 Schinoni MI Andrade Z de Freitas LA Oliveira R Paraná R Incomplete septal cirrhosis: an enigmatic disease Liver Int 2004 24 452 456 10.1111/j.1478-3231.2004.0989.x 15482342 \n14 Barnett JL Appelman HD Moseley RH A familial form of incomplete septal cirrhosis Gastroenterology 1992 102 674 678 1732137 \n15 Schouten JN Garcia-Pagan JC Valla DC Janssen HL Idiopathic noncirrhotic portal hypertension Hepatology 2011 54 1071 1081 10.1002/hep.24422 21574171 \n16 Sarin SK Kumar A Chawla YK Baijal SS Dhiman RK Jafri W Members of the APASL Working Party on Portal Hypertension Noncirrhotic portal fibrosis/idiopathic portal hypertension: APASL recommendations for diagnosis and treatment Hepatol Int 2007 1 398 413 10.1007/s12072-007-9010-9 19669336 \n17 Dhiman RK Chawla Y Vasishta RK Kakkar N Dilawari JB Trehan MS Non-cirrhotic portal fibrosis (idiopathic portal hypertension): experience with 151 patients and a review of the literature J Gastroenterol Hepatol 2002 17 6 16 11895549 \n18 Fan CQ Crawford JM Sinusoidal obstruction syndrome (hepatic veno-occlusive disease) J Clin Exp Hepatol 2014 4 332 346 25755580 \n19 European Association for the Study of the Liver Electronic address: easloffice@easloffice.eu. EASL Clinical Practice Guidelines: Vascular diseases of the liver J Hepatol 2016 64 179 202 26516032\n\n", "fulltext_license": "CC BY", "issn_linking": "0101-2800", "issue": "41(4)", "journal": "Jornal brasileiro de nefrologia : 'orgao oficial de Sociedades Brasileira e Latino-Americana de Nefrologia", "keywords": null, "medline_ta": "J Bras Nefrol", "mesh_terms": "D001201:Ascites; D051799:Delayed Graft Function; D006801:Humans; D006975:Hypertension, Portal; D016030:Kidney Transplantation; D008103:Liver Cirrhosis; D008297:Male; D008875:Middle Aged; D016891:Polycystic Kidney, Autosomal Dominant; D006435:Renal Dialysis; D051436:Renal Insufficiency, Chronic", "nlm_unique_id": "9426946", "other_id": null, "pages": "570-574", "pmc": null, "pmid": "30897191", "pubdate": "2019", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "25755580;12605645;9715728;21574171;28119010;8020909;18589188;29233098;19669336;26516032;11895549;27891288;1732137;17410444;15482342;7665869", "title": "Refractory ascites and graft dysfunction in early renal transplantation.", "title_normalized": "refractory ascites and graft dysfunction in early renal transplantation" }

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null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "065520", "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Transplant dysfunction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypovolaemia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Ascites", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Non-cirrhotic portal hypertension", "reactionmeddraversionpt": "23.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Oedema peripheral", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Intra-abdominal pressure increased", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Peritonitis", "reactionmeddraversionpt": "23.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "EUSEBIO CP, CORREIA S, SILVA F, ALMEIDA M, PEDROSO S, MARTINS S, ET AL. REFRACTORY ASCITES AND GRAFT DYSFUNCTION IN EARLY RENAL TRANSPLANTATION. J-BRAS-NEFROL 2019?41(4):570-574.", "literaturereference_normalized": "refractory ascites and graft dysfunction in early renal transplantation", "qualification": "3", "reportercountry": "PT" }, "primarysourcecountry": "PT", "receiptdate": "20200605", "receivedate": "20200605", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17864548, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200714" }, { "companynumb": "PT-VISTAPHARM, INC.-VER202103-000926", "fulfillexpeditecriteria": "1", "occurcountry": "PT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "210370", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN", "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": "MYCOPHENOLATE MOFETIL, USP" } ], "patientagegroup": "5", "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Non-cirrhotic portal hypertension", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "EUSEBIO C, CORREIA S, SILVA F, ALMEIDA M, PEDROSO S, MARTINS L. REFRACTORY ASCITES AND GRAFT DYSFUNCTION IN EARLY RENAL TRANSPLANTATION. J BRAS NEFROL. 2019?41(4):570?4. 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"reactionmeddrapt": "Hepatic cirrhosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2018" } }, "primarysource": { "literaturereference": "EUSEBIO CP, CORREIA S, SILVA F, ALMEIDA M, PEDROSO S, MARTINS S ET.AL. REFRACTORY ASCITES AND GRAFT DYSFUNCTION IN EARLY RENAL TRANSPLANTATION. J BRAS NEFROL. 2019", "literaturereference_normalized": "refractory ascites and graft dysfunction in early renal transplantation", "qualification": "3", "reportercountry": "PT" }, "primarysourcecountry": "PT", "receiptdate": "20190918", "receivedate": "20190918", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16822395, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20191005" }, { "companynumb": "PT-TEVA-2020-PT-1504206", "fulfillexpeditecriteria": "1", "occurcountry": "PT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": "065", 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hypertension", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intra-abdominal pressure increased", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Oedema peripheral", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypovolaemia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Ascites", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "EUSEBIO CP, CORREIA S, SILVA F, ALMEIDA M, PEDROSO S, MARTINS S, ET AL. REFRACTORY ASCITES AND GRAFT DYSFUNCTION IN EARLY RENAL TRANSPLANTATION. 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"drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "65379", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "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": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "1", "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": "METHYLPREDNISOLONE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": 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INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE" } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Transplant dysfunction", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Biliary cirrhosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Ascites", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "EUSEBIO CP, CORREIA S, SILVA F, ALMEIDA M, PEDROSO S, MARTINS S ET AL. REFRACTORY ASCITES AND GRAFT DYSFUNCTION IN EARLY RENAL TRANSPLANTATION. JORNAL BRASILEIRO DE NEFROLOGIA. 2019", "literaturereference_normalized": "refractory ascites and graft dysfunction in early renal transplantation", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190423", "receivedate": "20190423", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16227773, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" } ]

{ "abstract": "A 40-year-old female with a history of type 1 diabetes mellitus and solitary pancreas transplant, presented with pancreatic graft rejection 1-year post-transplant. Incidentally, a 1.1 cm right lower lobe cavity was identified during her workup. Given the augmentation of immunosuppression, voriconazole was empirically started for possible invasive pulmonary aspergillosis. As the patient was a painter, this resulted in a significant change in the colors of her paintings. Ultimately, she was diagnosed with pulmonary coccidioidomycosis and her visual disturbances resolved after the voriconazole was changed to fluconazole. Voriconazole causes visual disturbances in 20%-30% of the patients most commonly phototopsias; dyschromatopsias typically involving the tritan axis have also been reported. This case illustrates well the potential impact of voriconazole on spectral sensitivity and color perception.", "affiliations": "Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.;Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.;Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.;Department of Ophthalmology and Visual Sciences, University of Alberta, Edmonton, Alberta, Canada.;Division of Neurology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.;Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.", "authors": "Belga|Sara|S|https://orcid.org/0000-0003-1725-1407;MacDonald|Clayton|C|;Kabbani|Dima|D|https://orcid.org/0000-0003-3785-1098;Roelofs|Kelsey|K|;Hussain|Mohammed Wasif|MW|;Cervera|Carlos|C|https://orcid.org/0000-0002-0161-1749", "chemical_list": "D000935:Antifungal Agents; D014230:Triazoles; D065819:Voriconazole", "country": "Denmark", "delete": false, "doi": "10.1111/tid.13130", "fulltext": null, "fulltext_license": null, "issn_linking": "1398-2273", "issue": "21(4)", "journal": "Transplant infectious disease : an official journal of the Transplantation Society", "keywords": "art painting; coccidioidomycosis; visual disturbances; voriconazole", "medline_ta": "Transpl Infect Dis", "mesh_terms": "D000328:Adult; D000935:Antifungal Agents; D001154:Art; D003047:Coccidioidomycosis; D003116:Color; D005260:Female; D006801:Humans; D008168:Lung; D014057:Tomography, X-Ray Computed; D014230:Triazoles; D014786:Vision Disorders; D065819:Voriconazole", "nlm_unique_id": "100883688", "other_id": null, "pages": "e13130", "pmc": null, "pmid": "31220394", "pubdate": "2019-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "When medicine transforms art.", "title_normalized": "when medicine transforms art" }

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"reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BELGA S, DONALD C, KABBANI D, HUSSAIN MW, CERVERA C, ROELOFS K. WHEN MEDICINE TRANSFORMS ART. 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WHEN MEDICINE TRANSFORMS ART. DOI: 10.1111/TID.13130.. 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WHEN MEDICINE TRANSFORMS ART. TRANSPL INFECT DIS. 2019 JUN 20:E13130", "literaturereference_normalized": "when medicine transforms art", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20190706", "receivedate": "20190706", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16536671, "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" }, { "companynumb": "CA-SA-2019SA191255", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": 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"drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSE REDUCED", "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": "CYCLOSPORINE." } ], "patientagegroup": "5", "patientonsetage": "40", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Visual impairment", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dyschromatopsia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Coccidioidomycosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SARA BELGA, CLAYTON MACDONALD, DIMA KABBANI, KELSEY ROELOFS, MOHAMMED WASIF HUSSAIN, CARLOS CERVERA. WHEN MEDICINE TRANSFORMS ART. TRANSPL INFECT DIS.. 2019?UNKNOWN:UNKNOWN", "literaturereference_normalized": "when medicine transforms art", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20190719", "receivedate": "20190719", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16597513, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191004" } ]

{ "abstract": "Currently, isoniazid (INH) overdose seems to be a growing and life-threatening problem, partly due to the recent national roll-out of INHpreventive therapy (IPT) for HIV-positive adults. We present three cases, two of which were fatal, seen at Frere and Cecilia Makiwanehospitals, East London, South Africa over the past 16 months.", "affiliations": "Division of Infectious Diseases, Department of Medicine, Frere Hospital, East London; Department of Medicine, Frere and Cecilia Makiwane hospitals, East London; and Department of Medicine, Faculty of Health Sciences, Walter Sisulu University, Mthatha. dfstead@gmail.com.", "authors": "Stead|David Francis|DF|;Mason|Carolyn Ruth|CR|", "chemical_list": null, "country": "South Africa", "delete": false, "doi": "10.7196/SAMJ.2016.v106i9.10582", "fulltext": null, "fulltext_license": null, "issn_linking": null, "issue": "106(9)", "journal": "South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde", "keywords": null, "medline_ta": "S Afr Med J", "mesh_terms": null, "nlm_unique_id": "0404520", "other_id": null, "pages": "891-2", "pmc": null, "pmid": "27601114", "pubdate": "2016-08-11", "publication_types": "D016428:Journal Article", "references": null, "title": "Three cases of intentional isoniazid overdose - a life-threatening condition.", "title_normalized": "three cases of intentional isoniazid overdose a life threatening condition" }

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THREE CASES OF INTENTIONAL ISONIAZID OVERDOSE - A LIFE-THREATENING CONDITION. 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THREE CASES OF INTENTIONAL ISONIAZID OVERDOSE - A LIFE-THREATENING CONDITION. S AFR MED J. 2016;SEP; 106(9):891-892", "literaturereference_normalized": "three cases of intentional isoniazid overdose a life threatening condition", "qualification": "3", "reportercountry": "ZA" }, "primarysourcecountry": "ZA", "receiptdate": "20161027", "receivedate": "20161027", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12888211, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20170207" } ]

{ "abstract": "OBJECTIVE\nPatients with metastatic, gemcitabine-refractory pancreatic cancer typically have poor survival. Erlotinib, a targeted therapy that inhibits epidermal growth factor receptor (EGFR) activity (overexpressed in 40-60 % of pancreatic cancers), was FDA approved for the treatment of patients with advanced pancreatic cancer. Human epidermal growth factor receptor 2 (HER-2), another member of the ErbB family of growth factor receptor tyrosine kinases, has also been a therapeutic target of interest in pancreatic cancer; HER-2 overexpression is found in 20 % of pancreatic cancers. Lapatinib is a tyrosine kinase inhibitor that binds to both EGFR and HER-2. We conducted a single-arm phase II study to evaluate the combination of lapatinib and capecitabine in the second-line treatment of metastatic, gemcitabine-refractory pancreatic cancer.\n\n\nMETHODS\nSeventeen patients with metastatic, unresectable pancreatic cancer whose disease had progressed on first-line gemcitabine-based therapy were selected for this study. Patients were required to have an adequate performance status (ECOG 0-2) and normal hepatic and renal function prior to being enrolled. Patients received lapatinib 1250 mg PO daily 1 h before or after meals, and capecitabine 1000 mg/m(2) PO twice daily on days 1-14 of the 21-day cycle. The primary endpoint was median overall survival (OS), and the secondary endpoints were objective response rate, progression-free survival (PFS) and the safety profile of the combination therapy. Clinical toxicities were assessed according to the National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0. Radiographic response was evaluated by RECIST criteria.\n\n\nRESULTS\nClinically, six of the 17 patients treated had disease progression (PD) after two cycles, six of 17 patients had stable disease (SD) and received more than four cycles (SD, range 4-22 cycles). For all patients, median PFS was 2.6 months (95 % CI 1.3-3.8) and median OS was 5.2 months (95 % CI 3.4-9). Treatment-related toxicities were limited to three (17 %) patients developing grade 3 adverse events such as nausea, vomiting, diarrhea and fatigue. When stratifying patients by treatment response, we found a statistically significant difference in median PFS and OS: median PFS was 1.4 months (95 % CI 1.0-1.8) in the PD group versus 4.0 months (95 % CI 1.8-6.3) in the SD group (P value = 0.001). Median OS was 2.9 months (95 % CI 0-7.3) in the PD group versus 8.3 months (95 % CI 0-21.2) in the SD group (P value = 0.023).\n\n\nCONCLUSIONS\nThe combination of lapatinib and capecitabine is a tolerable regimen for patients with gemcitabine-refractory pancreatic cancer; however, this observation is based on the small number of patients enrolled in the trial. A subset of the enrolled patients had clinical benefit from treatment. Predictive biomarkers that allow selection of patients that will respond to this regimen should be further investigated.", "affiliations": "Division of Hematology and Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Road, NW, Washington, DC, 20007, USA.;Division of Hematology and Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Road, NW, Washington, DC, 20007, USA.;Division of Hematology and Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Road, NW, Washington, DC, 20007, USA.;Division of Hematology and Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Road, NW, Washington, DC, 20007, USA.;Division of Hematology and Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Road, NW, Washington, DC, 20007, USA.;Department of Biostatistics and Bioinformatics, Georgetown University, 3800 Reservoir Road, NW, Washington, DC, 20007, USA.;Division of Hematology and Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Road, NW, Washington, DC, 20007, USA.;Division of Hematology and Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Road, NW, Washington, DC, 20007, USA.;Division of Hematology and Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Road, NW, Washington, DC, 20007, USA. arh29@georgetown.edu.", "authors": "Wu|Zheng|Z|;Gabrielson|Andrew|A|;Hwang|Jimmy J|JJ|;Pishvaian|Michael J|MJ|;Weiner|Louis M|LM|;Zhuang|Tingting|T|;Ley|Lisa|L|;Marshall|John L|JL|;He|Aiwu Ruth|AR|", "chemical_list": "D011799:Quinazolines; D000077341:Lapatinib; D000069287:Capecitabine", "country": "Germany", "delete": false, "doi": "10.1007/s00280-015-2855-z", "fulltext": null, "fulltext_license": null, "issn_linking": "0344-5704", "issue": "76(6)", "journal": "Cancer chemotherapy and pharmacology", "keywords": "Capecitabine; Lapatinib; Pancreatic cancer", "medline_ta": "Cancer Chemother Pharmacol", "mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069287:Capecitabine; D003967:Diarrhea; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005221:Fatigue; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D000077341:Lapatinib; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms; D011799:Quinazolines; D016896:Treatment Outcome", "nlm_unique_id": "7806519", "other_id": null, "pages": "1309-14", "pmc": null, "pmid": "26507197", "pubdate": "2015-12", "publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article", "references": null, "title": "Phase II study of lapatinib and capecitabine in second-line treatment for metastatic pancreatic cancer.", "title_normalized": "phase ii study of lapatinib and capecitabine in second line treatment for metastatic pancreatic cancer" }

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PHASE II STUDY OF LAPATINIB AND CAPECITABINE IN SECOND-LINE TREATMENT FOR METASTATIC PANCREATIC CANCER. 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PHASE II STUDY OF LAPATINIB AND CAPECITABINE IN SECOND-LINE TREATMENT FOR METASTATIC PANCREATIC CANCER. 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PHASE II STUDY OF LAPATINIB AND CAPECITABINE IN SECOND-LINE TREATMENT FOR METASTATIC PANCREATIC CANCER. 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PHASE II STUDY OF LAPATINIB AND CAPECITABINE IN SECOND-LINE TREATMENT FOR METASTATIC PANCREATIC CANCER. CANCER CHEMOTHER PHARMACOL. 2015", "literaturereference_normalized": "phase ii study of lapatinib and capecitabine in second line treatment for metastatic pancreatic cancer", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151107", "receivedate": "20151107", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11708419, "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" }, { "companynumb": "US-CIPLA LTD.-2015US08408", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078759", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA PANCREAS", "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": "5", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA PANCREAS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ABRAXANE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Adenocarcinoma pancreas", "reactionmeddraversionpt": "18.1", "reactionoutcome": null }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HE AR, WU ZHENG, GABRIELSON A, HWANG JJ, PISHVAIAN MJ, WEINER LM ET AL.. PHASE II STUDY OF LAPATINIB AND CAPECITABINE IN SECOND-LINE TREATMENT FOR METASTATIC PANCREATIC CANCER. CANCER CHEMOTHER PHARMACOL. 2015", "literaturereference_normalized": "phase ii study of lapatinib and capecitabine in second line treatment for metastatic pancreatic cancer", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151107", "receivedate": "20151107", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11708400, "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" }, { "companynumb": "US-CIPLA LTD.-2015US08409", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAPATINIB" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1250 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PANCREATIC CARCINOMA METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1250", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAPATINIB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "078759", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA PANCREAS", "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": "CAPECITABINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MG/M2, BID, ON DAYS 1 TO 14 OF 21 DAY CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "PANCREATIC CARCINOMA METASTATIC", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAPECITABINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HE AR, WU ZHENG, GABRIELSON A, HWANG JJ, PISHVAIAN MJ, WEINER LM ET AL.. PHASE II STUDY OF LAPATINIB AND CAPECITABINE IN SECOND-LINE TREATMENT FOR METASTATIC PANCREATIC CANCER. CANCER CHEMOTHER PHARMACOL. 2015;1 TO 6", "literaturereference_normalized": "phase ii study of lapatinib and capecitabine in second line treatment for metastatic pancreatic cancer", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170728", "receivedate": "20151107", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 11708411, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" } ]

{ "abstract": "BACKGROUND\nLittle is known on racial differences in patients with diffuse large B-cell lymphoma (DLBCL). The aim of this retrospective study is to compare characteristics, prognostic factors and outcomes of Asian and Western patients with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP).\n\n\nMETHODS\nPatient-level data was collected from 8 centers. All patients were diagnosed with DLBCL and treated with R-CHOP. Patients were divided into Asian and Western, according to the country of report. Comparisons and univariate/multivariate survival analyses were performed.\n\n\nRESULTS\n712 patients, 455 Asian and 257 Western patients were included. Westerners were more likely to present with elevated LDH (64% vs. 48%, p<0.01) and advanced stage (58% vs. 49%, p<0.01). After a median follow-up of 36 months, there was no difference in progression-free (PFS; p=0.33) or overall survival (OS; p=0.69). There were no PFS or OS differences between races when evaluating separately each age-adjusted International Prognostic Index category. In the multivariate analyses, performance status and stage were associated with PFS and OS in both races.\n\n\nCONCLUSIONS\nThere are no differences in prognostic factors, PFS and OS between Asian and Western patients with DLBCL treated with R-CHOP.", "affiliations": "Division of Hematology and Oncology, Rhode Island Hospital/The Miriam Hospital, Providence, RI 02906, USA. jcastillo@lifespan.org", "authors": "Castillo|Jorge J|JJ|;Sinclair|Natalie|N|;Beltrán|Brady E|BE|;Song|Moo-Kon|MK|;Ilic|Ivana|I|;Leppa|Sirpa|S|;Nurmi|Heidi|H|;Seki|Ritsuko|R|;Uccella|Silvia|S|;Li|Jun-Min|JM|;Treaba|Diana O|DO|;Stachurski|Dariusz|D|;Butera|James N|JN|", "chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone", "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0145-2126", "issue": "37(4)", "journal": "Leukemia research", "keywords": null, "medline_ta": "Leuk Res", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D001208:Asia; D003520:Cyclophosphamide; D004317:Doxorubicin; D005060:Europe; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008875:Middle Aged; D011241:Prednisone; D011379:Prognosis; D000069283:Rituximab; D016896:Treatment Outcome; D014750:Vincristine; D055815:Young Adult", "nlm_unique_id": "7706787", "other_id": null, "pages": "386-91", "pmc": null, "pmid": "23352640", "pubdate": "2013-04", "publication_types": "D016428:Journal Article", "references": null, "title": "Similar outcomes in Asian and Western patients with diffuse large B-cell lymphoma treated with R-CHOP.", "title_normalized": "similar outcomes in asian and western patients with diffuse large b cell lymphoma treated with r chop" }

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null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DIFFUSE LARGE B-CELL LYMPHOMA", "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": "Drug ineffective", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CASTILLO JJ, SINCLAIR N, BELTRAN BE, SONG M, ILIC I, LEPPA S, ET AL. SIMILAR OUTCOMES IN ASIAN AND WESTERN PATIENTS WITH DIFFUSE LARGE B-CELL LYMPHOMA TREATED WITH R-CHOP. LEUKEMIA RESEARCH 2013;37 (4):326-391.", "literaturereference_normalized": "similar outcomes in asian and western patients with diffuse large b cell lymphoma treated with r chop", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150524", "receivedate": "20150412", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11018762, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150821" } ]

{ "abstract": "Drug abuse is a substantial problem in society today and is associated with significant morbidity and mortality. Various drugs are associated with serious complications affecting the brain, and it is critical to recognize the imaging findings of these complications to provide prompt medical management. The central nervous system (CNS) is a target organ for drugs of abuse as well as specific prescribed medications. Drugs of abuse affecting the CNS include cocaine, heroin, alcohol, amphetamines, toluene, and cannabis. Prescribed medications or medical therapies that can affect the CNS include immunosuppressants, antiepileptics, nitrous oxide, and total parenteral nutrition. The CNS complications of these drugs include neurovascular complications, encephalopathy, atrophy, infection, changes in the corpus callosum, and other miscellaneous changes. Imaging abnormalities indicative of these complications can be appreciated at both magnetic resonance (MR) imaging and computed tomography (CT). It is critical for radiologists to recognize complications related to drugs of abuse as well as iatrogenic effects of various medications. Therefore, diagnostic imaging modalities such as MR imaging and CT can play a pivotal role in the recognition and timely management of drug-related complications in the CNS.", "affiliations": "Department of Imaging Sciences, University of Rochester Medical Center, 601 Elmwood Ave, PO Box 648, Rochester, NY 14642, USA. benitatamrazi@gmail.com", "authors": "Tamrazi|Benita|B|;Almast|Jeevak|J|", "chemical_list": "D013287:Illicit Drugs", "country": "United States", "delete": false, "doi": "10.1148/rg.323115115", "fulltext": null, "fulltext_license": null, "issn_linking": "0271-5333", "issue": "32(3)", "journal": "Radiographics : a review publication of the Radiological Society of North America, Inc", "keywords": null, "medline_ta": "Radiographics", "mesh_terms": "D001921:Brain; D001927:Brain Diseases; D062787:Drug Overdose; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D013287:Illicit Drugs; D008279:Magnetic Resonance Imaging; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "8302501", "other_id": null, "pages": "701-19", "pmc": null, "pmid": "22582355", "pubdate": "2012", "publication_types": "D016428:Journal Article", "references": null, "title": "Your brain on drugs: imaging of drug-related changes in the central nervous system.", "title_normalized": "your brain on drugs imaging of drug related changes in the central nervous system" }

[ { "companynumb": "US-ALSI-202000301", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "NITROUS OXIDE" }, "drugadditional": null, "drugadministrationroute": "055", "drugauthorizationnumb": "206009", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "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": "NITROUS OXIDE." } ], "patientagegroup": null, "patientonsetage": "23", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Subacute combined cord degeneration", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LITERATURE REFERENCE: TAMRAZI B, ALMAST J. YOUR BRAIN ON DRUGS: IMAGING OF DRUG?RELATED CHANGES?IN THE CENTRAL NERVOUS SYSTEM. RADIOGRAPHICS. 1 MAI 2012?32(3):701?19.", "literaturereference_normalized": "your brain on drugs imaging of drug related changes in the central nervous system", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200811", "receivedate": "20200811", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 18135808, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]

{ "abstract": "BACKGROUND\nCisplatin-based combination chemotherapy before surgery is the standard of care for muscle-invasive bladder cancer. However, the optimal chemotherapy modalities have not been precisely defined to date.\n\n\nMETHODS\nIn the VESPER trial, patients received after randomization either gemcitabine and cisplatin (GC, 4 cycles) or methotrexate, vinblastine, doxorubicin and cisplatin (dose dense [dd]-MVAC, 6 cycles). Creatinine clearance (CrCl) was calculated before each cycle according to the Cockroft and Gault formula. Definition criteria for local control after neoadjuvant chemotherapy included pathological complete response (ypT0N0), pathological downstaging (<ypT2N0) and organ-confined disease (<ypT3N0) at cystectomy. Baseline and treatment characteristics were studied in multivariate logistic models to determine their potential role for each type of pathological responses.\n\n\nRESULTS\nA total of 2128 cycles of chemotherapy were delivered, including 2120 (99.6%) with cisplatin. Full doses of cisplatin were given in 1866 (88%) cycles. Twenty-three (4.7%) patients had to stop chemotherapy (12 GC, 11 dd-MVAC) because of renal failure. No difference in CrCl median values was observed between the 2 regimens during the first 4 cycles. A mild decrease occurred thereafter in patients treated with 2 additional cycles of dd-MVAC. A minimum total dose of 270 mg/m2 for cisplatin was mandatory to optimize pathological complete responses.\n\n\nCONCLUSIONS\nAt least 4 cycles of cisplatin-based chemotherapy should be delivered before cystectomy. Increasing the number of cycles beyond 4 cycles does not lead to a clinically significant deterioration in renal function but without obvious gain on local control.", "affiliations": "Department of Medical Oncology, Saint-Louis Hospital, AP-HP, Faculté de Paris, France. Electronic address: stephane.culine@aphp.fr.;North-West Canceropole Data Center, Baclesse Cancer Center, Caen, France.;Department of Medical Oncology, Paoli-Calmette Institute, Marseille, France.;Department of Medical Oncology, Léon Bérard Cancer Center, Lyon, France.;Department of Medical Oncology, ICR-IUCT Oncopole, Toulouse, France.;Department of Medical Oncology, Jean Perrin Cancer Center, Clermont-Ferrand, France.;Department of Medical Oncology, Eugène Marquis Cancer Center, Rennes, France.;Department of Medical Oncology, Lucien Neuwirth Cancer Institute, St Priest en Jarez, France.;Department of Medical Oncology, Baclesse Cancer Center, Caen, France.;Department of Medical Oncology, Institut de cancérologie de l'Ouest, Angers, France.;Department of Medical Oncology, Lorraine-Alexis Vautrin Cancer Institute, Nancy, France.;Digestive and uro-oncology Unit, Charles Nicolle University Hospital, Rouen, France.;Department of Medical Oncology, Bergonié Institute, Bordeaux, France.;Department of Medical Oncology, University Hospital, Strasbourg, France.;Victor Hugo Clinic, Le Mans, France.;Department of Medical Oncology, University Hospital, Poitiers, France.;Department of Medical Oncology, Diaconesses Croix Saint-Simon Hospital, Paris, France.;Department of Medical Oncology, Henri Mondor University Hospital, AP-HP, Créteil, France.;Department of Medical Oncology, University Hospital, Besançon, France.;Department of Cancer Medicine, Gustave Roussy, Inserm U981, Villejuif, France.;Department of Medical Oncology, Jean Godinot Institute, Reims, France.;Department of Medical Oncology, Cochin Port-Royal University Hospital, AP-HP Centre, Paris, France.;Department of Medical Oncology, West County Cancer Institute, Nantes, France.;Gard Cancer Institute, University Hospital, Nîmes, Inserm U1194 Montpellier Cancer Institute, Montpellier University, Nimes, France.;Department of Medical Oncology, Pitié Salpétrière University Hospital, AP-HP-SU, IUC, Paris, France.;Department of Oncology, Cap d'Or Clinic, La Seyne sur Mer, France.;Department of Oncology, Saint-Pierre Clinic, Perpignan, France.;Department of Medical Oncology, Vendée Regional Hospital, La Roche-sur-Yon, France.;Uro-Oncology Unit, Sainte Catherine Institute, Avignon, France.;Department of Pathology, Curie Institute, Saint-Cloud, France.;Department of Urology and Clinical Investigation Center, Inserm 1404, Charles Nicolle University Hospital, Rouen, France.", "authors": "Culine|Stéphane|S|;Harter|Valentin|V|;Gravis|Gwenaelle|G|;Fléchon|Aude|A|;Chevreau|Christine|C|;Mahammedi|Hakim|H|;Laguerre|Brigitte|B|;Guillot|Aline|A|;Joly|Florence|F|;Abadie-Lacourtoisie|Sophie|S|;Geoffrois|Lionnel|L|;Fiore|Frédéric Di|FD|;Roubaud|Guilhem|G|;Barthélémy|Philippe|P|;Voog|Eric|E|;Emambux|Sheik|S|;Serrate|Camille|C|;Saldana|Carolina|C|;Nguyen-Tan-Hon|Thierry|T|;Loriot|Yohann|Y|;Eymard|Jean-Christophe|JC|;Huillard|Olivier|O|;Rolland|Frédéric|F|;Houédé|Nadine|N|;Spano|Jean-Philippe|JP|;Demery|Mounira El|ME|;Vieillot|Sabine|S|;L'Haridon|Tifenn|T|;Hilgers|Werner|W|;Allory|Yves|Y|;Pfister|Christian|C|;|||", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.clgc.2021.08.005", "fulltext": null, "fulltext_license": null, "issn_linking": "1558-7673", "issue": null, "journal": "Clinical genitourinary cancer", "keywords": "Cisplatin-based chemotherapy; Neoadjuvant treatment; Pathological complete response; Pathological downstaging; Perioperative chemotherapy", "medline_ta": "Clin Genitourin Cancer", "mesh_terms": null, "nlm_unique_id": "101260955", "other_id": null, "pages": null, "pmc": null, "pmid": "34602349", "pubdate": "2021-09-08", "publication_types": "D016428:Journal Article", "references": null, "title": "Chemotherapy for Muscle-invasive Bladder Cancer: Impact of Cisplatin Delivery on Renal Function and Local Control Rate in the Randomized Phase III VESPER (GETUG-AFU V05) Trial.", "title_normalized": "chemotherapy for muscle invasive bladder cancer impact of cisplatin delivery on renal function and local control rate in the randomized phase iii vesper getug afu v05 trial" }

[ { "companynumb": "FR-AMNEAL PHARMACEUTICALS-2021-AMRX-04239", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DOXORUBICIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "208888", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Bladder cancer", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN HYDROCHLORIDE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Bladder cancer", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VINBLASTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Bladder cancer", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINBLASTINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Bladder cancer", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Renal failure", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Culine S, Harter V, Gravis G et al. Chemotherapy for Muscle-invasive Bladder Cancer: Impact of Cisplatin Delivery on Renal Function and Local Control Rate in the Randomized Phase III VESPER (GETUG-AFU V05) Trial. Clin. Genitourin. Cancer. 2021", "literaturereference_normalized": "chemotherapy for muscle invasive bladder cancer impact of cisplatin delivery on renal function and local control rate in the randomized phase iii vesper getug afu v05 trial", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20211019", "receivedate": "20211019", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19968414, "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": "Pregnant women with neurofibromatosis type 1 (NF-1) have increased complications during gestation, including hypertensive disorders that are sometimes caused by pheochromocytoma. Pheochromocytoma is an extremely rare condition during pregnancy, and the main clinical manifestation is hypertension. If not properly treated, pheochromocytoma has high maternal and fetal mortality rates. Early recognition and adequate clinical management before delivery have led to better outcomes in the last few decades. Despite the association of NF-1 and pheochromocytoma, there are few clinical reports of these two conditions in pregnant patients. We present a rare case of pheochromocytoma diagnosed during pregnancy in a patient with NF-1, and we describe the treatment and the obstetric and fetal outcomes. We also review other medical conditions related to NF-1 that complicated this patient's pregnancy.", "affiliations": "a Department of Endocrinology and Nutrition , Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla , Seville , Spain.;a Department of Endocrinology and Nutrition , Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla , Seville , Spain.;a Department of Endocrinology and Nutrition , Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla , Seville , Spain.", "authors": "Remón-Ruiz|Pablo|P|;Aliaga-Verdugo|Alberto|A|;Guerrero-Vázquez|Raquel|R|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1080/09513590.2016.1254181", "fulltext": null, "fulltext_license": null, "issn_linking": "0951-3590", "issue": "33(2)", "journal": "Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology", "keywords": "Hypertension; neurofibromatosis type 1; obstetric labor complications; pheochromocytoma; pregnancy", "medline_ta": "Gynecol Endocrinol", "mesh_terms": "D000310:Adrenal Gland Neoplasms; D000328:Adult; D005260:Female; D006801:Humans; D009456:Neurofibromatosis 1; D010673:Pheochromocytoma; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic", "nlm_unique_id": "8807913", "other_id": null, "pages": "93-95", "pmc": null, "pmid": "27908211", "pubdate": "2017-02", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Pheochromocytoma in neurofibromatosis type 1 during pregnancy.", "title_normalized": "pheochromocytoma in neurofibromatosis type 1 during pregnancy" }

[ { "companynumb": "ES-PFIZER INC-2017070655", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXAZOSIN MESYLATE" }, "drugadditional": "3", "drugadministrationroute": "064", "drugauthorizationnumb": "019668", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXAZOSIN MESILATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXAZOSIN MESYLATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "019668", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXAZOSIN MESILATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PROPYLTHIOURACIL" }, "drugadditional": "3", "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "BASEDOW^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPYLTHIOURACIL." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Premature baby", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Maternal exposure during pregnancy", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Low birth weight baby", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "REMON-RUIZ, P.. PHEOCHROMOCYTOMA IN NEUROFIBROMATOSIS TYPE 1 DURING PREGNANCY.. GYNECOLOGICAL ENDOCRINOLOGY. 2017;33 (2):93-95", "literaturereference_normalized": "pheochromocytoma in neurofibromatosis type 1 during pregnancy", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20170222", "receivedate": "20170222", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13261738, "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" } ]

{ "abstract": "Erysipelothrix rhusiopathiae is an omnipresent commensal in the environment, studied for over a century. It is a zoonotic pathogen known to cause infections in animals and humans. Cases of Erysipelothrix rhusiopathiae in humans have been classified into three distinct entities: localized skin infections, diffuse skin infections, and systemic organ involvement. This particular pathogen is an uncommon cause of endocarditis, with an affinity for the aortic valve. We present a case of Erysipelothrix rhusiopathiae in a patient with involvement of the tricuspid valve.", "affiliations": "Internal Medicine, The Wright Center for Graduate Medical Education, Scranton, USA.;Internal Medicine, The Wright Center for Graduate Medical Education, Scranton, USA.;Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA.;Internal Medicine, The Wright Center for Graduate Medical Education, Scranton, USA.;Radiology, Hospital of the University of Pennsylvania, Philadelphia, USA.", "authors": "Karambelkar|Pranav|P|;Rojulpote|Chaitanya|C|;Borja|Austin J|AJ|;Youngs|Cathrine|C|;Bhattaru|Abhijit|A|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.7759/cureus.7942", "fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.7942\nCardiology\nInternal Medicine\nInfectious Disease\nAn Unusual Case of Tricuspid Valve Infective Endocarditis Caused by Erysipelothrix Rhusiopathiae\nMuacevic Alexander Adler John R Karambelkar Pranav 1 Rojulpote Chaitanya 12 Borja Austin J 34 Youngs Cathrine 1 Bhattaru Abhijit 4 \n1 \nInternal Medicine, The Wright Center for Graduate Medical Education, Scranton, USA \n\n2 \nNuclear Cardiology and Cardiovascular Molecular Imaging, University of Pennsylvania, Philadelphia, USA \n\n3 \nRadiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA \n\n4 \nRadiology, Hospital of the University of Pennsylvania, Philadelphia, USA \n\nPranav Karambelkar karambelkarp@thewrightcenter.org\n3 5 2020 \n5 2020 \n12 5 e79429 3 2020 3 5 2020 Copyright © 2020, Karambelkar et al.2020Karambelkar et al.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 author and source are credited.This article is available from https://www.cureus.com/articles/28866-an-unusual-case-of-tricuspid-valve-infective-endocarditis-caused-by-erysipelothrix-rhusiopathiaeErysipelothrix rhusiopathiae is an omnipresent commensal in the environment, studied for over a century. It is a zoonotic pathogen known to cause infections in animals and humans. Cases of Erysipelothrix rhusiopathiae in humans have been classified into three distinct entities: localized skin infections, diffuse skin infections, and systemic organ involvement. This particular pathogen is an uncommon cause of endocarditis, with an affinity for the aortic valve. We present a case of Erysipelothrix rhusiopathiae in a patient with involvement of the tricuspid valve.\n\ninfective endocarditiserysipelothrix rhusiopathiaezoonosistricuspid valve endocarditisThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nErysipelothrix rhusiopathiae is a commonly encountered organism in the environment. Cases in humans involving this organism have been known to cause local and disseminated skin infections, and in rare cases, systemic involvement [1]. Rare cases of Erysipelothrix rhusiopathiae can cause endocarditis. Moreover, this bacteria is known to have a strong affinity for the aortic valve. We present a patient who came to us with overt heart failure. The patient had no typical signs or symptoms suggestive of infective endocarditis but was ultimately found to have significant vegetations on echocardiography. In our report, we describe a rare case of Erysipelothrix rhusiopathiae in a patient with endocarditis and atypical involvement of the tricuspid valve.\n\nCase presentation\nA 47-year-old man with a past medical history of hypertension and alcohol dependence and with a four-week history of progressive bilateral lower extremity edema presented. The patient is a lumberjack and was gradually developing difficulty working long hours. His swelling progressively extended to his knees, prompting a visit to his primary care physician. He underwent a lower extremity duplex in the outpatient setting, which was negative for deep vein thrombosis. The patient was started on oral furosemide but mentioned it did not improve his lower extremity swelling. After undergoing routine lab work with his primary care doctor, the patient was found to have abnormal kidney function and was admitted to the hospital for further evaluation. \n\nOn admission, the patient's vital signs were as follows: temperature of 36.7oC, blood pressure of 148/91 mm Hg, heart rate of 72 beats/minute, and respiratory rate of 16/min. Clinically, the patient was volume overloaded with bibasilar lung crackles and 3+ pitting edema in bilateral lower extremities. His laboratory findings were notable for a white count of 26,000 (elevated in part due to patient's oral steroids for unknown reason), anemia, thrombocytopenia, blood urea nitrogen of 56, creatinine of 3.8 (baseline creatinine levels 0.5), hyponatremia, and an N-terminal pro B-type natriuretic peptide (NT-pro-BNP) level of 29,959. Urine studies revealed microscopic hematuria without proteinuria. Electrocardiogram revealed normal sinus rhythm with no acute ST-T wave changes. Further imaging included computed tomography (CT) of the chest, which revealed mild interlobular septal thickening in bilateral lung bases, suggestive of pulmonary edema. CT of the abdomen revealed diffuse gallbladder wall thickening without gallstones with no evidence of ascites. \n\nAt this stage, our preliminary diagnosis was cardio-renal syndrome due to an unknown etiology. The patient was started on intravenous diuretic therapy and oral beta-blockers in light of his acute decompensated heart failure. Additional blood work revealed low complement levels along with elevated cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA) levels. Antinuclear antibodies, creatine kinase, and anti-streptolysin antibodies were negative. After 48 hours, the patient's blood cultures were positive for gram-positive rods. He was started on empiric treatment with intravenous vancomycin.\n\nSince the patient did not have a baseline heart evaluation on file, a transthoracic echocardiogram was ordered, which revealed a normal ejection fraction with severe tricuspid regurgitation, pulmonary hypertension, and multiple tricuspid valve vegetations (Figure 1).\n\nFigure 1 A 2-D echocardiography image of the tricuspid valve showing significant vegetations\nThe most significant vegetation was noted to be 2.6 cm x 1.6 cm in size. At this point, our working diagnosis was acute renal failure, with gram-positive bacteremia secondary to tricuspid valve infective endocarditis. After six days, repeat blood cultures showed gram-positive rods with sensitivities revealing Erysipelothrix rhusiopathiae as the causative agent, resistant to vancomycin and sensitive to Penicillin G and ceftriaxone. The patient's antibiotic regimen was converted to intravenous Penicillin G. Given that he was not a candidate for cardiac surgery, the decision was made to treat him on an outpatient basis with long-term intravenous antibiotics.\n\nDiscussion\nErysipelothrix rhusiopathiae is a gram-positive, rod-shaped, non-sporing bacillus, known to survive for extended periods in the environment. It is considered a zoonotic disease, well-known for its association with occupational exposure. It has been isolated from a wide range of animals, including pigs, sheep, and fish. Reported cases of Erysipelothrix rhusiopathiae have been found frequently in fishers, farmers, butchers, and other occupations involving close exposure to animals [1]. On rare occasions, Erysipelothrix rhusiopathiae has been isolated from domesticated animals, further revealing its ubiquity [2].\n\nPatients who are diagnosed with Erysipelothrix rhusiopathiae manifest with one of three distinct clinical pictures. The most common manifestation is a localized skin infection known as erysipeloid. It presents as local cellulitis, commonly involving the hands [1, 3]. It can usually be differentiated from more common skin infections with its lack of suppuration, lack of edema, and an unusual amount of pain. Diffuse skin infection caused by Erysipelothrix rhusiopathiae is uncommon. Patients usually present with scattered edematous lesions, fever, joint pain, and lymphadenopathy [3]. The third manifestation is systemic bacteremia, although rare, it is known for its high mortality rate. Systemic bacteremia tends to affect the heart, most commonly the aortic valve for unknown reasons [1, 4]. \n\nOur patient's demographic profile and social history correlated with previous reports of Erysipelothrix rhusiopathiae infections: a middle-aged male with a long-standing history of alcohol use [3, 4]. His occupation as a lumberjack may have increased his risk of contracting this organism. Our patient did admit to animal husbandry in the past, which is a well-known risk factor. However, he did not work in any farm setting over the last ten years. He did, however, admit to hunting and occasionally consuming deer, which may have been the potential source of his infection. The clinical presentation of our patient was unique, given that in the absence of heart disease, he presented with overt volume overload and acute renal failure. He lacked the more classic symptoms of infective endocarditis, including fever, chills, and skin lesions. Our patient did not have any significant past medical conditions increasing his risk for developing infective endocarditis or a history of intravenous drug use. The microscopic hematuria and low complement levels were suggestive of underlying post-infectious glomerulonephritis. However, a transthoracic echocardiogram revealed multiple tricuspid valve vegetations. The most significant vegetation was noted to be 2.6 cm x 1.6 cm in size, suggesting tricuspid valve endocarditis.\n\nIn past literature, reported cases of Erysipelothrix rhusiopathiae and endocarditis had shown a proclivity towards the aortic valve [1, 3]. In our case, we felt the most astonishing feature was the isolated involvement of the tricuspid valve. Based on our literature search, there has been a reported case of tricuspid valve involvement in the past [4]. However, to our knowledge, we could not reveal a documented case of Erysipelothrix rhusiopathiae, explicitly involving the tricuspid valve.\n\nThe most appropriate method for diagnosing Erysipelothrix rhusiopathiae is by blood culture confirmation. Skin lesions may be biopsied but are not as effective. The major concern when diagnosing Erysipelothrix rhusiopathiae is its similarities to other pathogens, including Listeria monocytogenes, Lactobacillus, and Corynebacterium species. It is crucial to differentiate these species promptly to initiate appropriate antibiotic treatment [1].\n\nThe importance of diagnosing Erysipelothrix rhusiopathiae cannot be underestimated. It has a higher mortality rate compared to other pathogens of infective endocarditis [5]. Erysipelothrix rhusiopathiae has also been documented to present as a valvular abscess. Aside from echocardiography, dual imaging modalities such as 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) has shown to be useful in diagnosing infections [6]. In fact, there has been increasing popularity in utilizing this modality for assessing cardiovascular disorders [7-10]. Nearly all reported cases of Erysipelothrix rhusiopathiae have shown susceptibility to penicillin, cephalosporins, and fluoroquinolones. They are known for their resistance to vancomycin [4]. Our patient did not meet the criteria for the surgical treatment of his valvular lesion and was treated with long term antibiotic therapy [11].\n\nConclusions\nErysipelothrix rhusiopathiae is a zoonotic disease, well-known throughout the animal kingdom, yet seldom reported in humans. There has been a great success with advanced farming techniques. However, it is still important to maintain a holistic approach when treating patients with a farming background. This holistic approach to assess patients will help reach a timely diagnosis and initiate appropriate therapy to help reduce mortality. \n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Erysipelothrix rhusiopathiae Principles and practice of infectious diseases Reboli AC Farrar WE 2226 2227 New York Churchill Livingstone 2010 \n2 Bacteriologic analysis of infected dog and cat bites N Engl J Med Talan DA Citron DM Abrahamian FM 85 92 340 1999 9887159 \n3 Erysipeloid: a review Clin Exp Dermatol Veraldi S Girgenti V Dassoni F 859 862 34 2009 19663854 \n4 Erysipelothrix rhusiopathiae-induced aortic valve endocarditis: case report and literature review Int J Clin Exp Med Hua P Liu J Tao J Liu J Yang Y Yang S 730 736 8 2015 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4358505/#b2 25785050 \n5 Erysipelothrix rhusiopathiae endocarditis: microbiologic, epidemiologic, and clinical features of an occupational disease Rev Infect Dis Gorby GL Peacock Jr JE 317 325 10 1988 3287562 \n6 An update on the role of 18F-FDG-PET/CT in major infectious and inflammatory diseases Am J Nucl Med Mol Imaging Kung BT Seraj SM Zadeh MZ 255 273 9 2019 http://www.ajnmmi.us/files/ajnmmi0100744.pdf 31976156 \n7 Role of FDG-PET/CT in assessing the correlation between blood pressure and \n\nmyocardial metabolic uptake Asia Ocean J Nucl Med Biol Rojulpote C Mehdizadeh Seraj S Zirakchian Zadeh M 36 45 8 2020 32064281 \n8 18F-FDG-PET/CT in the quantification of photon radiation therapy-induced vasculitis Am J Nucl Med Mol Imaging Borja AJ Hancin EC Dreyfuss AD 66 73 10 2020 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076303/ 32211220 \n9 Assessing the feasibility of NaF-PET/CT versus FDG-PET/CT to detect abdominal aortic calcification or inflammation in rheumatoid arthritis patients Ann Nucl Med Seraj SM Raynor WY Revheim M 2020 \n10 Gender differences in rates of arrhythmias, cardiac implantable electronic devices, and diagnostic modalities among sarcoidosis patients Cureus Durugu R Gonuguntla K Patil S 0 12 2020 \n11 Timing of surgery in infective endocarditis Heart Kang D 1786 1791 101 2015 26285598\n\n", "fulltext_license": "CC BY", "issn_linking": "2168-8184", "issue": "12(5)", "journal": "Cureus", "keywords": "erysipelothrix rhusiopathiae; infective endocarditis; tricuspid valve endocarditis; zoonosis", "medline_ta": "Cureus", "mesh_terms": null, "nlm_unique_id": "101596737", "other_id": null, "pages": "e7942", "pmc": null, "pmid": "32499982", "pubdate": "2020-05-03", "publication_types": "D002363:Case Reports", "references": "32277422;3287562;32064281;31976156;19663854;25785050;32419995;26285598;32211220;9887159", "title": "An Unusual Case of Tricuspid Valve Infective Endocarditis Caused by Erysipelothrix Rhusiopathiae.", "title_normalized": "an unusual case of tricuspid valve infective endocarditis caused by erysipelothrix rhusiopathiae" }

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{ "abstract": "Thoracic epidural analgesia (TEA) has been shown to reduce postsurgical morbidity and mortality; nevertheless, major and minor complications can occur. We report our 10-year experience with TEA and incidence of complications.\nPatients received continuous infusion TEA (0.2% ropivacaine and 2 µg ml-1 fentanyl) to control postoperative pain. Every 8 hours, the acute pain service recorded the analgesia regimen and occurrence of side effects. The initial infusion rate was tapered daily in response to improvement in pain symptoms or occurrence of side effects.\nA total of 3126 patients received TEA. The median age was 65 years (range, 18-94) and the duration of catheter placement was 3.5 days (range, 2-8). Three major complications were identified (1:1042): two subarachnoid blocks and one epidural abscess which led to permanent sequela (1:3126). Minor complications were hypotension (4.8%), pruritus (4.4%), accidental catheter removal (3.7%), insertion site inflammation (2.5%), motor weakness (2.0%), postoperative nausea and vomiting (1.8%), catheter disconnection (1.9%), catheter occlusion (0.3%), post-dural puncture headache (0.5%), and catheter fragment retention (0.06%), which were the reasons for a 7.4% rate of early discontinuation of epidural analgesia. No occurrence of epidural hematoma, local anesthetic systemic toxicity, and cardiovascular/respiratory depression was recorded.\nPostoperative TEA is an advanced technique that poses certain difficulties that can subvert its great potential. While serious complications were rare, minor complications occurred more often and affected the postoperative course negatively. A risk/benefit evaluation of each patient should be done before employing the technique.", "affiliations": "Department of Emergency and Critical Care, Division of Operating Room Management, S. Croce e Carle Hospital, Cuneo, Italy.;Department of Emergency and Critical Care, Division of Operating Room Management, S. Croce e Carle Hospital, Cuneo, Italy.;Department of Emergency and Critical Care, Division of Operating Room Management, S. Croce e Carle Hospital, Cuneo, Italy.;Department of Emergency and Critical Care, Division of Operating Room Management, S. Croce e Carle Hospital, Cuneo, Italy.", "authors": "Manassero|Alberto|A|0000-0001-9183-0605;Bossolasco|Matteo|M|0000-0003-2776-4337;Carrega|Mattia|M|;Coletta|Giuseppe|G|0000-0003-4327-7387", "chemical_list": null, "country": "New Zealand", "delete": false, "doi": "10.2147/LRA.S272410", "fulltext": "\n==== Front\nLocal Reg Anesth\nLocal Reg Anesth\nlra\nlra\nLocal and Regional Anesthesia\n1178-7112 Dove \n\n272410\n10.2147/LRA.S272410\nOriginal Research\nPostoperative Thoracic Epidural Analgesia: Adverse Events from a Single-Center Series of 3126 Patients\nManassero et alManassero et alhttp://orcid.org/0000-0001-9183-0605Manassero Alberto 1 http://orcid.org/0000-0003-2776-4337Bossolasco Matteo 1 Carrega Mattia 1 http://orcid.org/0000-0003-4327-7387Coletta Giuseppe 1 1 Department of Emergency and Critical Care, Division of Operating Room Management, S. Croce e Carle Hospital, Cuneo, Italy\nCorrespondence: Alberto Manassero C.so 4 Novembre 12, CN12100, ItalyTel +390171642025Fax +390171642010 Email manassero.al@ospedale.cuneo.it\n10 9 2020 \n2020 \n13 111 119\n23 7 2020 27 8 2020 © 2020 Manassero et al.2020Manassero et al.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).Purpose\nThoracic epidural analgesia (TEA) has been shown to reduce postsurgical morbidity and mortality; nevertheless, major and minor complications can occur. We report our 10-year experience with TEA and incidence of complications.\n\nPatients and Methods\nPatients received continuous infusion TEA (0.2% ropivacaine and 2 µg ml−1 fentanyl) to control postoperative pain. Every 8 hours, the acute pain service recorded the analgesia regimen and occurrence of side effects. The initial infusion rate was tapered daily in response to improvement in pain symptoms or occurrence of side effects.\n\nResults\nA total of 3126 patients received TEA. The median age was 65 years (range, 18–94) and the duration of catheter placement was 3.5 days (range, 2–8). Three major complications were identified (1:1042): two subarachnoid blocks and one epidural abscess which led to permanent sequela (1:3126). Minor complications were hypotension (4.8%), pruritus (4.4%), accidental catheter removal (3.7%), insertion site inflammation (2.5%), motor weakness (2.0%), postoperative nausea and vomiting (1.8%), catheter disconnection (1.9%), catheter occlusion (0.3%), post-dural puncture headache (0.5%), and catheter fragment retention (0.06%), which were the reasons for a 7.4% rate of early discontinuation of epidural analgesia. No occurrence of epidural hematoma, local anesthetic systemic toxicity, and cardiovascular/respiratory depression was recorded.\n\nConclusion\nPostoperative TEA is an advanced technique that poses certain difficulties that can subvert its great potential. While serious complications were rare, minor complications occurred more often and affected the postoperative course negatively. A risk/benefit evaluation of each patient should be done before employing the technique.\n\nKeywords\nthoracic epiduralpostoperative painepidural analgesiaspinal epidural abscessepidural catheter\n==== Body\nIntroduction\nThoracic epidural analgesia (TEA) has been shown to provide excellent analgesia and improve outcomes after many surgical procedures.1,2 A widely practiced analgesic technique, TEA is generally considered safe, though complications have been reported more in perioperative settings than in either chronic pain management or labor analgesia.3 Assessment and management of TEA-related adverse effects are essential for monitoring the perioperative course. Furthermore, reliable data on complications rate is key to guiding clinical decision making, adopting protective measures to prevent complications and their sequelae, and providing adequate information during the consent discussion with patients. Risk-benefit assessment has become foundational in routine practice owing to the increasing debate surrounding the role of TEA.4\n\nThe aim of this study was to investigate the incidence of major and minor TEA-related adverse effects over 10 years of experience.\n\nPatients and Methods\nThe medical records of patients who received postoperative TEA in the surgery wards at S. Croce e Carle Cuneo City Hospital, between September 2009 and August 2019, were included in this prospective data collection. Patients received epidural analgesia after having given written informed consent for procedure and data management. Exclusion criteria were: patient refusal, coagulation disorders, generalized sepsis, known allergy to local anesthetics, and anatomical abnormalities of the spinal column. The data extracted from the medical records (age, sex, type of surgery, duration and quality of treatment, adverse events or unusual findings), were entered anonymized in the institutional encrypted database and then analyzed in an aggregate manner. This prospective data collection and analysis was conducted as a postoperative pain management “quality improvement” initiative, approved by the Ethics Committee of the S. Croce e Carle Hospital (protocol number 10/2020) and conducted in accordance with the Declaration of Helsinki.\n\nEpidural catheters were placed in the operating theatre either immediately before induction of anesthesia or, to shorten anesthesia time, the afternoon of the day before surgery in patients scheduled for the first operating room time slot in the morning. Enoxaparin (40 mg) was given subcutaneously about 12 h before and after epidural catheter insertion. Antiplatelet therapy with aspirin was stopped 5 days before catheter insertion and therapy with clopidogrel and ticlopidine was stopped 7 or 10 days before. Platelet count >80,000 and coagulation times were ascertained to be within the normal range before catheter insertion and removal.\n\nEach anesthesiologist followed an established institutional procedure for catheter insertion, using maximum barrier precaution and 3-step skin disinfection with an iodo-povidone solution. With the patient sitting upright, an epidural 20G 3-hole catheter with a soft atraumatic tip was inserted via an 8-cm 18G Tuohy needle (Perifix ® Soft Tip 901 BBraun Melsungen, Germany) at a spinal level appropriate for the surgery (T5/6 for thoracic surgery and T8/9 or T9/10 for upper or lower abdominal surgery). The catheter was threaded into the epidural space for 5 to 7 cm, secured with a transfixing silk suture to the underlying skin, and covered with a transparent, semipermeable sterile adhesive dressing (Tegaderm, 3M, St Paul, MN, USA). After a negative aspiration test for cerebrospinal fluid and blood, a dose of 2 mL lidocaine 2% was given to further exclude subarachnoid location of the catheter. The correct spread of the local anesthetic was assured by the loss of cold discrimination in the appropriate segments. Bacterial filters were used on all epidural catheters. All patients underwent general anesthesia and a local anesthetic bolus through the epidural catheter at the discretion of the anesthetist. An infusion of 0.2% ropivacaine with 2 µg ml−1 fentanyl was started at 5 to 6 mL/h before the end of surgery. The mixture was prepared aseptically in 300-mL elastomeric pumps with an adjustable flow rate.\n\nAt the end of the surgery, patients were transferred to the postanesthesia care unit (PACU), where the efficacy of the analgesic regimen was checked and eventually adjusted based on a 4-point verbal rating scale (VRS, wherein a score of 0 indicates no pain at rest or on movement; 1 no pain at rest, slight pain on movement; 2 intermittent pain at rest, moderate on movement; and 3 continuous pain at rest, severe on movement). Patients were discharged to the wards if the VRS score was 0 to 1. The infusion regimen was continuous without the use of patient-controlled analgesia (PCA). The duration of epidural analgesia was planned as follows: 96 h (4 days) after pancreatectomy, esophagectomy, cystectomy, and thoracotomy surgery; b) 72 h (3 days) after nephrectomy, laparotomy for hysterectomy, liver, gastric, and colorectal surgery; c) 48 h (2 days) after laparoscopy surgery. The catheter was removed the day planned if patients reported satisfactory analgesia (VRS score 0 to 1) at a 3-mL/h infusion rate. Otherwise, epidural analgesia was continued after having evaluated it for clinical confirmation. The catheter was removed earlier if no longer required for analgesia. Pain episodes were treated with a rescue analgesic dose administered according to pain intensity as follows: VRS 1, paracetamol 1000 mg i.v.; VRS 2, Ketorolac 30 mg i.v.; VRS 3, morphine chlorhydrate 10 mg i.m. If an unacceptable pain level (VRS 3) persisted, a top-up with lidocaine 1% 5 mL was carried out to ascertain the correct catheter position. If not, the epidural analgesia was discontinued and replaced with an i.v. elastomeric pump.\n\nOn the ward, a structured round was performed by the acute pain service (APS) every 8 h and whenever there were calls for pain management or infusion system problems. The analgesia regimen and side effects were recorded and scored: episodes of sedation (0 awake; 1 drowsy; 2 sleepy but easy to arouse, 3 sleepy and unrousable), nausea or vomiting (0 no nausea, 1 mild nausea, no antiemetic given, 2 moderate nausea, antiemetic given, 3 severe nausea and vomiting despite antiemetic), respiratory depression (ventilatory frequency <8 bpm), hypotension (systolic arterial pressure <80 mm Hg after having excluded other common causes of hypotension after surgery) pruritus, leg numbness and weakness. Catheters were inspected daily and removed if signs of infection were observed (suppuration at the entry site). Catheters were also removed if disconnection from the filter was not immediately recognized. Motor impairment of any other drug-associated adverse event was managed by temporary reduction or discontinuation of infusion. Enoxaparin was withheld for at least 6 h after catheter removal. Within 24 h after catheter removal, the APS made at least two follow-up visits to check for any occurrences. The APS nurses compiled a tracking sheet for each patient. The tracking sheet contained information on epidural catheter insertion and daily evaluation of TEA efficacy and side effects. Major adverse events were defined as epidural hemorrhage or abscess, subarachnoid block, spinal cord-root injury leading to permanent motor deficits, TEA-associated cardiovascular/respiratory collapse, and local anesthetic toxicity. Minor adverse events were defined as signs of local inflammation/infection, episodes of hypotension, nausea or vomiting, sedation, pruritus, postdural puncture headache, motor weakness and numbness of the legs, catheter fragment retention, catheter occlusion, infusion system discontinuation, premature dislodgement. Neurological sequelae were considered permanent if they persisted for more than 6 months.\n\nThis study is descriptive with no prior hypothesis. Categorical variables are expressed as percentages and continuous variables as the median (min-max) because the distribution was non-normal. Statistical analysis was performed using GraphPad Prism for Windows, version 5.00 (GraphPad Software, San Diego, CA, USA).\n\nResults\nA total of 3126 patients (42% women and 58% men) received postoperative TEA (Figure 1). Table 1 presents the type of surgery and relative duration of TEA. The median age was 65 years (range, 18–94). The median duration of TEA was 3.5 days/84.0 hours (range, 2–8 days). TEA was ended as planned with satisfactory pain control after tapering the infusion rate to 3 mL/h in 1839 patients (58.8%) and was extended in 1056 (33.8%). TEA was discontinued because of complications in the remaining 231 (7.4%) patients: accidental catheter removal in 116; catheter disconnected from the filter in 60; catheter occlusion in 10; local infection in 26; PDPH in 17; and subarachnoid block in 2. Three major complications (1:1042) were recorded: two subarachnoid blocks and one epidural abscess, which led to permanent sequela (1:3126). Overall, 690 minor complications occurred in 431 (13.8%) patients, in 111 (3.5%) of which two or more complications occurred contemporaneously (Table 2 and Figure 2). No cases of epidural hematoma, local anesthetic systemic toxicity (LAST), TEA-associated cardiovascular/respiratory collapse or sedation were noted.Table 1 Types of Surgery and Duration of Thoracic Epidural Anesthesia\n\nType of Surgery\tNo. (%)\tDuration in Days Median (Min–Max)\t\nThoracotomy\t59 (1.8)\t5.7 (3–8)\t\nEsophagectomy\t104 (3.3)\t5.0 (3–8)\t\nPancreatectomy\t132 (4.3)\t4.2 (3–6)\t\nCystectomy\t182 (5.8)\t4.0 (3–7)\t\nLiver resection\t133 (4.2)\t3.7 (2–6)\t\nNephrectomy\t336 (10.8)\t3.5 (2–7)\t\nExplorative laparotomy\t188 (6.0)\t3.5 (2–7)\t\nColon resection\t355 (11.3)\t3.4 (2–6)\t\nGastric resection\t177 (5.6)\t3.4 (2–6)\t\nHysterectomy\t41 (1.3)\t3.4 (2–7)\t\nRectal resection\t251 (8.0)\t3.3 (2–5)\t\nLiver resection (LPS)\t22 (0.8)\t2.9 (2–4)\t\nGastric resection (LPS)\t50 (1.5)\t2.9 (2–6)\t\nRectal resection (LPS)\t129 (4.2)\t2.8 (2–7)\t\nColon resection (LPS)\t738 (23.7)\t2.6 (2–6)\t\nProstatectomy (open)\t197 (6.3)\t2.5 (2–5)\t\nNephrectomy (LPS)\t32 (1.1)\t2.4 (2–4)\t\nAll\t3126 (100)\t3.5 (2–8)\t\nAbbreviation: LPS, laparoscopy.\n\n\nTable 2 Thoracic Epidural Anesthesia-Related Complications\n\nNo. (%)\tMajor Complications\t\n2 (0.06)\tSubarachnoid block\t\n1 (0.03)\tEpidural abscess\t\n\tMinor complications\t\n150 (4.8)\tHypotension\t\n137 (4.4)\tPruritus\t\n116 (3.7)\tAccidental catheter removal\t\n80 (2.6)\tInflammation at the entry site\t\n61 (2.0)\tLeg weakness\t\n60 (1.9)\tCatheter disconnection at the filter\t\n57 (1.8)\tPostoperative Nausea and Vomiting\t\n17 (0.5)\tPost Dural Puncture Headache\t\n10 (0.3)\tCatheter occlusion\t\n2 (0.06)\tCatheter fragment retention\t\n\nFigure 1 Cumulative yearly number of TEA performed.\n\nFigure 2 Distribution of complications expressed as percentage of the total.\n\n\n\nDetails of Major Events\nEpidural Abscess\nOne case of epidural abscess (EA) (1:3126–3,2:10.000) was recorded.5 A 57-year-old man underwent a duodenopancreatectomy for an adenocarcinoma. The catheter entry point was examined daily, and no erythema or tenderness was noted. On postoperative day (POD) 2, the elastomeric pump was replaced. On POD 5, the patient developed pyrexia with no apparent cause. The epidural catheter was removed, and an erythematous swelling at the insertion site was noted. The same day, the patient started to complain of mild abdominal pain and distension. An abdominal computed tomography (CT) scan revealed two perihepatic fluid collections that were drained percutaneously. The patient became subpyretic. During the night of POD 12, the patient complained of mild back pain, which by the morning of POD 13 was associated with progressive bilateral leg weakness and difficulty walking. Sensory examination revealed decreased bilateral light touch up to the T4 dermatome. A magnetic resonance imaging (MRI) scan showed marked narrowing of the spinal canal and abnormal signals from the posterior epidural space between Th 6 and Th 8 (Figure 3). Within a few hours, complete paralysis of the lower extremities developed. An emergency decompressive laminectomy for drainage of the abscess was performed. Bacterial culture of purulent material produced methicillin-sensitive Staphylococcus aureus. Within 1 month, the patient recovered sensory deficit and motor power partially. At 1 year, the patient regained sphincter control but was unable to walk without the aid of crutches due to lower limb motor deficit.Figure 3 MRI documenting the epidural abscess.\n\n\n\nSubarachnoid Block\nTwo cases of sudden onset of subarachnoid block were recorded (1:1563–6,4:10.000). In both, the catheter was implanted without difficulty, nothing could be aspirated from the needle or the catheter, and no detectable sensory or motor changes were noted after the 2-mL lidocaine 2% test dose.\n\nIn the one case, a bolus of lidocaine 1% 5 mL administered during general anesthesia against surgical stress led to an unexpected drop in blood pressure and heart rate. As we suspected problems with the epidural catheter, no further anesthetic bolus was administered nor infusion started. Immediately after surgery, the patient was unable to move his legs, with sensory level of anesthesia at the T8 dermatome. Gentle aspiration through the catheter revealed cerebrospinal reflux. The block resolved within 1 h without sequelae. The catheter was removed; no headache developed. In the other case, no anesthetic bolus was administered during surgery and the infusion started at 5 mL/h before the end of surgery. The patient was transferred to the ward after an uneventful surgery and postoperative period; the catheter was fully functional. Six hours later, the patient started to complain of progressive lower limb motor impairment and numbness up to the T10 dermatome. The infusion was stopped immediately, but no cerebrospinal fluid could be aspirated via the catheter. The block resolved within 2 h without sequelae. The catheter was removed; no headache developed.\n\nDiscussion\nThe side-effect profile of postoperative epidural analgesia varies across studies depending on catheter level (thoracic or lumbar), analgesia duration, drugs administered, method of delivery, and accuracy of the data collected. With this prospective study, we wanted to determine the incidence of complications attributed to thoracic epidural infusion delivered at a standard concentration of ropivacaine and fentanyl and under a standardized protocol of infusion and management at a single teaching hospital. In so doing we believe the reported data are consistent.\n\nWe identified as major complications two subarachnoid blocks and one EA. Despite the frequency of catheter colonization, neither a definitive causal relationship with epidural abscess has been established nor its incidence. Prospective audits have reported cases of epidural abscess with an incidence between 1 in 1368 to 1 in 7000 patients.6–12 In the majority of the cases, there is no obvious cause and diagnosis is delayed. Presenting manifestations of spinal epidural abscess (SEA) may be insidious in nature: the classic clinical triad of back pain, fever, and neurological deficits are present in only a small percentage of patients. Early signs and symptoms of spinal epidural abscess can be non-specific and overlap with the common signs and symptoms of many other postoperative conditions. In our study, the delayed manifestation of back pain as a symptom, abdominal pain, and perihepatic fluid collections may have acted as confounding factors.13 The abdominal complications were often wrongly suspected as the cause of systemic infection. Regrettably, from the day of catheter removal (POD5) forward, the presence of pyrexia, laboratory findings, and, primarily, local signs of infection did not raise suspicion of an epidural infection and nor were swabs around the catheter insertion and catheter tip taken and cultured. A rigorous aseptic procedure was followed during catheter implant, but prolonged epidural catheterization, which lasted 5 days, including one elastomeric change, can have contributed to the development of infection. From this case forward, we changed several elements of our practice: the catheter remains in situ for a maximum of 4 days; if a prolonged epidural block is indicated, the risk/benefit ratio is reassessed. Skin signs of infection and dressing damage are promptly reported to a supervisor of the postoperative pain management team. While erythema alone was not considered a sufficient reason for catheter removal,14 in the presence of suppurative signs, the decision to continue with epidural analgesia was made after considering the risk/benefit ratio case-by-case. Differently, catheter removal and bacteriological examination were performed whenever clinical symptoms indicated the possibility of infection of the epidural space.\n\nAccidental subarachnoid block after epidural catheterization can be a life-threatening event, especially if it occurs in the ward where medical response time may be delayed.15–17 It is commonly attributed to catheter migration; however, as we used a soft-tipped epidural catheter in both cases, they could not by themselves have penetrated the dura.18 Probably, the catheters were accidentally placed in the subdural space in both cases, as neither the aspiration test nor the test dose was positive for subarachnoid placement. In the first case, we assume that the catheter moved into the subarachnoid space soon after its placement while in the second, the catheter was probably placed partly subdural and its distal segment remained across the dural membrane. Because it is a 3-holed catheter, some of the regularly injected solution (no bolus were given) flowed into the epidural space, providing regular epidural analgesia for about 6 h, and some into the subdural space. The amount of solution that entered the subdural space gradually distended the arachnoid membrane enough to tear it and then suddenly create a subarachnoid block. Unfortunately, no MRI was performed in either case to determine the exact location of the catheter.\n\nHypotension was the most common minor complication (incidence, 4.8%) and was within the range reported in previous studies (2.4–6.8%).19–23 Hypotension is a clinically relevant postoperative side effect of TEA. Primarily due to blockade of the sympathetic nervous system and resulting in arterial and venous vasodilation with subsequent “functional” hypovolemia, it can delay early patient mobilization and, if corrected only with IV fluids, can cause fluid overload and reduce splanchnic perfusion, with potential negative effects on bowel anastomosis.24 Hypotension was recorded mainly in the immediate postoperative period, primarily when a laparoscopic technique was used (first night after surgery or the morning after). The symptom was corrected by reducing the epidural infusion rate; we linked this observation to an imbalance between nociception and antinociception.\n\nThe second most frequent complication was pruritus (incidence, 4.4%); in 126 (92%) patients its onset was within 24 h of the start of epidural infusion. The reported incidence of pruritus is dose-dependent (range, 1.8–16.7%), making it the most common side effect of neuraxial opioids.19–23 In 33% of our patients who complained of pruritus, the elastomeric pump was replaced with an opioid-free one, which resolved the problem. In the remaining patients, it was sufficient to decrease the infusion rate.\n\nWe recorded 80 catheters with cutaneous signs of inflammation at the entry site (incidence, 2.6%). The infection was suspected in 26 catheters because of either serous or purulent local discharge. The catheters were immediately removed, and a swab from the skin around the insertion site and from the tip of the catheter were cultured. The catheter tip and the skin around the insertion site were positive for same microorganism in 4/26 (15.3%). All insertion site infections resolved shortly after catheter removal. Clinical signs of inflammation/infection at the catheter entry site are variously defined and reported. Cameron reported a 2.8% incidence of insertion site infection among 7142 thoracic catheters with a mean insertion duration of 3.0 days compared to an incidence of 0.8% for 1068 lumbar catheters with a mean insertion duration of 2.1 days. There was a significant association between epidural insertion site infection and length of catheterization.6 Burstal reported an incidence of 5.3% for catheter site inflammation, with a highly significant difference in the incidence between a catheter left in situ for 3 days or less compared to those left for 4 or more days.22 Yuan found a strong relationship between bacterial colonization of the skin around the epidural catheter insertion site and tip segments of the catheter, with a significant correlation between catheter tip colonization and dressing change and/or accidental catheter disconnection from the filter.25 Colonization of the catheter tip with the same organisms colonizing the skin, as in our 4 patients, reinforces the hypothesis that a common route for catheter colonization is via migration of bacteria along the catheter track or during its placement. This underscores the importance of employing aseptic practice during catheter placement and careful management to maintain the skin sterile around the catheter insertion site on the ward while limiting, whenever possible, dressing damage, accidental hub disconnection, bag changes, top-up infusate, and infusion for more than 96 h.26\n\nMotor weakness (Bromage score >0) and/or leg numbness was reported by 2.0% of patients. These symptoms correlate with the level of catheter placement, as the complication seems to be much lower when an epidural catheter is placed at the thoracic level.27 The incidence was similar to that reported by Ahmed (2.4%) in a series of patients with the thoracic epidural catheter implanted at the T11-T12 interspace as a lower limit.28 The choice of ropivacaine 0.2%, as well as the lower regimen of infusion (max 6 mL/h) and the absence of epidural bolus, may have resulted in the overall low incidence of motor impairment. As numbness was reported only as a discomforting symptom, lower limb motor weakness was a temporary restriction on patient mobilization. The highest frequency of motor impairment was seen in the first postoperative period and was successfully managed by decreasing the infusion flow rate without the need to stop the infusion.\n\nAccidental dural puncture occurred in 58 patients (1.8%) but postdural puncture headache (PDPH) developed in only 17 (0.5%). The incidence of inadvertent dural puncture in our series is similar to the 1.5% and the 2.1% reported by Jackson Su29 and Deni,20 respectively, for their series of thoracic epidural catheters.\n\nPostoperative nausea and vomiting (PONV) was recorded in 1.8% of patients; it can be a side effect of opioid administration itself. With fentanyl concentrations up to 10 µg ml−1, PONV rates range from 2.8 to 14.8%.19,20,22,23 The incidence recorded in our series was lower than reported in the literature. A plausible explanation for this finding is the low fentanyl concentration.\n\nTwo cases of catheter fragment retention were recorded. In the first, the distal 5-mm soft material coating the catheter tip was retained; because of its small size, we were unable to confirm its position in the patient’s body. In the second case, during catheter removal, the epidural catheter broke, and a fragment about 7 cm from the distal tip remained in the patient’s body. The catheter fragment was visualized on a CT scan of the epidural space cephalad from the tip of the spinous process of the eleventh thoracic vertebra (Figure 4). Complications such as these have been described in previous case reports and studies. Recently, Hösslin reported a rate similar to ours. In accordance with current recommendations, we left both catheter fragments in situ.30–32Figure 4 Thoracic spine CT showing the retained catheter fragment.\n\n\n\nAccidental catheter removal occurred in 116 (3.7%) patients, catheter disconnection at the filter in 60 (1.9%), and catheter occlusion in 10 (0.3%). Technical reasons for early discontinuation are a consistently reported problem in up to 19% of patients.19 Our data compare favorably with previously published series.21–23 We recorded a low rate of accidental catheter removal, similar to the 3.3% reported by Hösslin,30 who adopted our technique of securing the catheter to the skin with a transfixing silk suture. In addition, to prevent outward movement, we also threaded the catheter into the epidural space for at least 5 to 7 cm.27\n\nThe overall mean duration of TEA was 3.5 days (range, 2–8) for a total of 10,436 days, of which 1749 days (20%) were more than those planned. In 1839 patients (58%) TEA ended as planned with satisfactory pain control after tapering the infusion rate to 3 mL/h, while in 1056 (34%) patients, it was continued past the scheduled time. The principal reason was that, at the planned day of catheter removal, either the analgesia level was not satisfactory or the coagulation profile was not within the normal range. In these cases, catheter removal was postponed for the next day. In some ways, prolonged duration of epidural analgesia may be viewed as another type of complication because it can delay recovery and increase the probability of catheter infection.\n\nWe recorded neither cases of epidural hematoma, nor of LAST; furthermore, the low concentration of fentanyl used may also explain the absence of dose-dependent opioid-related complications such as sedation and respiratory depression.\n\nStudy Limitations\nThe study population included patients undergoing continuous thoracic epidural infusion for postoperative analgesia; therefore, our findings can be translated only in part to patients undergoing patient-controlled or lumbar epidural analgesia. We cannot exclude the possibility of undetected adverse events.\n\nConclusions\nPostoperative epidural analgesia is a sophisticated technique. It poses challenges that can subvert its great potential. Furthermore, adverse effects are more common than after other postoperative analgesia modalities.20 While serious complications happen rarely, less investigated minor complications may frequently occur and affect the postoperative course negatively, especially in the setting of an Enhanced Recovery After Surgery program.33,34 Some catheter-related complications are time dependent (eg, catheter infection and dislodgement), while others are drug dosage-dependent (eg, respiratory and conscious depression, hypotension, pruritus, PONV, motor weakness). Anesthetists need to be aware of these potentially avoidable complications. Taking into account that the epidural failed to provide satisfactory analgesia (at least one episode of VRS ≥ 2) in 18% of patients, adding the incidence of complications (13.8%) we can conclude that epidural analgesia was effective and safe in about two-thirds of patients. 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Management of the sheared epidural catheter: is surgical extraction really necessary?\n\nJ Clin Anesth . 2007 ;19 (4 ):310 –314\n. doi:10.1016/j.jclinane.2006.11.005 17572331 \n32. Kasivisvanathan \nR , Sodhi \nM , Setty \nS . The broken epidural catheter: to remove or not to remove?\n\nBr J Hosp Med (Lond) . 2012 ;73 (12 ):718 . doi:10.12968/hmed.2012.73.12.718 23502211 \n33. Rosen \nDR , Wolfe \nRC , Damle \nA , et al. Thoracic epidural analgesia: does it enhance recovery?\n\nDis Colon Rectum . 2018 ;61 (12 ):1403 –1409\n. doi:10.1097/DCR.0000000000001226 30308525 \n34. Gustafsson \nUO , Scott \nMJ , Hubner \nM , et al. Guidelines for perioperative care in elective colorectal surgery: enhanced recovery after surgery (ERAS®) society recommendations: 2018\n. World J Surg . 2019 ;43 (3 ):659 –695\n.30426190\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1178-7112", "issue": "13()", "journal": "Local and regional anesthesia", "keywords": "epidural analgesia; epidural catheter; postoperative pain; spinal epidural abscess; thoracic epidural", "medline_ta": "Local Reg Anesth", "mesh_terms": null, "nlm_unique_id": "101566276", "other_id": null, "pages": "111-119", "pmc": null, "pmid": "32982397", "pubdate": "2020", "publication_types": "D016428:Journal Article", "references": "30791208;10598636;3789375;14751478;23502211;31008725;30308525;26584187;21308559;8777121;30426190;8916814;2181886;18156891;12402724;7574052;19139027;27051364;9523813;14612482;11167440;26584188;17572331;26954252;18671685;17457132;15028325;22531384;18945716;9564395;8683091;22353749;24096762;8848884", "title": "Postoperative Thoracic Epidural Analgesia: Adverse Events from a Single-Center Series of 3126 Patients.", "title_normalized": "postoperative thoracic epidural analgesia adverse events from a single center series of 3126 patients" }

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POSTOPERATIVE THORACIC EPIDURAL ANALGESIA: ADVERSE EVENTS FROM A SINGLE-CENTER SERIES OF 3126 PATIENTS. LOCAL AND REGIONAL ANESTHESIA. 2020?13:111-119", "literaturereference_normalized": "postoperative thoracic epidural analgesia adverse events from a single center series of 3126 patients", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20201228", "receivedate": "20201202", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18570175, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210114" } ]

{ "abstract": "Kawasaki disease is an acute self-limited vasculitis of unknown aetiology. The prognosis depends mainly on coronary damage. There is no consensus regarding optimal adjunctive therapeutics for refractory forms to treatment by intravenous immunoglobulins and corticosteroids. We report the case of an 18-month-old infant with refractory Kawasaki disease complicated by diffuse aneurysms of coronary arteries and successfully treated by anakinra with partial regression of coronary aneurysms.", "affiliations": "1Pediatric Cardiology,CHU Lille and University of Lille,Lille,France.;2Pediatric Rheumatology Unit,CHU Lille and University of Lille,Lille,France.;3Pediatric Emergency unit and Infectious Diseases,CHU Lille and University of Lille,Lille,France.", "authors": "Guillaume|Marie-Paule|MP|;Reumaux|Héloïse|H|;Dubos|François|F|", "chemical_list": "D018501:Antirheumatic Agents; D053590:Interleukin 1 Receptor Antagonist Protein", "country": "England", "delete": false, "doi": "10.1017/S1047951117002864", "fulltext": null, "fulltext_license": null, "issn_linking": "1047-9511", "issue": "28(5)", "journal": "Cardiology in the young", "keywords": "Refractory Kawasaki disease; anakinra; children; coronary aneurysm", "medline_ta": "Cardiol Young", "mesh_terms": "D018501:Antirheumatic Agents; D003323:Coronary Aneurysm; D017023:Coronary Angiography; D003331:Coronary Vessels; D004305:Dose-Response Relationship, Drug; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D007279:Injections, Subcutaneous; D053590:Interleukin 1 Receptor Antagonist Protein; D008297:Male; D009080:Mucocutaneous Lymph Node Syndrome; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome", "nlm_unique_id": "9200019", "other_id": null, "pages": "739-742", "pmc": null, "pmid": "29455693", "pubdate": "2018-05", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Usefulness and safety of anakinra in refractory Kawasaki disease complicated by coronary artery aneurysm.", "title_normalized": "usefulness and safety of anakinra in refractory kawasaki disease complicated by coronary artery aneurysm" }

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{ "abstract": "The therapeutic options for disease modification in relapsing-remitting multiple sclerosis (RRMS) have expanded remarkably in the last 15 years. Although intravenous immunoglobulins (IVIg) have shown some therapeutic effects in multiple sclerosis, reducing global supplies, restriction of treatment to essential indications and availability of effective alternative treatments for MS currently exclude IVIg from being an accepted therapy for MS, other than for some exceptional considerations. We report the case of a female patient with RRMS who was diagnosed with Ehlers-Danlos syndrome (EDS) and Muir-Torre syndrome (MTS) soon after the diagnosis of active RRMS was made. The coexisting conditions precluded the use of available disease-modifying treatments. She benefited from monthly and then bi-monthly IVIg, with a single mild relapse over 10 years. Discontinuation of IVIg due to reduced availability with a brief aborted course of subcutaneous PEGylated interferon-beta was followed by significant relapses. Five months after the first ocrelizumab infusion, she developed caecal cancer requiring colectomy. Reinstitution of IVIg is contemplated.", "affiliations": "Department of Neurology, Queen's Medical Centre Campus, Nottingham University Hospitals NHS Trust, Derby Road, Nottingham, UK. srishti.gupta@nuh.nhs.uk.;Clinical Genetics Service, City Hospital Campus, Nottingham University Hospitals NHS Trust, Nottingham, UK.;Department of Neurology, Queen's Medical Centre Campus, Nottingham University Hospitals NHS Trust, Derby Road, Nottingham, UK. cris.constantinescu@nottingham.ac.uk.", "authors": "Gupta|Srishti|S|;Suri|Mohnish|M|;Constantinescu|Cris S|CS|http://orcid.org/0000-0003-2066-7585", "chemical_list": null, "country": "New Zealand", "delete": false, "doi": "10.1007/s40120-020-00209-0", "fulltext": "\n==== Front\nNeurol Ther\nNeurol Ther\nNeurology and Therapy\n2193-8253\n2193-6536\nSpringer Healthcare Cheshire\n\n32780270\n209\n10.1007/s40120-020-00209-0\nCase Report\nMaintenance Intravenous Immunoglobulin Treatment for Multiple Sclerosis Coexisting with Ehlers-Danlos Syndrome and Muir-Torre Syndrome: A Case Study\nGupta Srishti srishti.gupta@nuh.nhs.uk\n\n1\nSuri Mohnish 2\nhttp://orcid.org/0000-0003-2066-7585\nConstantinescu Cris S. cris.constantinescu@nottingham.ac.uk\n\n13\n1 grid.240404.6 0000 0001 0440 1889 Department of Neurology, Queen’s Medical Centre Campus, Nottingham University Hospitals NHS Trust, Derby Road, Nottingham, UK\n2 grid.240404.6 0000 0001 0440 1889 Clinical Genetics Service, City Hospital Campus, Nottingham University Hospitals NHS Trust, Nottingham, UK\n3 grid.4563.4 0000 0004 1936 8868 Division of Clinical Neuroscience, Section of Clinical Neurology, University of Nottingham, Nottingham, UK\n11 8 2020\n11 8 2020\n12 2020\n9 2 605610\n9 7 2020\n© The Author(s) 2020\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.\nThe therapeutic options for disease modification in relapsing-remitting multiple sclerosis (RRMS) have expanded remarkably in the last 15 years. Although intravenous immunoglobulins (IVIg) have shown some therapeutic effects in multiple sclerosis, reducing global supplies, restriction of treatment to essential indications and availability of effective alternative treatments for MS currently exclude IVIg from being an accepted therapy for MS, other than for some exceptional considerations. We report the case of a female patient with RRMS who was diagnosed with Ehlers-Danlos syndrome (EDS) and Muir-Torre syndrome (MTS) soon after the diagnosis of active RRMS was made. The coexisting conditions precluded the use of available disease-modifying treatments. She benefited from monthly and then bi-monthly IVIg, with a single mild relapse over 10 years. Discontinuation of IVIg due to reduced availability with a brief aborted course of subcutaneous PEGylated interferon-beta was followed by significant relapses. Five months after the first ocrelizumab infusion, she developed caecal cancer requiring colectomy. Reinstitution of IVIg is contemplated.\n\nKeywords\n\nEhlers-Danlos syndrome\nIVIg\nMuir-Torre syndrome\nMultiple sclerosis\nissue-copyright-statement© The Author(s) 2020\n==== Body\nKey Summary Points\n\nA complex case of RRMS with EDS and MTS-probable association/trigger/unmasking\t\nIVIg has been found beneficial as an immunomodulatory and potential cancer immunoprophylaxis agent\t\nUnmet need of treatment options in this rare case—IVIg kept MS and cancer in remission\t\nDespite the global shortage of IVIg, it should be considered for clinically indicated cases\t\n\nIntroduction\n\nThe landscape for disease-modifying treatments for multiple sclerosis (MS), in particular for the relapsing-remitting forms, has changed dramatically over the last two decades. All current treatments target the immune system by reducing pro-inflammatory responses, blocking lymphocyte migration, providing non-specific immunosuppression or depleting selected immune cell populations.\n\nDespite the evidence of a potential therapeutic benefit, intravenous immunoglobulin (IVIg) is currently only very rarely used in MS, where it is reserved for special situations, for example in the post-partum period to prevent post-partum relapses [1]. However, as resumption of disease-modifying treatments in the immediate post-partum period is increasingly accepted, IVIg use has declined even for this indication.\n\nSecondary antibody deficiencies are increasingly diagnosed during the course of B cell-depleting therapies for central nervous inflammatory conditions, but these are typically seen with neuromyelitis optica spectrum disorders under rituximab treatment. Some of the affected patients benefit from IVIg given as prophylaxis against recurrent infections [2].\n\nA major consideration in restricting the use of IVIg to conditions where alternatives are lacking is the declining supply of immunoglobulin worldwide, related to a reducing number of donors. This further excludes MS as an indication for IVIg other than for exceptional cases.\n\nWe report a unique case of a patient with relapsing-remitting multiple sclerosis (RRMS) whose constellation of co-morbidities (which included predisposition to cancer) precluded the use of the other available disease-modifying treatments. She benefited from monthly and then bi-monthly IVIg, with a single MS relapse and no recurrence of cancer in > 10 years.\n\nCase Report\n\nA 67-year old woman had optic neuritis at age 46 and was diagnosed with RRMS 1 year later. She had three clinical relapses requiring corticosteroid treatment in the first 18 months of the disease. A short course of subcutaneous interferon beta 1a (Rebif®) was discontinued because of side effects (mood changes and severe bruising at the injection sites).\n\nThree years after the first symptoms, she was recruited into a randomized placebo-controlled clinical trial of anti-IL-12 antibody for RRMS [3]. As part of the screening for the trial, a past personal and strong family history of hypermobility, increased skin elasticity and frequent joint dislocations was elicited, leading to the diagnosis of hypermobile Ehlers-Danlos syndrome (EDS), possibly with additional features (e.g., vascular fragility). Further family history was notable for endometrial adenocarcinoma in her mother and sister.\n\nDuring the trial, she remained stable neurologically. Towards the end of the trial she developed a skin lesion on the left shoulder, which was biopsied and diagnosed as sebaceous adenoma.\n\nThis diagnosis taken together with her family history of endometrial cancer raised concerns about a diagnosis of Muir-Torre syndrome (MTS), which is a variant/subtype of Lynch syndrome [4]. Genetic testing showed that she was heterozygous for a constitutional pathogenic nonsense variant (p.(Lys537Ter) in the MSH2 gene. Screening for Lynch syndrome-related visceral malignancies was commenced. Soon after the end of the trial, where she had been allocated to the treatment arm (anti-IL-12 antibody), she was assessed for and confirmed as having endometrial carcinoma and hospitalized for hysterectomy and bilateral salpingo-oophorectomy. She suffered massive bleeding with hypovolemic shock during surgery. Excessive vascular fragility attributed to her EDS was noted during the surgery. After two severe MS relapses within 6 months, therapeutic choices were considered in multidisciplinary discussions. Beta-interferon and glatiramer acetate were avoided because of severe bruising with frequent injections. Immunosuppressants and natalizumab were ruled out in view of increased risk of MTS-associated malignancies during immunosuppression [5].\n\nIVIg was considered the safest option, and the treatment was approved by the hospital’s IVIg panel committee.\n\nDue to vein fragility, a porta-cath was placed, and she was started on IVIg, 0.4 g/kg, one infusion every month for the first 2 years and then every 2 months subsequently. She had no further relapses for 3.5 years while being on IVIg except a short episode of oscillopsia lasting about 3 weeks, which resolved spontaneously. The MRI scan of the brain at that time did not show any new or acute lesions. She continued on IVIg with no relapses, no side effects and minimal disease progression (0.5 EDSS step) for a further 7 years. The frequency of UTI dropped to almost none during the IVIg treatment. She underwent routine periodic screening for malignancies throughout this period and did not develop new malignancy indicating the potential role of IVIg as an anti-cancer therapy [6, 7].\n\nAfter 10 years, because of the global shortage of IVIg, the treatment was discontinued. After some deliberations, the patient agreed to start the fortnightly preparation of pegylated interferon beta 1-a (Plegridy®) in view of the low frequency of administration. After persevering for 6 months despite bruising at the injection site and low mood, she had increased suicidal ideation and hence stopped the interferon treatment. Two months later, she had a severe relapse with paraplegia requiring hospitalization and intravenous steroids. After her recovery, ocrelizumab, a B cell-depleting agent, was initiated. Five months after the first infusion, she was diagnosed with caecal carcinoma during a routine surveillance colonoscopy.\n\nShe underwent colectomy (with extensive precautions to prevent bleeding) with a stoma placement. In the post-operative period, she experienced a further significant relapse presenting with severe weakness and cerebellar dysfunction. She is currently rehabilitating, though not completely returned to her preoperative baseline. A reinstitution of IVIg has been requested and awaits approval.\n\nDiscussion\n\nWe report a unique case of a patient with active RRMS who experienced significant relapses off treatment that were all but abolished during treatment with IVIg. In this case we had no choice but to give IVIg because of her coexisting conditions barring her from regular injectable drugs and immunosuppressive treatment.\n\nDue to the increasing number and efficacy of therapeutic agents for MS, in addition to the global shortage, IVIg is no longer advocated as a treatment for MS. However, aside from these considerations, the body of evidence for IVIg is substantial. A meta-analysis by Sorensen et al. [8] combined four studies to assess the efficacy of IVIg in RRMS in a randomized, placebo-controlled manner. The study showed a significant beneficial effect on the annual relapse rate (effect size − 0.5; P = 0.00003) on the proportion of relapse-free patients (0.29 difference; P = 2.1 × 10–8), change in the Expanded Disability Status Scale (EDSS) (effect size: 0.25; P = 0.04) and a trend towards a reduction in the proportion of patients who deteriorated (P = 0.03). Each single study in the meta-analysis had its weaknesses, but all studies were positive regarding their primary end point, and the results yield concordant evidence for reduction of the relapse rate and progression [8].\n\nAnother meta-analysis by Olayeemanesh et al. [9] combined six studies using a parallel-group design. The pooled results revealed significant differences in the number of relapses experienced on an annual basis in favour of IVIg (SMD = − 0.218; 95% CI − 0.412 to − 0.024; P = 0.028) [9].\n\nEhlers-Danlos syndrome is not commonly associated with neurological manifestations. The most common are vascular features, such as aneurysm, subarachnoid haemorrhage and spontaneous arterial dissection. Various congenital malformations of the vessels and the brain parenchyma have been reported along with symptomatic and idiopathic epilepsy [10, 11]. Our case series of four patients with MS and EDS showed joint laxity as the most prominent feature [12]. There have been case reports of EDS and leukodystrophy [13]. Extracellular matrix (ECM) proteins play an important role in CNS inflammation and myelination, endothelial lining, binding of soluble cytokines and adhesion of inflammatory cells, cellular migration and organization [14]. There is a suspicion that abnormalities in ECM protein can increase the susceptibility to autoimmune conditions [15]. Health care professionals need to be aware of several management issues in patients with MS and EDS such as increased risk of joint dislocation or arterial dissection during active physiotherapy [12].\n\nAlso, in this case due to EDS the skin can be very fragile and easily bruised, which would make any vascular access difficult. The patient was deemed unsuitable for subcutaneous injectable disease-modifying treatment because of skin fragility. Notably, there is a case series of two patients who had hypermobile EDS and MS/NMOSD-like CNS manifestations that were responsive to corticosteroids and plasmapheresis treatment. The authors found paraplegia more reversible in this category of patients compared to MS/NMOSD following immunotherapy [16].\n\nMuir-Torre syndrome (MTS), an autosomal dominant condition caused by mutations in the mismatch repair genes, often MSH2, is part of the spectrum of Lynch syndrome (formerly called hereditary nonpolyposis colorectal cancer) that in addition presents sebaceous tumors including sebaceous adenoma. The onset of these tumors has been shown to be triggered or unmasked by immunocompromised states, either through pharmacological immunosuppression or through acquired immunodeficiency [5, 17, 18]. Once such a tumor is diagnosed, screening for visceral malignancies (colorectal and genito-urinary) and suspicion of MTS is essential. Avoidance of immunosuppressive therapies is also important.\n\nAn argument has been made for implementing immuno-interception using immune checkpoint inhibitors in MTS, following a report of a successful immuno-interception in a patient with 136 cutaneous and visceral tumours [19]. However, immune checkpoint inhibitors have been associated with a number of autoimmune neurological syndromes and can cause severe, even fatal, exacerbations of MS [20].\n\nIn our patient, it is tempting to speculate that IVIg, in addition to its sustained and thorough control of MS disease activity, may have also provided effective immuno-interception. The anti-tumor and anti-metastatic effect of IVIg has been recognized, and the occurrence of colon cancer after discontinuation of a 10-year-long course of IVIg may represent cessation of immuno-interception, more likely than an immunosuppressive effect of ocrelizumab, given that the patient only had one course of this drug.\n\nIn conclusion, despite the restrictions in the use of IVIg due to its globally reduced availability, this unique case illustrates a multitude of beneficial effects that warrant its continued use as a rare clinically indicated exception.\n\nAcknowledgements\n\nFunding\n\nNo funding or sponsorship was received for this study or publication of this article.\n\nAuthorship\n\nAll named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.\n\nDisclosures\n\nSrishti Gupta and Mohnish Suri have nothing to disclose. Cris S Constantinescu is an editorial board member for this journal.\n\nCompliance with Ethics Guidelines\n\nA written consent was obtained from the patient for the case to be published anonymously.\n\nData Availability\n\nThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nOpen Access\n\nThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.\n\nDigital Features\n\nTo view digital features for this article go to 10.6084/m9.figshare.12759788.\n==== Refs\nReferences\n\n1. Haas J High dose IVIG in the post partum period for prevention of exacerbations in MS Mult Scler 2000 6 Suppl 2 S18 S20 10.1177/135245850000602S05 11188773\n2. Tallantyre EC Whittam DH Jolles S Secondary antibody deficiency: a complication of anti-CD20 therapy for neuroinflammation J Neurol 2018 265 5 1115 1122 10.1007/s00415-018-8812-0 29511864\n3. Vollmer TL Wynn DR Alam MS Valdes J A phase 2, 24-week, randomized, placebo-controlled, double-blind study examining the efficacy and safety of an anti-interleukin-12 and -23 monoclonal antibody in patients with relapsing-remitting or secondary progressive multiple sclerosis Mult Scler 2011 17 2 181 191 10.1177/1352458510384496 21135022\n4. Shalin SC Lyle S Calonje E Sebaceous neoplasia and the Muir-Torre syndrome: important connections with clinical implications Histopathology 2010 56 1 133 147 10.1111/j.1365-2559.2009.03454.x 20055911\n5. Landis MN Davis CL Bellus GA Wolverton SE Immunosuppression and sebaceous tumors: a confirmed diagnosis of Muir-Torre syndrome unmasked by immunosuppressive therapy J Am Acad Dermatol 2011 65 1054 1058 10.1016/j.jaad.2010.08.003 21550136\n6. Tal S Yehuda S Uncovering the hidden potential of intravenous immunoglobulin as an anticancer therapy Clin Rev Allergy Immunol 2005 29 307 310 10.1385/CRIAI:29:3:307 16391406\n7. Xu Q Zhang Z Chen Z Nonspecific immunoglobulin G is effective in preventing and treating cancer in mice Cancer Manag Res 2019 11 2073 2085 10.2147/CMAR.S188172 30881131\n8. Sorensen PS Fazekas F Lee M Intravenous immunoglobulin G for the treatment of relapsing–remitting multiple sclerosis: a meta-analysis Eur J Neurol 2002 9 557 563 10.1046/j.1468-1331.2002.00501.x 12453069\n9. Olyaeemanesh A Rahmani M Goudarzi R Safety and effectiveness assessment of intravenous immunoglobulin in the treatment of relapsing-remitting multiple sclerosis: a meta-analysis Med J Islam Repub Iran 2016 30 336 27390706\n10. Jacome DE Epilepsy in Ehlers-Danlos syndrome Epilepsia 1999 40 467 473 10.1111/j.1528-1157.1999.tb00742.x 10219273\n11. Echaniz-Laguna A de Saint-Martin A Lafontaine AL Bilateral focal polymicrogyria in Ehlers-Danlos syndrome Arch Neurol 2000 57 123 127 10.1001/archneur.57.1.123 10634459\n12. Vilisaar J Harikrishnan S Suri M Constantinescu CS Ehlers-Danlos syndrome and multiple sclerosis: a possible association Mult Scler 2007 14 1 4\n13. Spranger S Spranger M Kirchhof K Ehlers-Danlos syndrome type VIII and leukodystrophy Am J Med Genet 1996 66 239 240 10.1002/(SICI)1096-8628(19961211)66:2<239::AID-AJMG23>3.0.CO;2-T 8958339\n14. Sobel RA The extracellular matrix in multiple sclerosis: an update Braz J Med Biol Res 2001 34 603 609 10.1590/S0100-879X2001000500007 11323746\n15. Gustafson A, Griswold B, Burchett ME, et al. Do abnormalities of extracellular matrix elements lead to autoimmune disorders? Unexpectedly high incidence of rheumatologic disorders in persons with Ehlers Danlos syndrome. In: Annual Meeting of the American Society of Human Genetics. New Orleans, Louisiana, 2006.\n16. Araki M Lin Y Ono H Application of immunotherapy for neurological manifestations in hypermobile Ehlers-Danlos syndrome Ther Adv Neurol Disord 2018 11 1 5 10.1177/1756286418793766\n17. Frantz S Greiner A Schoen C A sebaceous tumor in a patient with acquired immunodeficiency syndrome Eur J Med Res 2002 7 135 137 11953286\n18. Stone MS Duncan WC McGavran MH Torre's syndrome: exacerbation of cutaneous manifestations with immunosuppression J Am Acad Dermatol 1986 15 1001 10.1016/S0190-9622(86)70273-9\n19. Mancuso JG Foulkes WD Pollak MN Cancer immunoprevention: a case report raising the possibility of “immuno-interception” Cancer Prev Res 2020 13 4 351 356 10.1158/1940-6207.CAPR-19-0528\n20. Garcia CR Jayswal R Adams V Anthony LB Villano JL Multiple sclerosis outcomes after cancer immunotherapy Clin Transl Oncol 2019 21 10 1336 1342 10.1007/s12094-019-02060-8 30788836\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2193-6536", "issue": "9(2)", "journal": "Neurology and therapy", "keywords": "Ehlers-Danlos syndrome; IVIg; Muir-Torre syndrome; Multiple sclerosis", "medline_ta": "Neurol Ther", "mesh_terms": null, "nlm_unique_id": "101637818", "other_id": null, "pages": "605-610", "pmc": null, "pmid": "32780270", "pubdate": "2020-12", "publication_types": "D016428:Journal Article", "references": "5937879;21135022;2805836;21550136;30881131;12453069;27390706;10219273;10634459;8958339;11323746;11953286;30788836", "title": "Maintenance Intravenous Immunoglobulin Treatment for Multiple Sclerosis Coexisting with Ehlers-Danlos Syndrome and Muir-Torre Syndrome: A Case Study.", "title_normalized": "maintenance intravenous immunoglobulin treatment for multiple sclerosis coexisting with ehlers danlos syndrome and muir torre syndrome a case study" }

[ { "companynumb": "GB-BIOGEN-2020BI00914285", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OCRELIZUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RELAPSING-REMITTING MULTIPLE SCLEROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OCRELIZUMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PEGINTERFERON BETA-1A" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "125499", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RELAPSING-REMITTING MULTIPLE SCLEROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PLEGRIDY" } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Suicidal ideation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Injection site bruising", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Colon cancer", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Depressed mood", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GUPTA S, CONSTANTINESCU C, SURI M. MAINTENANCE INTRAVENOUS IMMUNOGLOBULIN TREATMENT FOR MULTIPLE SCLEROSIS COEXISTING WITH EHLERS-DANLOS SYNDROME AND MUIR-TORRE SYNDROME: A CASE STUDY.. 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MAINTENANCE INTRAVENOUS IMMUNOGLOBULIN TREATMENT FOR MULTIPLE SCLEROSIS COEXISTING WITH EHLERS DANLOS SYNDROME AND MUIR TORRE SYNDROME: A CASE STUDY.. NEUROL THER... ?:?.", "literaturereference_normalized": "maintenance intravenous immunoglobulin treatment for multiple sclerosis coexisting with ehlers danlos syndrome and muir torre syndrome a case study", "qualification": "1", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20200904", "receivedate": "20200904", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 18230815, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]

{ "abstract": "BACKGROUND\nApatinib is an oral tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2. It has been shown that apatinib is effective and safe for treatment of multiple solid tumors, including gastric cancer, liver cancer, non-small-cell lung cancer, and breast cancer. However, there is currently no consensus as to using Apatinib for the treatment of pleural synovial sarcoma, due to the rarity of primary pleural synovial sarcoma and lack of clinical studies as a consequence.\nWe reported here in the case of a 26-year-old Chinese woman diagnosed with pleural synovial sarcoma. She has undergone 2 surgeries, multiple regimens of chemotherapy and traditional Chinese medicine in other hospitals. Then the patient was admitted to our hospital with the compliant of chest pain and dyspnea. The medical history and available data supported the diagnosis of recurrence of pleural synovial sarcoma.\n\n\nRESULTS\nDue to the lack of efficacy of previous standard treatment, the patient was given apatinib and radiotherapy to relieve the symptoms. This patient achieved stable disease with apatinib at a dose of 500 mg/day. Her progression-free survival time was more than 7 months, and her overall survival was 8.5 months. Except for hand-foot syndrome, no grade 3 or 4 side effects were observed.\n\n\nCONCLUSIONS\nApatinib may thus be an option for treatment of advanced synovial sarcoma after failure of other treatments. However, further study is needed to determine the efficacy of apatinib in pleural synovial sarcoma.", "affiliations": "Department of Radiation Oncology, Hangzhou Cancer Hospital.;Department of Radiation Oncology, Hangzhou Cancer Hospital.;Department of Radiation Oncology, Hangzhou Cancer Hospital.;Department of Radiation Oncology, Hangzhou Cancer Hospital.;Hangzhou First People's Hospital, Affiliated to Zhejiang University, Hangzhou, Zhejiang, China.;Department of Radiation Oncology, Hangzhou Cancer Hospital.", "authors": "Chen|Sumei|S|;Zhang|Ke|K|;Wan|Xianqin|X|;Chen|Yuanyuan|Y|;Ma|Shenglin|S|;Deng|Qinghua|Q|", "chemical_list": "D047428:Protein Kinase Inhibitors; D011725:Pyridines; C553458:apatinib", "country": "United States", "delete": false, "doi": "10.1097/MD.0000000000018382", "fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 31861000MD-D-19-0077310.1097/MD.0000000000018382183825700Research ArticleClinical Case ReportThe use of apatinib in treating primary pleural synovial sarcoma A case reportChen Sumei MD, PhDaZhang Ke MD, PhDaWan Xianqin BSaChen Yuanyuan MD, PhDaMa Shenglin MDbDeng Qinghua BSa∗NA. a Department of Radiation Oncology, Hangzhou Cancer Hospitalb Hangzhou First People's Hospital, Affiliated to Zhejiang University, Hangzhou, Zhejiang, China.∗ Correspondence: Qinghua Deng, Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang 310002, China (e-mail: qinghuadeng69@163.com).12 2019 20 12 2019 98 51 e1838207 2 2019 31 10 2019 14 11 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nApatinib is an oral tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2. It has been shown that apatinib is effective and safe for treatment of multiple solid tumors, including gastric cancer, liver cancer, non-small-cell lung cancer, and breast cancer. However, there is currently no consensus as to using Apatinib for the treatment of pleural synovial sarcoma, due to the rarity of primary pleural synovial sarcoma and lack of clinical studies as a consequence.\n\nPatient concerns and diagnoses:\nWe reported here in the case of a 26-year-old Chinese woman diagnosed with pleural synovial sarcoma. She has undergone 2 surgeries, multiple regimens of chemotherapy and traditional Chinese medicine in other hospitals. Then the patient was admitted to our hospital with the compliant of chest pain and dyspnea. The medical history and available data supported the diagnosis of recurrence of pleural synovial sarcoma.\n\nInterventions and outcomes:\nDue to the lack of efficacy of previous standard treatment, the patient was given apatinib and radiotherapy to relieve the symptoms. This patient achieved stable disease with apatinib at a dose of 500 mg/day. Her progression-free survival time was more than 7 months, and her overall survival was 8.5 months. Except for hand-foot syndrome, no grade 3 or 4 side effects were observed.\n\nConclusions:\nApatinib may thus be an option for treatment of advanced synovial sarcoma after failure of other treatments. However, further study is needed to determine the efficacy of apatinib in pleural synovial sarcoma.\n\nKeywords\napatinibpleural synovial sarcomasoft tissue sarcomasVEGFR-2OPEN-ACCESSTRUE\n==== Body\n1 Introduction\nSynovial sarcomas are one subtype of soft tissue sarcomas accounting for approximately 1% of all adult malignancies.[1] Synovial sarcomas are rare and aggressive, and most commonly affect extremities near large joints in young adults. They also occur in other parts of the body, including head and neck, lung, pleura, mediastinum, mesentery, and intra-abdominal, and pelvic spaces. Primary pleural synovial sarcoma is extremely rare, with only about 40 cases reported so far since the disease was first documented by Gaertner in 1996.[2]\n\nThe 5-year survival rate for synovial sarcoma ranges from 0% to 88%.[3] Histologic subtype and grade, patient age, tumor size, location, clinical stage, vascular invasion, and pathologic resection margins are all significant prognosis predictors.[4,5] Because of its low incidence and the lack of clinical studies, there is currently no consensus as to the optimal therapy for pleural synovial sarcoma. Surgical resection is the only potentially curative treatment for localized pleural synovial sarcoma.[6] Unfortunately, by the time most patients are diagnosed, the disease is too advanced and opportunity for surgery is lost.[6] Moreover, even localized pleural synovial sarcomas have a high recurrence rate and usually become refractory to treatment.[7] The disease-free interval for pleural synovial sarcoma is 2 to 14 months after surgical resection. The benefits of adjuvant radiochemotherapy for primary synovial sarcoma of the pleura is unclear, since there are no randomized controlled trials.[8] A 5-year disease-free period after radical multidisciplinary therapy has been reported in 20.9% of cases.[9]\n\nAngiogenesis is a hallmark of solid tumors. Since Folkman put forward the idea of anti-tumor angiogenesis therapy, numerous drugs targeting vascular endothelial growth factors (VEGFs) or VEGF receptors (VEGFRs) have been explored.[10] For example, the VEGF-A antagonist bevacizumab has been successfully used for anti-tumor angiogenesis therapy in various types of cancers.[11–13] Apatinib is a novel, orally bioavailable small-molecule tyrosine kinase inhibitor selective for VEGFR-2, which has shown significant beneficial effects in the treatment of a variety of solid tumors including soft tissue sarcomas.[14–19] However, there is not any report of using apatibnib for the treatment of primary pleural synovial sarcoma. We herein report a case of primary pleural synovial sarcoma treated with apatinib after the failure of multiple therapies.\n\n2 Ethical statement and consent\nInformed written consent was obtained from the patient's elder sister for publication of this case report and accompanying images. Ethical committee approval was waived because of unnecessity. Since the information of this case was collected retrospectively after patient's decease, there was no adverse effect on the patient caused by this study.\n\n3 Case presentation\nA 26-year-old Chinese woman was admitted to the hospital in June 2011 because of repeated pneumothorax. Chest x-rays showed a right sided hydropneumothorax and an area of ill-defined soft tissue density in the lower half of the right lung. Computed tomography (CT) showed a nodule with the size of 4 × 4 centimeter (cm)2 in the right lower mediastinum. Exploratory thoracotomy was performed. The treatment process for this patient was shown in Figure 1.\n\nFigure 1 The treatment process for this patient.\n\nThe first radical resection pathological margin was negative, and the minimal resection margin was 5 cm. The postoperative pathological diagnosis was spindle cell synovial sarcoma with the following immunohistochemical features: CD99(+), vimentin (+), Bcl-2 (+), HBME1(−),WT-1 (+), TTF1(−), Napsin A (−), S-100 (−), CK (−), p16 (−), EMA (partly +), NSE (−), Chromogranin A (−). The patient failed to provide immunohistochemistry pictures. The patient received no postoperative chemotherapy or radiotherapy.\n\nOne year later, chest CT and Positron emission tomography/computed tomography (PET/CT) revealed recurrent tumors within the right chest. The chest CT was showed in Figure 2. She was again treated surgically in July 2012, and the pathological margin was negative, but the minimal resection margin was less than 5 cm. The postoperative pathological diagnosis was reoccurrence of synovial sarcoma with the following immunohistochemical features: CD99 (+), vimentin (+), WT-1 (+), CK (−), HBME1 (−), TTF1 (−), Napsin A (−), p16 (−), NSE (−), Chromogranin A (−), Bcl-2(+) (Fig. 3).\n\nFigure 2 Computed tomography showed that mass in the right pleura.\n\nFigure 3 An analysis of the surgical specimen revealed a spindle cell tumor (A and B). A: Hematoxylin and Eosin (H&E) staining (100 × ), A2: H&E staining (200 × ). The immunohistochemical staining was positive for Bcl-2 (C) and CD99 (D) and WT-1(E) and vimentin(F) (400X).\n\nThe SYT-SSX fusion gene is the hallmark of synovial sarcoma. Cytogenetic analysis and fluorescent in situ hybridization revealed chromosomal translocation at t(X;18)(p11.2;q11.2) (Fig. 4). During the following 4 years (2012–2016), the patient was administrated with multiple-line therapies, including chemotherapy, radiotherapy, Chinese medicine, and target therapy.\n\nFigure 4 Cytogenetic analysis and FISH resulted from the chromosomal translocation t(X;18)(p11.2;q11.2).\n\nSuffering with chest pain and dyspnea, the patient was admitted to our hospital in March 2016. Chest and abdominal CT revealed large masses in the lower right chest and extending to the liver, raising the possibility of metastasis there. We administered a total of 45Gy of intensity modulated radiation therapy, which made the symptoms disappear. But the patient refused systematic treatment and was discharged after completion of radiation therapy. The patient visited our hospital again with serious abdominal pain (NRS 7) and constipation fatigue in December 2016. Figure 5A shows the extensive soft tissue masses with heterogeneous density within the chest, abdominal, and pelvic regions. Tumor progressed after multiline treatment, there is no further standard treatment at present. After the patient provided written, informed consent, oral apatinib (500 mg/d) was administered on December 6, 2016. We also assessed expression of VEGFR-2, c-Ret, c-Src and c-Kit. Of those, VEGFR-2, c-Src and c-Kit were all overexpressed, while c-Ret was negative (Fig. 6). After 3 months of treatment (March 26, 2017), the abdominal and pelvic masses was slightly smaller, and the therapeutic evaluation was stable disease (SD) (Fig. 5B). After 6 months (July 10, 2017), the size of some of the masses had decreased further, and some of metastatic lesions were stable (Fig. 5C). Tumor density gradually decreased, and necrosis increased. The patient developed an outbreak of the tumor more than 7 months after taking apatinib. Since the patient's general condition after tumor progress was very poor, we did not escalate the dosage of apatinib. At last the patient gave up anticancer treatments. A progression-free survival time of more than 7 months was achieved, and overall survival was 8.5 months.\n\nFigure 5 Computed tomography showed huge masses in the right lower chest and pelvis before taking apatinib (A); Computed tomography showed the size of mass following treatment with apatinib of 500 mg daily for 3 months (B); Computed tomography showed the size of mass after taking apatinib for 6 months (C).\n\nFigure 6 Immunohistochmeistry showing expressions of VEGFR-2, c-Ret, c-Src, and c-Kit proteins (400X), the red arrows point at the positive protein.\n\nTreatment-related side effects were monitored every 2 weeks during the apatinib treatment. After 2 months, the patient experienced mainly non-hematological toxicities, including skin rash (grade 3), elevated transaminase (grade 1), and proteinuria (grade 1). Thrombocytopenia (grade 2) was detected after 3 months of apatinib treatment. These side effects were controlled with supportive treatment.\n\n4 Discussion\nAs far as we know, this is the first report of using apatinib to treat a patient with reoccurrence of pleural synovial sarcoma. Apatinib is a potent and selective multi-targeted receptor tyrosine-kinase inhibitor. Ji et al[20] reported a case of advanced malignant fibrous histiocytoma in which the patient treated with apatinib exhibited a partial response and progression-free survival for >6 months. They also reported a case of angiosarcoma in which apatinib provided 12 months of progression-free survival.[21] In our case, the patient achieved more than 7 months, progression-free survival time and 8.5 months overall survival. We initially increased the dose of apatinib from 250 mg/d to 850 mg/d gradually and stayed at the dose of 500 mg/d for XXX, which was well tolerated with the minor adverse effect of skin rash (grade 3), elevated transaminase (grade 1), proteinuria (grade 1) and thrombocytopenia (grade 2). These results indicate that apatinib may be a treatment option for patients with advanced synovial sarcoma.\n\nApatinib may thus be a useful new choice for patients with primary pleural synovial sarcomas. Apatinib (YN968D1, N-[4-(1-cyano-cyclopentyl) phenyl]-2-(4-pyridylmethyl) amino-3-pyridine carboxamide mesylate) is one of the latest orally antiangiogenic agents with attractive pre-clinical and clinical data on the treatment of various solid tumors. However, the exact molecular mechanism of the anticancer effects of apatinib for sarcomas is not well defined. As a small-molecule tyrosine kinase inhibitor, apatinib selectively binds to and strongly inhibits VEGFR-2. Angiogenesis is essential for the growth and progression of solid tumors, and inhibition of VEGF signaling, which plays a key role in angiogenesis, has been a promising anticancer approach. Moreover, VEGF signaling is regulated by a variety of activators and inhibitors,[22–24] which also represent potential targets for anti-angiogenesis therapy. VEGF promotes angiogenesis by stimulating vascular endothelial cells to migrate towards and into hypoxic zones within tumors while protecting them from apoptotic death during the migration.[24–26] VEGFRs (VEGFR-1, -2 and -3) are tyrosine kinases that function as key regulators of this process. VEGFR-2 promotes endothelial proliferation by activating signaling in the mitogen-activated protein kinase pathway during angiogenesis.[27] Overexpression of VEGF/VEGFRs increases the tumor cell proliferation and migration and metastasis. It is thought that by inhibiting VEGF binding to VEGFR-2 and the receptor's subsequent autophosphorylation, apatinib suppresses endothelial cell proliferation, and angiogenesis.[28] It may also inhibit VEGFR-2-mediated down stream phosphorylation of extracellular signal-regulated kinase (ERK), resulting in antiangiogenic and anticancer effects.[28] VEGFR-2 level in the tumor tissue of our patient was overexpressed, which might be the main reason for the anticancer effect of apatinib.\n\nIn addition, Tian et al[29] observed that apatinib impaired VEGF-stimulated proliferation, migration and tube formation by human umbilical vein endothelial cells, and blocked rat aortic ring budding in vitro, which may be associated with suppression of VEGFR-2-mediated phosphorylation of Ret, c-kit and c-src. We also tested expression of Ret, c-Src and c-Kit and found that c-Src and c-Kit were overexpressed in our patient. These overexpressed proteins may be related to anticancer effect of apatinib. In other words, VEGFR-2, Ret and c-kit may account for the positive result in our patient.\n\nOne major challenge to conventional antineoplastic drug therapy is multidrug resistance (MDR), which greatly decreases the efficacy of cancer chemotherapy. Mi et al[30] demonstrated that apatinib increases the effect of paclitaxel against ABCB1 resistant cancer cell xenografts in nude mice. This team also tested whether apatinib would enhance the anticancer effect of doxorubicin on side population phenotype cells and ABCB1-overexpressing MDR leukemia cells by directly suppressing the drug transport function of ABCB1 and increasing the intracellular concentrations of substrate chemotherapeutic drugs.[31] In addition, another study showed that apatinib may restore the sensitivity of lung cancer cells to cisplatin by downregulating MDR1 and inhibiting the activities of proteins in the ERK signaling pathway.[32] In preclinical trials, the synergistic antitumor effect of apatinib was further assessed in combination with docetaxel or doxorubicin and oxaliplatin or 5-FU.[29] However, the ability of apatinib to reverse resistance to cytotoxic chemotherapy agents has not been fully studied in clinical trials.\n\n5 Conclusions\nIn summary, this case report suggests apatinib might be effective for the treatment of primary pleural synovial sarcomas. However, the observed beneficial effect should be verified in further clinical trials. The efficacy of apatinib against other sarcoma subtypes should also be tested.\n\nAuthor contributions\nConceptualization: Shenglin Ma, Qinghua Deng.\n\nProject administration: Sumei Chen.\n\nSupervision: Shenglin Ma, Qinghua Deng.\n\nWriting – original draft: Sumei Chen.\n\nWriting – review & editing: Ke Zhang, Xianqin Wan, Yuanyuan Chen, Qinghua Deng.\n\nAbbreviations: cm = centimeter, CT = computed tomography, ERK = extracellular signal-regulated kinase, MDR = multidrug resistance, mg = milligram, PET/CT = positron emission tomography/computed tomography, SD = stable disease, VEGFRs = vascular endothelial growth factor receptors, VEGFs = vascular endothelial growth factors.\n\nHow to cite this article: Chen S, Zhang K, Wan X, Chen Y, Ma S, Deng Q. The use of apatinib in treating primary pleural synovial sarcoma: A case report. Medicine. 2019;98:51(e18382).\n\nThis study was supported by Scientific research funds of Zhejiang Province Health Department (Grant no. 2017ky532) General project of Hangzhou Science and Technology Bureau China (Grant no. 20170533B96).\n\nInformed written consent was obtained from the patient's elder sister for publication of this case report and accompanying images.\n\nThe authors report no conflicts of interest.\n==== Refs\nReferences\n[1] Siegel RL Miller KD Jemal A \nCancer statistics, 2016 . CA Cancer J Clin \n2016 ;66 :7 –30 .26742998 \n[2] Gaertner E Zeren EH Fleming MV \nBiphasic synovial sarcomas arising in the pleural cavity. A clinicopathologic study of five cases . Am J Surg Pathol \n1996 ;20 :36 –45 .8540607 \n[3] Hartstein ME Silver FL Ludwig OJ \nPrimary synovial sarcoma . Ophthalmology \n2006 ;113 :2093 –6 .17074567 \n[4] Nojima T \nClassification of soft tissue tumors and current approach to pathologic diagnosis . 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BMC Cancer \n2010 ;10 :529 .20923544 \n[15] Zhang L Shi M Huang C \nA phase II, multicenter, placebo-controlled trial of apatinib in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) after two previous treatment regimens . J Clin Oncol \n2012 ;30 :7548 .\n[16] Li J Qin S Xu J \nApatinib for chemotherapy-refractory advanced metastatic gastric cancer: results from a randomized, placebo-controlled, parallel-arm, phase II trial . J Clin Oncol \n2013 ;31 :3219 –25 .23918952 \n[17] Qin S \nPhase III study of apatinib in advanced gastric cancer: a ran-domized, double-blind, placebo-controlled trial . J Clin Oncol \n2014 ;32 :Abst4003 .\n[18] Hu X Zhang J Xu B \nMulticenter phase II study of apatinib, a novel VEGFR inhibitor in heavily pretreated patients with metastatic triple-negative breast cancer . Int J Cancer \n2014 ;135 :1961 –9 .24604288 \n[19] Hu X Cao J Hu W \nMulticenter phase II study of apatinib in non-triple-negative metastatic breast cancer . BMC Cancer \n2014 ;14 :820 .25376790 \n[20] Ding L Li QJ You KY \nThe use of apatinib in treating non-small-cell lung cancer case report and review of literature . Medicine \n2016 ;95 :e3598 .27196461 \n[21] Ji G Hong L Yang P \nSuccessful treatment of advanced malignant fibrous histiocytoma of the right forearm with apatinib: a case report . Onco Targets Ther \n2016 ;643 –7 .26917971 \n[22] Bergers G Benjamin LE \nTumorigenesis and the angiogenic switch . Nat Rev Cancer \n2003 ;3 :401 –10 .12778130 \n[23] Cao Y \nTumor angiogenesis and therapy . Biomed Pharmacother \n2005 ;59 :S340 –343 .16507405 \n[24] Trapp V Parmakhtiar B Papazian V \nAnti-angiogenic effects of resveratrol mediated by decreased VEGF and increased TSP1 expression in melanoma- endothelial cell co-culture . Angiogenesis \n2010 ;13 :305 –15 .20927579 \n[25] Darland DC D’Amore PA \nBlood vessel maturation: vascular development comes of age . J Clin Invest \n1999 ;103 :157 –8 .9916126 \n[26] Neufeld G Cohen T Gengrinovitch S \nVascular endothelial growth factor (VEGF) and its receptors . FASEB J \n1999 ;13 :9 –22 .9872925 \n[27] Ding J Chen X Dai X \nSimultaneous determination of apatinib and its four major metabolites in human plasma using liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic study . J Chromatogr B Analyt Technol Biomed Life Sci \n2012 ;895-896 :108 –15 .\n[28] Scott AJ Messersmith WA Jimeno A \nApatinib: a promising oral antiangiogenic agent in the treatment of multiple solid tumors . Drugs of today (Barcelona, Spain: 1998) \n2015 ;51 :223 –9 .\n[29] Tian S Quan H Xie C \nYN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase with potent activity in vitro and in vivo . Cancer Sci \n2011 ;102 :1374 –80 .21443688 \n[30] Mi YJ Liang YJ Huang HB \nApatinib (YN968D1) reverses multidrug resistance by inhibiting the efflux function of multiple ATP-binding cassette transporters . Cancer Res \n2010 ;70 :7981 –91 .20876799 \n[31] Tong XZ Wang F Liang S \nApatinib (YN968D1) enhances the efficacy of conventional chemotherapeutical drugs in side population cells and ABCB1-overexpressing leukemia cells . Biochem Pharmacol \n2012 ;83 :586 –97 .22212563 \n[32] Liu ZL Jin BJ Cheng CG \nApatinib resensitizes cisplatin-resistant non-small cell lung carcinoma A549 cell through reversing multidrug resistance and suppressing ERK signaling pathway . Eur Rev Med Pharmacol Sci \n2017 ;21 :5370 –7 .29243778\n\n", "fulltext_license": "CC BY", "issn_linking": "0025-7974", "issue": "98(51)", "journal": "Medicine", "keywords": null, "medline_ta": "Medicine (Baltimore)", "mesh_terms": "D000328:Adult; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D010997:Pleural Neoplasms; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D018714:Radiotherapy, Adjuvant; D016879:Salvage Therapy; D013584:Sarcoma, Synovial", "nlm_unique_id": "2985248R", "other_id": null, "pages": "e18382", "pmc": null, "pmid": "31861000", "pubdate": "2019-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "4600889;23918952;9872925;27196461;22212563;9916126;17074567;26020064;16507405;20876799;10371121;15364967;19773229;8540607;12778130;25376790;21443688;17167137;15175435;21643637;29243778;18160686;26917971;15725802;20923544;20496763;24604288;20927579;22503745;26742998", "title": "The use of apatinib in treating primary pleural synovial sarcoma: A case report.", "title_normalized": "the use of apatinib in treating primary pleural synovial sarcoma a case report" }

[ { "companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-231903", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "22534", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Synovial sarcoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201309", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GEMCITABINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Synovial sarcoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201309", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE" } ], "patientagegroup": null, "patientonsetage": "26", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Chen S, Zhang K, Wan X, Chen Y, Ma S, Deng Q. The use of apatinib in treating primary pleural synovial sarcoma: A case report. Medicine. 2019;98(51):e18382", "literaturereference_normalized": "the use of apatinib in treating primary pleural synovial sarcoma a case report", "qualification": "1", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20220127", "receivedate": "20200110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17255892, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" } ]

{ "abstract": "Visceral leishmaniasis is a severe disease caused by protozoan parasites that include Leishmania (L.) infantum. The disease is established when parasites subvert the immune response of the host. Notably, chemotherapy-based use of antimonial compounds can partially alleviate disease burden. Unfortunately, the resistance to drug treatments is increasing in areas endemic to the disease. In this report, we investigated immune responses within macrophages infected with antimony-resistant L. infantum isolates from patients with a relapse in the disease. Results revealed that antimony-resistant parasites persist in the first 24 h of infection. Activation of macrophage or blocking of thiol production during infection shows enhanced clearance of parasites, which is coordinately associated with increased production of pro-inflammatory cytokines. Taken together, these results suggest that the mechanism of antimony resistance in L. infantum isolates may be related to a decrease in macrophage microbicidal functions.", "affiliations": "Laboratory of Molecular Biology and Immunology, Federal University of Sergipe, Aracaju, Brazil.;Health Sciences Graduate Program, Federal University of Sergipe, Aracaju, Brazil.;Health Sciences Graduate Program, Federal University of Sergipe, Aracaju, Brazil.;Health Sciences Graduate Program, Federal University of Sergipe, Aracaju, Brazil.;Department of Health Education, Federal University of Sergipe, Lagarto, Brazil.;Department of Biology, Howard University, Washington, D.C., USA.;Health Sciences Graduate Program, Federal University of Sergipe, Aracaju, Brazil.;Health Sciences Graduate Program, Federal University of Sergipe, Aracaju, Brazil.;Health Sciences Graduate Program, Federal University of Sergipe, Aracaju, Brazil. tmoura.ufs@gmail.com.", "authors": "Magalhães|Lucas Sousa|LS|;Bomfim|Lays Gisele Santos|LGS|;Santos|Camilla Natália Oliveira|CNO|;Dos Santos|Priscila Lima|PL|;Tanajura|Diego Moura|DM|;Lipscomb|Michael Wheeler|MW|;de Jesus|Amélia Ribeiro|AR|;de Almeida|Roque Pacheco|RP|;de Moura|Tatiana Rodrigues|TR|", "chemical_list": "D000077485:Meglumine Antimoniate; D000965:Antimony", "country": "Germany", "delete": false, "doi": "10.1007/s00436-021-07231-7", "fulltext": null, "fulltext_license": null, "issn_linking": "0932-0113", "issue": "120(8)", "journal": "Parasitology research", "keywords": "Leishmania infantum; Macrophages; Meglumine antimoniate; Visceral leishmaniasis", "medline_ta": "Parasitol Res", "mesh_terms": "D000965:Antimony; D004351:Drug Resistance; D006801:Humans; D018314:Leishmania infantum; D007896:Leishmaniasis; D008264:Macrophages; D000077485:Meglumine Antimoniate", "nlm_unique_id": "8703571", "other_id": null, "pages": "2959-2964", "pmc": null, "pmid": "34272999", "pubdate": "2021-08", "publication_types": "D016428:Journal Article", "references": "17244793;30126638;21936800;24096610;26481489;19633606;10489835;11181934;31473855;22845426;10929144;2335376;23749230;16719806;29236925;12061835;23341611;26283478;8816809;7883967;29240765;29294040;22580230", "title": "Antimony resistance associated with persistence of Leishmania (Leishmania) infantum infection in macrophages.", "title_normalized": "antimony resistance associated with persistence of leishmania leishmania infantum infection in macrophages" }

[ { "companynumb": "BR-ASTELLAS-2015US041262", "fulfillexpeditecriteria": "1", "occurcountry": "BR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMPHOTERICIN B" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "50740", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Injection", "drugdosagetext": "UNK, UNKNOWN FREQ.", "drugenddate": null, "drugenddateformat": null, "drugindication": "Visceral leishmaniasis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMPHOTERICIN B" } ], "patientagegroup": null, "patientonsetage": "65", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Splenectomy", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Therapeutic product effect incomplete", "reactionmeddraversionpt": "24.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "Magalhaes, L, Bomfim L, Santos C, Santos P, Tanajura, D, Lipscomb M, et al... Antimony resistance associated with persistence of Leishmania (Leishmania) infantum infection in macrophages.. Parasitology Research. 2021;120:2959-2964", "literaturereference_normalized": "antimony resistance associated with persistence of leishmania leishmania infantum infection in macrophages", "qualification": "3", "reportercountry": "BR" }, "primarysourcecountry": "BR", "receiptdate": "20211231", "receivedate": "20151106", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11704304, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" } ]

{ "abstract": "BACKGROUND\nRecreational drug toxicity is frequent. Availability of new psychoactive substances is steadily increasing. However, data with verified analyses from clinical settings are limited. To evaluate the impact of novel psychoactive substances (NPS) on recreational drug toxicity in Oslo, Norway, we analysed samples from a selection of patients.\n\n\nMETHODS\nAll the patients presenting with recreational drug toxicity at the Oslo Accident and Emergency Outpatient Clinic (OAEOC) and at the Oslo University Hospital (OUH) were registered from April through September 2014. Oral fluid samples were collected at the OAEOC. Blood samples were collected at the OUH. The samples were screened using ultra-high performance liquid chromatography - tandem mass spectrometry (UHPLC-MS/MS).\n\n\nRESULTS\nNine hundred and sixty-four cases were included, 841 (87.2%) at the OAEOC and 123 (12.8%) at the OUH. A total of 55 oral fluid samples (OAEOC) and 103 blood samples (OUH) could be analysed. NPS were not clinically suspected in any of the screened cases. At the outpatient clinic, the most commonly found substances were clonazepam in 42/55 (76.4%) cases, amfetamines in 40/55 (72.7%) and heroin in 39/55 (70.9%). In seven (12.7%) cases NPS were detected: 4-methylamfetamine in three cases, dimethyltryptamine in two, methylone in one, and N,N-dimethyl-3,4-methylenedioxyamfetamine in one. Among the hospital patients, the most commonly found substances were clonazepam in 51/103 (49.5%) cases, amfetamines in 48/103 (46.6%), heroin in 31/103 (30.1%), and diazepam in 30/103 (29.1%). In five (4.9%) cases NPS were detected: JWH-210 in two cases, AM-2201 in two, and 5-EAPB in one.\n\n\nCONCLUSIONS\nNPS were clinically not suspected, though found in eight percent of cases. Still, the vast majority of patients treated for recreational drug toxicity in Oslo have taken classical drugs. Management of these patients should be based on their clinical condition. However, it is highly important to be alert to atypical presentations possibly resulting from unsuspected drugs.", "affiliations": "a Department of General Practice , University of Oslo , Oslo , Norway.;c Department of Acute Medicine , Oslo University Hospital , Oslo , Norway.;d Department of Forensic Sciences , Oslo University Hospital , Oslo , Norway.;d Department of Forensic Sciences , Oslo University Hospital , Oslo , Norway.;f The Norwegian CBRNe Centre of Medicine, Department of Acute Medicine , Oslo University Hospital , Oslo , Norway.;f The Norwegian CBRNe Centre of Medicine, Department of Acute Medicine , Oslo University Hospital , Oslo , Norway.", "authors": "Vallersnes|Odd Martin|OM|http://orcid.org/0000-0003-1213-392X;Persett|Per Sverre|PS|;Øiestad|Elisabeth Leere|EL|;Karinen|Ritva|R|;Heyerdahl|Fridtjof|F|;Hovda|Knut Erik|KE|", "chemical_list": "D013287:Illicit Drugs; D011619:Psychotropic Drugs", "country": "England", "delete": false, "doi": "10.1080/15563650.2017.1312002", "fulltext": null, "fulltext_license": null, "issn_linking": "1556-3650", "issue": "55(7)", "journal": "Clinical toxicology (Philadelphia, Pa.)", "keywords": "Poisoning; laboratory confirmation; novel psychoactive substances; overdose; recreational drugs", "medline_ta": "Clin Toxicol (Phila)", "mesh_terms": "D000328:Adult; D002851:Chromatography, High Pressure Liquid; D064790:Clinical Laboratory Services; D003430:Cross-Sectional Studies; D062787:Drug Overdose; D004636:Emergency Service, Hospital; D005260:Female; D006785:Hospitals, University; D006801:Humans; D013287:Illicit Drugs; D008297:Male; D009664:Norway; D011041:Poisoning; D011237:Predictive Value of Tests; D011619:Psychotropic Drugs; D015203:Reproducibility of Results; D012189:Retrospective Studies; D015813:Substance Abuse Detection; D053719:Tandem Mass Spectrometry", "nlm_unique_id": "101241654", "other_id": null, "pages": "636-644", "pmc": null, "pmid": "28406320", "pubdate": "2017-08", "publication_types": "D016428:Journal Article; D016448:Multicenter Study", "references": null, "title": "Underestimated impact of novel psychoactive substances: laboratory confirmation of recreational drug toxicity in Oslo, Norway.", "title_normalized": "underestimated impact of novel psychoactive substances laboratory confirmation of recreational drug toxicity in oslo norway" }

[ { "companynumb": "PHHY2017NO121964", "fulfillexpeditecriteria": "1", "occurcountry": "NO", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMPHETAMINE" }, "drugadditional": "3", "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": "AMPHETAMINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "74925", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBSTANCE USE", "drugintervaldosagedefinition": null, "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": "4-HYDROXYBUTANOIC ACID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBSTANCE USE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GAMMA-HYDROXYBUTYRATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DIAMORPHINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBSTANCE USE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEROIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FENTANYL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBSTANCE USE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL." } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Heart rate decreased", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional product misuse", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Body temperature decreased", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Coma scale abnormal", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Respiratory rate decreased", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VALLERSNESA OM, PERSETT PS, OIESTAD EL, KARINEN R, HEYERDAHL F, HOVDA KE.. UNDERESTIMATED IMPACT OF NOVEL PSYCHOACTIVE SUBSTANCES: LABORATORY CONFIRMATION OF RECREATIONAL DRUG TOXICITY IN OSLO, NORWAY. CLINICAL TOXICOLOGY. 2017;55 (7):636-44", "literaturereference_normalized": "underestimated impact of novel psychoactive substances laboratory confirmation of recreational drug toxicity in oslo norway", "qualification": "3", "reportercountry": "NO" }, "primarysourcecountry": "NO", "receiptdate": "20170831", "receivedate": "20170824", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13903156, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "NO-JNJFOC-20170810711", "fulfillexpeditecriteria": "1", "occurcountry": "NO", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBSTANCE USE", "drugintervaldosagedefinition": null, "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": "DIAMORPHINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBSTANCE USE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEROIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "4-HYDROXYBUTANOIC ACID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBSTANCE USE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GAMMA-HYDROXYBUTYRATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FENTANYL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "019813", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBSTANCE USE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL." } ], "patientagegroup": "5", "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Respiratory rate decreased", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Coma scale abnormal", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Heart rate decreased", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Body temperature decreased", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional product misuse", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VALLERSNESA OM, PERSETT PS, OIESTAD EL, KARINEN R, HEYERDAHL F, HOVDA KE. UNDERESTIMATED IMPACT OF NOVEL PSYCHOACTIVE SUBSTANCES: LABORATORY CONFIRMATION OF RECREATIONAL DRUG TOXICITY IN OSLO, NORWAY. CLINICAL TOXICOLOGY 2017;55 (7):636-644 .", "literaturereference_normalized": "underestimated impact of novel psychoactive substances laboratory confirmation of recreational drug toxicity in oslo norway", "qualification": "1", "reportercountry": "NO" }, "primarysourcecountry": "NO", "receiptdate": "20170816", "receivedate": "20170816", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13873880, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "NO-BIODELIVERY SCIENCES INTERNATIONAL-2017BDSI0163", "fulfillexpeditecriteria": "1", "occurcountry": "NO", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DIAMORPHINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBSTANCE USE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEROIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBSTANCE USE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "4-HYDROXYBUTANOIC ACID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBSTANCE USE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GAMMA-HYDROXYBUTYRATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FENTANYL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "022266", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBSTANCE USE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL." } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Respiratory rate decreased", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Coma scale abnormal", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Heart rate decreased", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional product misuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Body temperature decreased", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VALLERSNESA O, PERSETT P, OIESTAD E, KARINEN R, HEYERDAHL F, HOVDA K. UNDERESTIMATED IMPACT OF NOVEL PSYCHOACTIVE SUBSTANCES: LABORATORY CONFIRMATION OF RECREATIONAL DRUG TOXICITY IN OSLO, NORWAY. CLINICAL TOXICOLOGY. 2017?55(7):636-644.", "literaturereference_normalized": "underestimated impact of novel psychoactive substances laboratory confirmation of recreational drug toxicity in oslo norway", "qualification": "1", "reportercountry": "NO" }, "primarysourcecountry": "NO", "receiptdate": "20190314", "receivedate": "20190314", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 16074661, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "NO-TEVA-798935ACC", "fulfillexpeditecriteria": "1", "occurcountry": "NO", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "4-HYDROXYBUTANOIC ACID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBSTANCE USE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GAMMA-HYDROXYBUTYRATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBSTANCE USE", "drugintervaldosagedefinition": null, "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": "DIAMORPHINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBSTANCE USE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEROIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FENTANYL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "020747", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBSTANCE USE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL." } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Heart rate decreased", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional product misuse", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Body temperature decreased", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Coma scale abnormal", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Respiratory rate decreased", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VALLERSNESA O,PERSETT P,OIESTAD E,KARINEN R,HEYERDAHL F,HOVDA K. UNDERESTIMATED IMPACT OF NOVEL PSYCHOACTIVE SUBSTANCES: LABORATORY CONFIRMATION OF RECREATIONAL DRUG TOXICITY IN OSLO, NORWAY. CLINICAL TOXICOLOGY 2017;55 (7):636-644 .. 2017 JAN 01;55 (7):636-644.", "literaturereference_normalized": "underestimated impact of novel psychoactive substances laboratory confirmation of recreational drug toxicity in oslo norway", "qualification": "1", "reportercountry": "NO" }, "primarysourcecountry": "NO", "receiptdate": "20170901", "receivedate": "20170823", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13896071, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" } ]

{ "abstract": "OBJECTIVE\nTo evaluate the clinical response to Tocilizumab (TCZ) in three patients with non-infectious uveitis refractory to anti-TNF-α drugs.\n\n\nMETHODS\nAssessment of TCZ-treated patients with immune-mediated uveitis from two Spanish medical referral centers. Uveitis had been refractory to previous standard synthetic immunosuppressive drugs and at least one TNF-α inhibitor. A literature review of patients with immune-mediated uveitis treated with TCZ therapy was also conducted.\n\n\nRESULTS\n3 women (5 eyes) with uveitis refractory to conventional immunosuppressive therapy and at least one anti-TNF-α drug were treated with TCZ. The mean age of the patients was 48.6±16.1 (range 37-67) years. In two cases uveitis was bilateral and in the other unilateral. The underlying diseases were rheumatoid arthritis in one case and Behçet's disease in the other two cases. After a mean follow-up of 7.3±5.7 (range 1-12) months using TCZ therapy, all patients experienced ocular improvement. Also, in 3 eyes inactive intraocular inflammation was achieved. None of the patients had side effects during the period of treatment with this drug. A literature review disclosed that our observations are in keeping with other reports that showed good response to TCZ in 11 of 12 patients with immune-mediated uveitis refractory to other biologic agents.\n\n\nCONCLUSIONS\nTCZ appears to be an effective and safe therapy for the management of patients with uveitis refractory to other biologic drugs.", "affiliations": "Division of Rheumatology, Hospital Universitario Marqués de Valdecilla, IFIMAV, Santander, Spain. fiorelfa@hotmail.com.", "authors": "Calvo-Río|Vanesa|V|;de la Hera|David|D|;Beltrán-Catalán|Emma|E|;Blanco|Ricardo|R|;Hernandez|Marisa|M|;Martínez-Costa|Lucía|L|;Loricera|Javier|J|;Cañal|Joaquín|J|;Ventosa|Juan|J|;Ortiz-Sanjuán|Francisco|F|;Pina|Trinitario|T|;González-Vela|M Carmen|MC|;Rodríguez-Cundín|Paz|P|;González-Gay|Miguel A|MA|", "chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D007166:Immunosuppressive Agents; C502936:tocilizumab", "country": "Italy", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0392-856X", "issue": "32(4 Suppl 84)", "journal": "Clinical and experimental rheumatology", "keywords": null, "medline_ta": "Clin Exp Rheumatol", "mesh_terms": "D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D004351:Drug Resistance; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D016896:Treatment Outcome; D014605:Uveitis", "nlm_unique_id": "8308521", "other_id": null, "pages": "S54-7", "pmc": null, "pmid": "25005576", "pubdate": "2014", "publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review", "references": null, "title": "Tocilizumab in uveitis refractory to other biologic drugs: a study of 3 cases and a literature review.", "title_normalized": "tocilizumab in uveitis refractory to other biologic drugs a study of 3 cases and a literature review" }

[ { "companynumb": "ES-JNJFOC-20141011621", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "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": "METHOTREXATE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "103772", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LYOPHILIZED POWDER", "drugdosagetext": "LOADING DOSE OF 5MG/KG AT 0,2,6 FOLLOWED BY A MAINTENANCE THERAPY OF ONCE EVERY 8 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "BEHCET^S SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INFLIXIMAB, RECOMBINANT" } ], "patientagegroup": "6", "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Uveitis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CALVO-RIO V, HERA DD, BELTRAN-CATALAN E, RICARDO B, HERNANDEZ M, MARTINEZ-COSTA L, ET AL. TOCILIZUMAB IN UVEITIS REFRACTORY TO OTHER BIOLOGIC DRUGS: A STUDY OF 3 CASES AND A LITERATURE REVIEW. CLIN EXP RHEUMATOL 2014;32 (SUPPL 84):S54-S57.", "literaturereference_normalized": "tocilizumab in uveitis refractory to other biologic drugs a study of 3 cases and a literature review", "qualification": "1", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20141111", "receivedate": "20141023", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10539019, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150529" } ]

{ "abstract": "Postmortem investigation often reveals various conditions, which may or may not have played a part in the death of the individual. The case of a 32-year-old woman is reported, with a long history of drug addiction. She was found dead in her bed. The autopsy revealed diffuse pulmonary edema with congestion of the lungs, brain, liver, and spleen. Microscopic examination of the lungs showed multiple intra-alveolar and interstitial foamy macrophages and extracellular fat droplets surrounded by polynuclear giant cells. Death was attributed to acute polydrug intoxication. As microscopic examination had revealed severe pulmonary lesions, lipoid pneumonia was considered as a contributing factor to death. Lipoid pneumonia is an uncommon entity with the characteristic radiograph features and histologic findings of alveoli filled with vacuolated, lipid-laden histiocytes. It can be either exogenous or endogenous in cause, based on the source of the lipid. Exogenous lipoid pneumonia usually results from aspiration or inhalation of fat-like material, such as mineral oil or petroleum-based lubricants and decongestants, resulting in pulmonary inflammatory reactions.", "affiliations": "Institut Médico-Légal, CHRU de Tours, F-37044, Tours, France; Université François Rabelais, F-37020, Tours, France.", "authors": "Moreau|Emilie|E|;Rérolle|Camille|C|;Deveaux|Marc|M|;Paraf|François|F|;Saint-Martin|Pauline|P|", "chemical_list": "D009292:Narcotic Antagonists; D002047:Buprenorphine", "country": "United States", "delete": false, "doi": "10.1111/1556-4029.12677", "fulltext": null, "fulltext_license": null, "issn_linking": "0022-1198", "issue": "60(2)", "journal": "Journal of forensic sciences", "keywords": "autopsy; buprenorphine; drug intoxication; forensic pathology; forensic science; lipoid pneumonia; unexpected finding", "medline_ta": "J Forensic Sci", "mesh_terms": "D000328:Adult; D002047:Buprenorphine; D005260:Female; D006801:Humans; D008168:Lung; D009292:Narcotic Antagonists; D011017:Pneumonia, Lipid; D011654:Pulmonary Edema; D019966:Substance-Related Disorders", "nlm_unique_id": "0375370", "other_id": null, "pages": "514-7", "pmc": null, "pmid": "25556392", "pubdate": "2015-03", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Exogenous lipoid pneumonia as a contributory factor in a drug-related death.", "title_normalized": "exogenous lipoid pneumonia as a contributory factor in a drug related death" }

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CAMILLE REROLLE? MARC DEVEAUX? FRANCOIS PARAF? AND PAULINE SAINT-MARTIN.. EXOGENOUS LIPOID PNEUMONIA AS A CONTRIBUTORY FACTOR IN A DRUG-RELATED DEATH.. 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congestion", "reactionmeddraversionpt": "19.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Spleen congestion", "reactionmeddraversionpt": "19.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "19.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "MOREAU E, REROLLE C, DEVEAUX M, PARAF F, SAINT-MARTIN P. EXOGENOUS LIPOID PNEUMONIA AS A CONTRIBUTORY FACTOR IN A DRUG-RELATED DEATH. 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null, "drugtreatmentdurationunit": null, "medicinalproduct": "TROPATEPINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "NITRAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "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": "NITRAZEPAM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, 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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": "SUBUTEX" } ], "patientagegroup": null, "patientonsetage": "32", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia lipoid", "reactionmeddraversionpt": "19.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "MOREAU E, REROLLE C, DEVEAUX M, PARAF F, SAINT-MARTIN P. EXOGENOUS LIPOID PNEUMONIA AS A CONTRIBUTORY FACTOR IN A DRUG-RELATED DEATH. J-FORENSIC-SCI 2015?60(2):514-7.", "literaturereference_normalized": "exogenous lipoid pneumonia as a contributory factor in a drug related death", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20160202", "receivedate": "20160202", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11988656, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" }, { "companynumb": "FR-MYLANLABS-2016M1002942", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "NITRAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", 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"drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AMITRIPTYLINE" }, "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": "AMITRIPTYLINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE" }, "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": "SUBUTEX" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pneumonia lipoid", "reactionmeddraversionpt": "19.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "19.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "MOREAU E, REROLLE C, DEVEAUX M, PARAF F, SAINT-MARTIN P. EXOGENOUS LIPOID PNEUMONIA AS A CONTRIBUTORY FACTOR IN A DRUG-RELATED DEATH. J-FORENSIC-SCI 2015?60(2):514-7.", "literaturereference_normalized": "exogenous lipoid pneumonia as a contributory factor in a drug related death", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20160125", "receivedate": "20160125", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11949101, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160526" } ]

{ "abstract": "Severe neuropathy is a known adverse effect of vincristine in patients with Charcot-Marie-Tooth disease (CMT). We present the case of a 16-year-old girl with anaplastic medulloblastoma treated with gross total resection and high-dose craniospinal radiation with adjuvant vincristine chemotherapy who developed acute-onset severe quadriplegia and vocal cord paralysis. Vincristine and radiation therapy were discontinued. Although her neuropathy slowly improved over several weeks, she developed metastatic extraneural medulloblastoma and died 5 months after diagnosis. Subsequent genetic testing revealed previously asymptomatic and undiagnosed CMT1A. Our case highlights the importance of early recognition of acute vincristine neurotoxicity that should raise suspicion of an underlying hereditary neuropathy.", "affiliations": "School of Medicine, University of California San Diego, San Diego, California, USA.;Division of Hematology-Oncology, Department of Pediatrics, Rady Children's Hospital-San Diego, San Diego, California, USA.;Neurosciences and Pediatrics, University of California San Diego, San Diego, California, USA.", "authors": "Aghajan|Yasmin|Y|;Yoon|Janet M|JM|;Crawford|John Ross|JR|", "chemical_list": "D000972:Antineoplastic Agents, Phytogenic; D014750:Vincristine", "country": "England", "delete": false, "doi": "10.1136/bcr-2016-218981", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2017()", "journal": "BMJ case reports", "keywords": "CNS cancer; Chemotherapy; Neurology; Neuromuscular disease; Neurooncology", "medline_ta": "BMJ Case Rep", "mesh_terms": "D000293:Adolescent; D000972:Antineoplastic Agents, Phytogenic; D001932:Brain Neoplasms; D002607:Charcot-Marie-Tooth Disease; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008527:Medulloblastoma; D011115:Polyneuropathies; D014750:Vincristine", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "28438772", "pubdate": "2017-04-24", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "12679647;16386273;19539237;22246157;22271166", "title": "Severe vincristine-induced polyneuropathy in a teenager with anaplastic medulloblastoma and undiagnosed Charcot-Marie-Tooth disease.", "title_normalized": "severe vincristine induced polyneuropathy in a teenager with anaplastic medulloblastoma and undiagnosed charcot marie tooth disease" }

[ { "companynumb": "US-PFIZER INC-2017194972", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "071484", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MEDULLOBLASTOMA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE SULFATE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "071484", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (SECOND DOSE)", "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": "VINCRISTINE SULFATE." } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Muscular weakness", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dysphonia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Dysphagia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vocal cord paralysis", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Toxic neuropathy", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Paraparesis", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Quadriplegia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "AGHAJAN, Y.. SEVERE VINCRISTINE-INDUCED POLYNEUROPATHY IN A TEENAGER WITH ANAPLASTIC MEDULLOBLASTOMA AND UNDIAGNOSED CHARCOT-MARIE-TOOTH DISEASE.. BMJ CASE REPORTS. 2017;10.1136/BCR-2016-218981", "literaturereference_normalized": "severe vincristine induced polyneuropathy in a teenager with anaplastic medulloblastoma and undiagnosed charcot marie tooth disease", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170508", "receivedate": "20170508", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13523144, "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" } ]

{ "abstract": "We report an AIDS patient with a high HIV RNA copy number in the plasma who was successfully treated for prolonged Mycobacterium avium bacteremia and other complications. An HIV-infected patient with high fever, anemia, high alkaline phosphatase, cystic lung lesions, hepatitis B virus infection and Kaposi's sarcoma was referred to our hospital. PCR of the blood revealed Mycobacterium avium bacteremia and the time to blood culture positivity was 8 days. The HIV-1 RNA copy number in the plasma was more than ten million copies/ml and the CD4-positive T cell count was 21 cells/μL. Although the high fever resolved five days after therapy for Mycobacterium avium was started, the fever recurred just before starting anti-retroviral therapy (ART) including dolutegravir. The patient experienced repeated but self-limiting bouts of severe inflammation. Mycobacteremia was intermittently detected up to 79 days, suggesting that the recurrent episodes of inflammation were due to the intermittent dissemination of mycobacteria, and that persistent treatment is needed. Five months after the beginning of ART, the HIV-1 RNA copy number in the plasma was still 28,000 copies/ml. An HIV drug-resistance test revealed sensitivity to all anti-retroviral drugs. Eleven months after the initiation of ART, the HIV RNA copy number in the plasma decreased to 45 copies/mL and the CD4-positive T cell count recovered to 205 cells/μL. Our case also suggests that dolutegravir can be effective in cases with prolonged high levels of HIV RNA. Our findings emphasize that prompt diagnosis and persistent therapy for mycobacterial infection are important for successful treatment.", "affiliations": "Division of Blood Transfusion Medicine and Cell Therapy, Kagoshima University Hospital, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan. Electronic address: furukawy@m2.kufm.kagoshima-u.ac.jp.;Division of Blood Transfusion Medicine and Cell Therapy, Kagoshima University Hospital, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.;Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.;Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.;Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.;Department of Diagnostic Pathology, Imamura General Hospital, 11-23 Kamoikeshinmachi, Kagoshima, 890-0064, Japan.;Division of Antiviral Chemotherapy, Joint Research Center for Human Retrovirus Infection, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.;Division of Antiviral Chemotherapy, Joint Research Center for Human Retrovirus Infection, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.;Laboratory and Vascular Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.", "authors": "Furukawa|Yoshitaka|Y|;Hamada|Heiichiro|H|;Kamikawaji|Kazuto|K|;Unoki|Taiji|T|;Inoue|Hiromasa|H|;Tashiro|Yukie|Y|;Okamoto|Mika|M|;Baba|Masanori|M|;Hashiguchi|Teruto|T|", "chemical_list": "D000900:Anti-Bacterial Agents; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D012367:RNA, Viral; C562325:dolutegravir", "country": "Netherlands", "delete": false, "doi": "10.1016/j.jiac.2019.08.012", "fulltext": null, "fulltext_license": null, "issn_linking": "1341-321X", "issue": "26(2)", "journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy", "keywords": "Disseminated non-tuberculosis mycobacterium; Dolutegravir; Mycobacterium avium; Recurrent inflammation", "medline_ta": "J Infect Chemother", "mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D000163:Acquired Immunodeficiency Syndrome; D000328:Adult; D000900:Anti-Bacterial Agents; D023241:Antiretroviral Therapy, Highly Active; D016470:Bacteremia; D018791:CD4 Lymphocyte Count; D017726:Cytomegalovirus Retinitis; D015658:HIV Infections; D019428:HIV Integrase Inhibitors; D006509:Hepatitis B; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D007249:Inflammation; D008297:Male; D009162:Mycobacterium avium; D015270:Mycobacterium avium-intracellulare Infection; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D012367:RNA, Viral; D012514:Sarcoma, Kaposi; D016896:Treatment Outcome", "nlm_unique_id": "9608375", "other_id": null, "pages": "279-281", "pmc": null, "pmid": "31543435", "pubdate": "2020-02", "publication_types": "D002363:Case Reports", "references": null, "title": "Successful treatment of an AIDS patient with prolonged Mycobacterium avium bacteremia, high HIV RNA, HBV infection, Kaposi's sarcoma and cytomegalovirus retinitis.", "title_normalized": "successful treatment of an aids patient with prolonged mycobacterium avium bacteremia high hiv rna hbv infection kaposi s sarcoma and cytomegalovirus retinitis" }

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"drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ABACAVIR." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CEFOPERAZONE\\SULBACTAM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOBACTERIUM AVIUM COMPLEX INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFOPERAZONE/SULBACTAM" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Nephropathy toxic", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus chorioretinitis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FURUKAWA Y, HAMADA H, KAMIKAWAJI K, UNOKI T, INOUE H, TASHIRO Y, ET AL. SUCCESSFUL TREATMENT OF AN AIDS PATIENT WITH PROLONGED MYCOBACTERIUM AVIUM BACTEREMIA, HIGH HIV RNA, HBV INFECTION, KAPOSI^S SARCOMA AND CYTOMEGALOVIRUS RETINITIS. J INFECT CHEMOTHER. 2020?26(2):279-281", "literaturereference_normalized": "successful treatment of an aids patient with prolonged mycobacterium avium bacteremia high hiv rna hbv infection kaposi s sarcoma and cytomegalovirus retinitis", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200313", "receivedate": "20200313", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17536976, "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 a 59-year-old woman with a perforating eyeball injury to the right eye, the emergency physician induced a preclinical general anesthesia with propofol, fentanyl and the depolarizing muscle relaxant succinylcholine. Anesthesia was maintained using propofol and remifentanil infusion throughout the preoperative period and the subsequent surgical procedure. Postoperatively, isolated rhabdomyolysis with an increase in serum creatine kinase to >20,000 U/l was observed. The diagnosis of malignant hyperthermia (MH) susceptibility could be confirmed in the patient 4 months after the acute event by the in vitro contracture test and detection of the MH causative mutation p.Val4849Ile in exon 101 of the ryanodine receptor gene. Due to the variable expression, for a long time MH often remained unrecognized. Warning symptoms, such as unspecific tachycardia or masseter spasm following succinylcholine injection, should alert emergency physicians to include MH susceptibility in the differential diagnostics. With an estimated genetic MH prevalence of 1:2000-3000, individuals with known or so far unrecognized MH disposition are likely to be among patients treated in the preclinical setting. If a person develops MH symptoms after exposure to triggering agents, immediate hospital admission is essential in order to initiate guideline-conform treatment without further delay because preclinically the life-saving causal measures are not possible due to the lack of supply of dantrolene.", "affiliations": "Klinik und Poliklinik für Anästhesiologie, Zentrum für Operative Medizin, Universitätsklinikum Würzburg, Oberdürrbacher Str. 6, 97080, Würzburg, Deutschland.;Klinik und Poliklinik für Anästhesiologie, Zentrum für Operative Medizin, Universitätsklinikum Würzburg, Oberdürrbacher Str. 6, 97080, Würzburg, Deutschland.;Klinik und Poliklinik für Anästhesiologie, Zentrum für Operative Medizin, Universitätsklinikum Würzburg, Oberdürrbacher Str. 6, 97080, Würzburg, Deutschland.;Klinik und Poliklinik für Anästhesiologie, Zentrum für Operative Medizin, Universitätsklinikum Würzburg, Oberdürrbacher Str. 6, 97080, Würzburg, Deutschland.;Klinik und Poliklinik für Anästhesiologie, Zentrum für Operative Medizin, Universitätsklinikum Würzburg, Oberdürrbacher Str. 6, 97080, Würzburg, Deutschland. Schuster_F@ukw.de.", "authors": "Helf|D|D|;Schneiderbanger|D|D|;Markus|C K|CK|;Johannsen|S|S|;Schuster|F|F|", "chemical_list": "D018686:Anesthetics, Intravenous; D009467:Neuromuscular Depolarizing Agents; D003620:Dantrolene; D013390:Succinylcholine; D005283:Fentanyl; D015742:Propofol", "country": "Germany", "delete": false, "doi": "10.1007/s00101-018-0419-4", "fulltext": null, "fulltext_license": null, "issn_linking": "0003-2417", "issue": "67(4)", "journal": "Der Anaesthesist", "keywords": "Malignant hyperthermia; Muscle relaxant; Rapid sequence induction; Rhabdomyolysis; Succinylcholine", "medline_ta": "Anaesthesist", "mesh_terms": "D000768:Anesthesia, General; D018686:Anesthetics, Intravenous; D003620:Dantrolene; D005260:Female; D005283:Fentanyl; D006801:Humans; D008305:Malignant Hyperthermia; D008875:Middle Aged; D009467:Neuromuscular Depolarizing Agents; D015742:Propofol; D012206:Rhabdomyolysis; D013390:Succinylcholine", "nlm_unique_id": "0370525", "other_id": null, "pages": "275-279", "pmc": null, "pmid": "29480319", "pubdate": "2018-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "28235546;10895753;25047158;26238698;26188342", "title": "Abortive course of malignant hyperthermia following preclinical induction of general anesthesia using succinylcholine.", "title_normalized": "abortive course of malignant hyperthermia following preclinical induction of general anesthesia using succinylcholine" }

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"drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPOFOL." } ], "patientagegroup": "5", "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Rhabdomyolysis", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HELF D, SCHNEIDERBANGER D, MARKUS CK, JOHANNSEN S, SCHUSTER F. ABORTIVE COURSE OF MALIGNANT HYPERTHERMIA FOLLOWING PRECLINICAL INDUCTION OF GENERAL ANESTHESIA USING SUCCINYLCHOLINE. 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SCHNEIDERBANGER D, MARKUS K, JOHANNSEN S, SCHUSTER F. ABORTIVE COURSE OF MALIGNANT HYPERTHERMIA FOLLOWING PRECLINICAL INDUCTION OF GENERAL ANESTHESIA USING SUCCINYLCHOLINE. ANAESTHESIST. 2018?67(4):275-279.", "literaturereference_normalized": "abortive course of malignant hyperthermia following preclinical induction of general anesthesia using succinylcholine", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "DE", "receiptdate": "20200131", "receivedate": "20200131", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 17355352, "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": "Cytokine-based mobilization in light chain (AL) amyloidosis is frequently complicated by fluid overload, weight gain, cardiac arrhythmias, and peri-mobilization mortality. We analyzed hematopoietic progenitor cells (HPC) mobilization outcomes in 49 consecutive AL amyloidosis patients at our institution between 2004 and 2013 with granulocyte colony-stimulating factor (G) (10 μg/kg/day) (n = 25) versus an institutional protocol to limit G exposure using plerixafor (P) (.24 mg/kg s.c. starting day 3 of G 10 μg/kg) (n = 24). G+P strategy yielded higher total CD34(+) cells/kg (12.8 × 10(6) versus 6.3 × 10(6); P < .001) and CD34(+) cells/kg collected on day 1 (10.8 × 10(6) versus 4.9 × 10(6), P = .004) compared with the G cohort. More G+P patients collected ≥5 × 10(6) CD34(+) HPCs/kg (22 versus 16, P = .02) and ≥ 10 × 10(6) CD34(+) HPCs/kg (13 versus 5, P = .01). Four patients (16%) had mobilization failure with G; none with G+P. Peri-mobilization weight gain was lower with G+P strategy (median weight gain 1 versus 7 pounds, P = .009). Numbers of apheresis sessions (median, 1 versus 1, P = .52), number of hospitalization days (median, 1.1 versus 1.6, P = .52), transfusions, use of intravenous antibiotics, and cardiac arrhythmias were similar. In conclusion, our study demonstrates that upfront use of G+P as a mobilization strategy results in superior HPC collection, no mobilization failures, and less weight gain than G alone.", "affiliations": "Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin.;Department of Internal Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.;Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin.;Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin.;Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin.;Division of Biostatistics, Medical College of Wisconsin, Milwaukee, Wisconsin.;Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin.;Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin.;Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin.;Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin.;Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin.;Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin. Electronic address: mhamadani@mcw.edu.", "authors": "Dhakal|Binod|B|;Strouse|Christopher|C|;D'Souza|Anita|A|;Arce-Lara|Carlos|C|;Esselman|Jeanie|J|;Eastwood|Daniel|D|;Pasquini|Marcelo|M|;Saber|Wael|W|;Drobyski|William|W|;Rizzo|J Douglas|JD|;Hari|Parameswaran N|PN|;Hamadani|Mehdi|M|", "chemical_list": "D019380:Anti-HIV Agents; D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D016179:Granulocyte Colony-Stimulating Factor; C088327:plerixafor", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1083-8791", "issue": "20(12)", "journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation", "keywords": "Granulocyte colony–stimulating factor (G-CSF); Light chain amyloidosis (AL amyloidosis); Plerixafor; Stem cell mobilization", "medline_ta": "Biol Blood Marrow Transplant", "mesh_terms": "D000328:Adult; D000368:Aged; D000686:Amyloidosis; D019380:Anti-HIV Agents; D064592:Autografts; D001596:Benzylamines; D000080027:Cyclams; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006571:Heterocyclic Compounds; D006801:Humans; D008297:Male; D008875:Middle Aged", "nlm_unique_id": "9600628", "other_id": null, "pages": "1926-31", "pmc": null, "pmid": "25111581", "pubdate": "2014-12", "publication_types": "D016430:Clinical Trial; D016428:Journal Article", "references": null, "title": "Plerixafor and abbreviated-course granulocyte colony-stimulating factor for mobilizing hematopoietic progenitor cells in light chain amyloidosis.", "title_normalized": "plerixafor and abbreviated course granulocyte colony stimulating factor for mobilizing hematopoietic progenitor cells in light chain amyloidosis" }

[ { "companynumb": "US-AMGEN-USASP2020168597", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "FILGRASTIM" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": "103353", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "10 MICROGRAM/KILOGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "HAEMATOPOIETIC STEM CELL MOBILISATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "008", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FILGRASTIM" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Therapy non-responder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Weight increased", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arrhythmia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac failure", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "STROUSE, C.. PLERIXAFOR AND ABBREVIATED-COURSE GRANULOCYTE COLONY-STIMULATING FACTOR FOR MOBILIZING HEMATOPOIETIC PROGENITOR CELLS IN LIGHT CHAIN AMYLOIDOSIS. BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION. 2014?20(12):1926-1931", "literaturereference_normalized": "plerixafor and abbreviated course granulocyte colony stimulating factor for mobilizing hematopoietic progenitor cells in light chain amyloidosis", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201020", "receivedate": "20201020", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18405497, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210114" }, { "companynumb": "US-AMGEN-USASP2020168618", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PLERIXAFOR" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.24 MILLIGRAM/KILOGRAM (STARTING DAY 3 OF FILGRASTIM)", "drugenddate": null, "drugenddateformat": null, "drugindication": "HAEMATOPOIETIC STEM CELL MOBILISATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "200910", "drugstartdateformat": "610", "drugstructuredosagenumb": ".24", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PLERIXAFOR" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FILGRASTIM" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": "103353", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "10 MICROGRAM/KILOGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "HAEMATOPOIETIC STEM CELL MOBILISATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "008", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FILGRASTIM" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Weight increased", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage intracranial", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Cardiac failure", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Febrile neutropenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arrhythmia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "STROUSE, C. PLERIXAFOR AND ABBREVIATED COURSE GRANULOCYTE COLONY-STIMULATING FACTOR FOR MOBILIZING HEMATOPOIETIC PROGENITOR CELLS IN LIGHT CHAIN AMYLOIDOSIS. BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION. 2014?20(12):1926-1931", "literaturereference_normalized": "plerixafor and abbreviated course granulocyte colony stimulating factor for mobilizing hematopoietic progenitor cells in light chain amyloidosis", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201021", "receivedate": "20201021", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18408790, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210114" } ]

{ "abstract": "Coronavirus 2019 (COVID-19) is caused by a novel coronavirus. Although liver injury is common in patients with COVID-19, little is known about its clinical presentation and management in liver transplantation. This is the first report from Iran that presented two cases of liver transplantation with COVID-19, neither of which had pulmonary signs and symptoms, but after diagnostic imaging, both had lung involvement. We also reviewed some literature on the management of COVID-19 in liver transplant patients. In conclusion, our patients improved after starting hydroxychloroquine and continuing to take all immunosuppressive agents except mycophenolate based on the multidisciplinary team's decision.", "affiliations": "Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.;Shiraz Transplant Center, Abu Ali Sina Hospital, Shiraz University of Medical Sciences, Shiraz, Iran.;Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.;Shiraz Transplant Center, Abu Ali Sina Hospital, Shiraz University of Medical Sciences, Shiraz, Iran.", "authors": "Niknam|Ramin|R|0000-0002-2608-8018;Malek-Hosseini|Seyed Ali|SA|;Hashemieh|Seyed Saeid|SS|;Dehghani|Masoud|M|", "chemical_list": null, "country": "New Zealand", "delete": false, "doi": "10.2147/IMCRJ.S265910", "fulltext": "\n==== Front\nInt Med Case Rep J\nInt Med Case Rep J\nimcrj\nimcrj\nInternational Medical Case Reports Journal\n1179-142X Dove \n\n265910\n10.2147/IMCRJ.S265910\nCase Report\nCOVID-19 in Liver Transplant Patients: Report of 2 Cases and Review of the Literature\nNiknam et alNiknam et alhttp://orcid.org/0000-0002-2608-8018Niknam Ramin 1 Malek-Hosseini Seyed Ali 2 Hashemieh Seyed Saeid 1 Dehghani Masoud 2 1 Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran\n2 Shiraz Transplant Center, Abu Ali Sina Hospital, Shiraz University of Medical Sciences, Shiraz, Iran\nCorrespondence: Masoud Dehghani Shiraz Transplant Center, Abu Ali Sina Hospital, Shiraz University of Medical Sciences, Shiraz, IranTel +989131415796 Email dehghanimasood@yahoo.com\n31 7 2020 \n2020 \n13 317 321\n09 6 2020 16 7 2020 © 2020 Niknam et al.2020Niknam et al.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).Abstract\nCoronavirus 2019 (COVID-19) is caused by a novel coronavirus. Although liver injury is common in patients with COVID-19, little is known about its clinical presentation and management in liver transplantation. This is the first report from Iran that presented two cases of liver transplantation with COVID-19, neither of which had pulmonary signs and symptoms, but after diagnostic imaging, both had lung involvement. We also reviewed some literature on the management of COVID-19 in liver transplant patients. In conclusion, our patients improved after starting hydroxychloroquine and continuing to take all immunosuppressive agents except mycophenolate based on the multidisciplinary team’s decision.\n\nKeywords\nCOVID-19coronavirusliver transplantationimmunosuppressantmanagement\n==== Body\nIntroduction\nCoronavirus 2019 (COVID-19) is caused by a novel coronavirus.1,2 Clinical presentation and management of liver injury in patients with COVID-19 in liver transplantation is unclear and may be an increasing challenge for the transplant centers.3,4\n\nIn this report, we have described 2 liver transplant cases with COVID-19. We also reviewed some literature on the management of COVID-19 in liver transplant patients.\n\nCase 1\nA 60-year-old woman with diabetes mellitus has been referred to the transplant center at Abu Ali Sina hospital, the main center of liver transplantation in Iran, due to intermittent fever, weakness, and anorexia. She underwent liver transplant 10 months before her recent visit due to autoimmune hepatitis. All symptoms started 2 weeks before being referred to our hospital. The patient had no history of any respiratory symptoms include cough and dyspnea. There was no history of high blood pressure or coronary artery disease. She was taking medications including mycophenolate (720 mg per day), tacrolimus (2 mg per day), prednisolone (15 mg per day), folic acid (1 mg per day), and ursodeoxycholic acid (900 mg per day). The patient’s vital signs were oral temperature, 37.9°C, heart rate of 105 beats per minute, respiration rate of 16 beats per minute, blood pressure of 110/70 mm Hg. On physical examination, the patient had jaundice, but lung and other organs were normal. The patient admitted to hospital for more evaluation and samples of nasal and pharyngeal swabs for COVID-19 diagnosis were tested using real-time polymerase chain reaction (RT-PCR), which showed positive results. Computed tomography (CT) scan of the chest was performed, in which multiple bilateral nodular infiltrates of varying sizes and a few patchy ground-glass opacity were observed (Figure 1). Table 1 shows the patient’s laboratory results. After discussing the patient’s condition in a multidisciplinary team, the patient was transferred to isolated room, mycophenolate was discontinued, and meropenem (1g IV q.8h), co-trimoxazole (400/80) one tablet twice daily, and hydroxychloroquine (HCQ) (400 mg/day) were started for 14 days. According to the cholestatic pattern of liver tests, ultrasound and magnetic resonance cholangiopancreatography were performed, the results of which were in favor of common bile duct stricture, and radiological intervention was considered to treat this problem. During the hospitalization period, the patient did not show any pulmonary symptoms. Although the patient’s condition improved after 5 weeks of follow-up, due to the concomitant treatment of bile duct stenosis and COVID-19 in this patient, it is difficult to separate the effect and contribution of treatment of the two diseases in the patient’s recovery.Table 1 The Results of Laboratory Parameters of the Liver Transplant Patients with Coronavirus 2019 (COVID-19)\n\nLaboratory Data\tCase 1\tCase 2\tNormal Range\t\nWhite blood cells (/mm3)\t6700\t5.1\t4000–10,000\t\nHemoglobin (g/dl)\t13.3\t11.1\t12–16\t\nPlatelets (mm3)\t74,000\t137,000\t140,000–400,000\t\nDirect bilirubin (mg/dl)\t18.8\t0.45\t<0.2\t\nTotal bilirubin (mg/dl)\t28.6\t1.24\t0.1–1.2\t\nAspartate aminotransferase(U/L)\t204\t40\t<31\t\nAlanine aminotransferase (U/L)\t333\t88\t<31\t\nAlkaline phosphatase (U/L)\t1140\t244\t64–306\t\nProthrombin Time. Patient (S)\t12\t12\t12.5\t\nProthrombin Time. Control (S) 9\t12\t12\t12.5\t\nErythrocyte sedimentation rate (mm/hr)\t48\t61\t<29\t\n\nFigure 1 Computed tomography scan of the chest of a liver transplant woman with coronavirus 2019 (COVID-19) showed multiple bilateral nodular infiltrates of varying sizes and a few patchy ground-glass opacity.\n\n\n\nCase 2\nA 46-year-old man was admitted to the post-transplant ward at Abu Ali Sina hospital due to fever, severe headache, anorexia, nausea, and vomiting. He underwent liver transplant 2 years ago due to budd chiari syndrome. All symptoms started 7 days before admission. The patient had no history of any respiratory symptoms. There was no history of diabetes, high blood pressure, or coronary artery disease. He was taking medications including mycophenolate (1440 mg per day), tacrolimus (3 mg per day), prednisolone (10 mg per day), folic acid (1 mg per day), and aspirin (80 mg per day). The patient’s vital signs on the day of admission were oral temperature, 38.7°C, heart rate of 115 beats per minute, respiration rate of 15 beats per minute, blood pressure of 100/70 mm Hg. Physical examinations, including neurological and pulmonary, were normal. The brain magnetic resonance imaging was normal and the laboratory parameters are shown in Table 1. The patient did not consent to the sampling through lumbar puncture. Due to unexplained fever in a patient with suppressed immunity and normal brain MRI, samples of nasal and pharyngeal swabs were taken for COVID-19 evaluation. Samples were tested using RT-PCR, which showed positive results. CT scan of the chest was performed, in which only a small peripheral patchy ground-glass opacity was observed in right lung (Figure 2). After discussing the patient’s condition in a multidisciplinary team, the patient was transferred to an isolated room and received HCQ (400 mg/day) for 5 days. Mycophenolate was discontinued, while other patient’s medications were continued. The patient’s fever, headache, and nausea subsided 2 weeks later, and the patient’s appetite improved by the fourth week.Figure 2 Computed tomography scan of the chest of a liver transplant man with coronavirus 2019 (COVID-19) showed a small peripheral patchy ground-glass opacity in right lung.\n\n\n\nDiscussion\nThis is the first report from Iran that presented two cases of liver transplantation with COVID-19, neither of which had pulmonary symptoms, but after diagnostic imaging, both had lung involvement, one of which was severe.\n\nThe first cases of COVID-19 were identified in China.5 COVID-19 is caused by a novel virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus spread rapidly around the world and is now a public health emergency.2 The clinical features of COVID-19 patients are very diverse. Pulmonary symptoms are common in COVID-19, but some patients may show symptoms other than the respiratory tract, including neurological manifestations, and changes in smell and taste.1,6 One of our patients presented with severe headache as a sign of neurological disease.\n\nIncreased liver enzymes are a common problem in hospitalized patients with COVID-19. Liver injury is more common in severe cases of COVID-19 than in mild cases, which do not require special treatment in mild cases. It has been suggested that increasing liver enzymes in hospitalized patients should not be a contraindication to using the research or off-label therapies for COVID-19, but regular monitoring of liver enzymes should be performed.3 Although liver injury is common in patients with COVID-19, little is known about its clinical presentation and management in liver transplantation.3,4 In a report by Bhoori et al, 3 of the 111 long-term survivors of liver transplantation died in a few weeks following severe COVID-19.7 Huang et al described a case of COVID-19 in a liver transplant patient with symptoms of respiratory disease. Various therapies have been used for the patient, including nebulized α-interferon, umifenovir, and lopinavir/ritonavir, methylprednisolone, antibiotic therapy, biliary drainage by endoscopic retrograde cholangiopancreatography, continuous renal replacement therapy, and plasma exchange. Their patient’s condition progressed rapidly from mild to critical illness and was complicated by multi-organ failure, and he eventually died.8 Contrary to this report, none of our patients had respiratory symptoms.\n\nIn another report, Zhong et al described two cases of COVID-19 in liver transplant recipients that ultimately had good outcomes. Immunosuppression medications were discontinued for the first patient who had a liver rejection, but for the second case, immunosuppression agents were only reduced.9 Liu et al reported a case of COVID-19 in a liver transplant patient who presented with fever and multiple peripheral patchy ground-glass in CT scan. They tried various therapies for the patient, including umifenovir, lopinavir/ritonavir, methylprednisolone, intravenous immunoglobulin, antibiotic, and alpha interferon. Immunosuppression medications were also discontinued and eventually the patient recovered.10\n\nAlthough there are concerns that organ transplant patients may be at greater risk for COVID-19 due to immunosuppressive therapy, there is still no conclusive evidence that the immunosuppressive protocol has been modified.11 Liver transplant recipients without COVID-19 may not need to adjust the dose of immunosuppressive medications. For patients with mild to moderate COVID-19, it is recommended that immunosuppression be continued,4 but if there is fever, lymphopenia, or worsening of the patient’s pneumonia, dose reduction of azathioprine or mycophenolate should be considered.3 Patients with severe or rapidly progressing COVID-19 should be considered to reduce the dose of calcineurin inhibitor and discontinue anti-metabolic medications.4 In our patients, mycophenolate was discontinued, while other immunosuppressive agents were continued. It is recommended that the high-dose prednisone be minimized, but at least a daily dose of 10 mg prednisone or its equivalent should be used to prevent adrenal insufficiency. Corticosteroids or other immunosuppressive medications can be re-used with caution where the potential clinical benefit might be outweighed by the risks.3,4 In our report, low-dose prednisolone was continued for both patients. If patients need antipyretics, acetaminophen at a daily dose of ≤2 g/day is recommended.3 Although the use of HCQ and azithromycin is controversial for the treatment of liver transplant recipients with COVID-19,3 our multidisciplinary team decided to initiate HCQ for both patients. Although HCQ has been used in different diseases for many years, its mechanism of action is still on the rise. Some studies have reported that HCQ has antiviral activity against SARS-CoV-2, so due to the lack of a definite antiviral medication or vaccine, it was recommended as a potential intervention strategy for COVID-19 treatment.3,12,13 However, HCQ has various side effects and warnings, including cardiac arrhythmia, heart failure, blindness, and renal toxicity, especially when taken in higher doses.12,14 Evidence currently does not support the use of lopinavir/ritonavir for the treatment of COVID-19 in liver transplant recipients,3,4 so we did not use this medication to treat our patients.\n\nAt a pediatric liver center in Latin America, patients were routinely screened for any clinical signs of COVID-19 during the current outbreak. According to their published report, although patients theoretically had high-risk factors for COVID-19, including receiving multiple immunosuppressive mediations or autoimmune disease, only six patients developed mild upper airway infection and fever. None of the patients, including those with a positive SARS-CoV-2 test, developed clinical lung disease. They concluded that there are no reasons to delay life-saving treatments such as liver transplantation in children during the current coronavirus outbreak.15 It is recommended that all patients with severe COVID-19 be screened for hyper-inflammation status using laboratory methods to identify the subgroup of participants for whom suppression of the immune system can improve mortality.16 It is not clear why, in mentioned reports, transplanted patients with COVID-19 have fewer complications than expected. One hypothesis is that SARS-CoV-2 may cause disease through the immune system, so the use of immunosuppressive mediations may reduce the complications by inhibiting the immune response. But further research is needed to prove this hypothesis.\n\nIn conclusion, none of our patients had respiratory symptoms, and lung imaging as well as RT-PCR tests were performed based on high clinical suspicion of COVID-19 for diagnosis. On the other hand, both patients improved after starting HCQ and continuing to take all immunosuppressive medications except mycophenolate. But data on clinical features and management of COVID-19 in the liver transplant patients are still very limited and more research is needed.\n\nPatient Consent\nInformed consent was obtained from the study participants prior to study commencement. They also consented for publication of their treatment and image details. This report does not contain personal information that could lead to the identification of patients. In addition, no institutional approval was required to publish the details of the cases. All organs were donated voluntarily with written informed consent, and that this was conducted in accordance with the Declaration of Istanbul.\n\nDisclosure\nThe authors report no conflicts of interest in this work.\n==== Refs\nReferences\n1. Guan \nWJ , Ni \nZY , Hu \nY , et al. Clinical characteristics of coronavirus disease 2019 in China\n. N Engl J Med . 2020 ;382 (18 ):1708 –1720\n.32109013 \n2. World Health Organization . Coronavirus disease situation reports\n. March 18 , 2020 \nAvailable from: \nhttps://www.who.int/emergencies/diseases/novel -coronavirus-2019/situation-reports. Accessed 3 19 , 2020.\n3. Fix \nOK , Hameed \nB , Fontana \nRJ , et al. Clinical best practice advice for hepatology and liver transplant providers during the COVID-19 pandemic: AASLD expert panel consensus statement\n. Hepatology . 2020 ;72 (1 ):287 –304\n. doi:10.1002/hep.31281 32298473 \n4. Liu \nH , He \nX , Wang \nY , et al. Management of COVID-19 in patients after liver transplantation: beijing working party for liver transplantation\n. Hepatol Int . 2020 ;14 (4 ):432 –436\n. doi:10.1007/s12072-020-10043-z 32277387 \n5. Huang \nC , Wang \nY , Li \nX , et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China\n. Lancet . 2020 ;395 (10223 ):497 –506\n. doi:10.1016/S0140-6736(20)30183-5 31986264 \n6. Mao \nL , Jin \nH , Wang \nM , et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China\n. JAMA Neurol . 2020 ;77 (6 ):683 . doi:10.1001/jamaneurol.2020.1127 \n7. Bhoori \nS , Rossi \nRE , Citterio \nD , Mazzaferro \nV . COVID-19 in long-term liver transplant patients: preliminary experience from an Italian transplant centre in Lombardy\n. Lancet Gastroenterol Hepatol . 2020 ;5 (6 ):532 –533\n. doi:10.1016/S2468-1253(20)30116-3 32278366 \n8. Huang \nJF , Zheng \nKI , George \nJ , et al. Fatal outcome in a liver transplant recipient with COVID-19\n. Am J Transplant . 2020 ;20 (7 ):1907 –1910\n. doi:10.1111/ajt.15909 32277591 \n9. Zhong \nZ , Zhang \nQ , Xia \nH , et al. Clinical characteristics and immunosuppressant management of coronavirus disease 2019 in solid organ transplant recipients\n. Am J Transplant . 2020 ;20 (7 ):1916 –1921\n. doi:10.1111/ajt.15928 32282986 \n10. Liu \nB , Wang \nY , Zhao \nY , Shi \nH , Zeng \nF , Chen \nZ . Successful treatment of severe COVID-19 pneumonia in a liver transplant recipient\n. Am J Transplant . 2020 ;20 (7 ):1891 –1895\n. doi:10.1111/ajt.15901 32243673 \n11. Saigal \nS , Gupta \nS , Sudhindran \nS , et al. Liver transplantation and COVID-19 (coronavirus) infection: guidelines of the liver transplant society of India (LTSI)\n. Hepatol Int . 2020 ;14 (4 ):429 –431\n. doi:10.1007/s12072-020-10041-1 32270388 \n12. Alanagreh \nL , Alzoughool \nF , Atoum \nM . Risk of using hydroxychloroquine as a treatment of COVID-19\n. Int J Risk Saf Med . 2020 ;1 –6\n. doi:10.3233/JRS-200024 \n13. Meo \nSA , Klonoff \nDC , Akram \nJ . Efficacy of chloroquine and hydroxychloroquine in the treatment of COVID-19\n. Eur Rev Med Pharmacol Sci . 2020 ;24 (8 ):4539 –4547\n. doi:10.26355/eurrev_202004_21038 32373993 \n14. Uzelac \nI , Iravanian \nS , Ashikaga \nH , et al. Fatal arrhythmias: another reason why doctors remain cautious about chloroquine/hydroxychloroquine for treating COVID-19\n. Heart Rhythm . 2020 . doi:10.1016/j.hrthm.2020.05.030 \n15. Tannuri \nU , Tannuri \nACA , Cordon \nMNA , Miyatani \nHT . Low incidence of COVID-19 in children and adolescent post-liver transplant at a Latin American reference center\n. Clinics . 2020 ;75 :e1986 . doi:10.6061/clinics/2020/e1986 32520226 \n16. Mehta \nP , McAuley \nDF , Brown \nM , et al. COVID-19: consider cytokine storm syndromes and immunosuppression\n. Lancet . 2020 ;395 (10229 ):1033 –1034\n. doi:10.1016/S0140-6736(20)30628-0 32192578\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1179-142X", "issue": "13()", "journal": "International medical case reports journal", "keywords": "COVID-19; coronavirus; immunosuppressant; liver transplantation; management", "medline_ta": "Int Med Case Rep J", "mesh_terms": null, "nlm_unique_id": "101566269", "other_id": null, "pages": "317-321", "pmc": null, "pmid": "32801943", "pubdate": "2020", "publication_types": "D002363:Case Reports", "references": "32277591;32520226;32277387;32109013;32479900;32298473;32474476;32282986;32373993;32243673;32278366;31986264;32270388;32192578;32275288", "title": "COVID-19 in Liver Transplant Patients: Report of 2 Cases and Review of the Literature.", "title_normalized": "covid 19 in liver transplant patients report of 2 cases and review of the literature" }

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{ "abstract": "The distinction between persistent infection and immunologic reactions in leprosy is often difficult but critically important since their management is different. We present the case of a 51-year-old Vietnamese female who presented in 2015 with areas of erythema and skin infiltration on face and chest, as well as edema on her hands and feet. Skin biopsy was consistent with lepromatous leprosy. She was treated with rifampin, clarithromycin, and levofloxacin for 2 years. Her lower extremity edema was attributed to type 2 immunological reaction for which she was started on prednisone and methotrexate, but she was lost to follow-up for 19 months. She presented with new skin lesions and pain on her extremities. New biopsies revealed an intense neutrophilic infiltrate in the dermis and acid-fast bacilli focally within cutaneous nerve twigs. As compared with the initial biopsy, the inflammatory infiltrates were diminished and the bacilli had a degenerating appearance. These findings were consistent with type 2 immunological reaction. The patient was treated with thalidomide with improvement in the appearance of the skin lesions. A follow-up biopsy showed lack of neutrophilic infiltrates and decreased number of bacilli. This case illustrates the importance of differentiating between persistent infection and immunologic reactions in leprosy. Clinicians should be aware of these complications. A high index of suspicion and accurate interpretation of skin biopsy results are essential for appropriate diagnosis.", "affiliations": "University of Texas Medical Branch, Galveston, TX, USA.;University of Texas Medical Branch, Galveston, TX, USA.;University of Texas Medical Branch, Galveston, TX, USA.;National Hansen's Disease Program, Baton Rouge, LA, USA.;University of Texas Medical Branch, Galveston, TX, USA.", "authors": "Tanabe|Melinda B|MB|;Group|Ashley Rae|AR|;Rincon|Liliana|L|;Stryjewska|Barbara M|BM|;Sarria|Juan C|JC|", "chemical_list": "D007917:Leprostatic Agents; D011241:Prednisone", "country": "United States", "delete": false, "doi": "10.1177/2324709620927884", "fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096 SAGE Publications Sage CA: Los Angeles, CA \n\n10.1177/2324709620927884\n10.1177_2324709620927884\nCase Report\nPersistent Infection Versus Type 2 Immunological Reaction in\nLepromatous Leprosy\nTanabe Melinda B. MD1 Group Ashley Rae MD1 Rincon Liliana MD1 Stryjewska Barbara M. MD2 Sarria Juan C. MD1 1 University of Texas Medical Branch,\nGalveston, TX, USA\n2 National Hansen’s Disease Program, Baton\nRouge, LA, USA\nMelinda B. Tanabe, MD, Department of\nInfectious Diseases, University of Texas Medical Branch, 301 University Blvd,\nRoute 0435, Galveston, TX 77555, USA. Email:\nmbtanabe@utmb.edu\n28 5 2020 \nJan-Dec 2020 \n8 232470962092788421 2 2020 17 4 2020 18 4 2020 © 2020 American Federation for Medical\nResearch2020American Federation for Medical\nResearchThis article is distributed under the terms of the Creative Commons\nAttribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which\npermits non-commercial use, reproduction and distribution of the work\nwithout further permission provided the original work is attributed as\nspecified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).The distinction between persistent infection and immunologic reactions in leprosy\nis often difficult but critically important since their management is different.\nWe present the case of a 51-year-old Vietnamese female who presented in 2015\nwith areas of erythema and skin infiltration on face and chest, as well as edema\non her hands and feet. Skin biopsy was consistent with lepromatous leprosy. She\nwas treated with rifampin, clarithromycin, and levofloxacin for 2 years. Her\nlower extremity edema was attributed to type 2 immunological reaction for which\nshe was started on prednisone and methotrexate, but she was lost to follow-up\nfor 19 months. She presented with new skin lesions and pain on her extremities.\nNew biopsies revealed an intense neutrophilic infiltrate in the dermis and\nacid-fast bacilli focally within cutaneous nerve twigs. As compared with the\ninitial biopsy, the inflammatory infiltrates were diminished and the bacilli had\na degenerating appearance. These findings were consistent with type 2\nimmunological reaction. The patient was treated with thalidomide with\nimprovement in the appearance of the skin lesions. A follow-up biopsy showed\nlack of neutrophilic infiltrates and decreased number of bacilli. This case\nillustrates the importance of differentiating between persistent infection and\nimmunologic reactions in leprosy. Clinicians should be aware of these\ncomplications. A high index of suspicion and accurate interpretation of skin\nbiopsy results are essential for appropriate diagnosis.\n\nleprosyMycobacterium lepraetype 2 immunological reactionerythema nodosum leprosumcover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nLeprosy is a deforming disease that affects nerves, skin, eyes, and facial mucosa.\nThe disease is caused by Mycobacterium leprae and M\nlepromatosis. Clinical presentation is based on the host’s immune response.1 Distinction between persistent infection and immunologic reactions in leprosy\nis often difficult but critically important since their management is different.\nPersistent infection often reflects poor adherence to antimycobacterial treatment.\nMechanisms leading to immunological reactions are poorly understood, clinical\npresentation is nonspecific, and treatment is not standardized. We present a case of\npreviously treated lepromatous leprosy who presented with a type 2 immunological\nreaction (T2R). Diagnostic and management considerations are discussed.\n\nCase Report\nA 51-year-old Vietnamese female, who migrated to the United States at age 25 years,\nwas seen at an outside clinic in East Texas in 2015. She had a 1-year history of\nlesions consistent with areas of erythema and infiltration of dermis of the cheeks,\nchin, nose, and chest. She reported numbness, weakness, and edema of her hands and\nfeet for 4 months. Skin biopsy of the left ear showed chronic inflammatory\ninfiltrates replacing 75% of dermis but separated from the basal layer of the\nepidermis by a clear zone. The infiltrates were composed of foamy histiocytes and\nlymphocytes involving cutaneous nerves. Fite stain revealed numerous acid-fast\nbacilli within histiocytes and cutaneous nerves. She was diagnosed with lepromatous\nleprosy. The treatment consisted of rifampin 600 mg daily (eventually monthly),\nclarithromycin 500 mg daily, and levofloxacin 500 mg daily for 2 years. Dapsone and\nminocycline were also prescribed but discontinued due to adverse effects (hemolytic\nanemia and hyperpigmentation, respectively). She did not receive clofazimine due to\nprior hyperpigmentation. Her extremity edema was attributed to T2R; however, edema\nis also an identified feature of lepromatous leprosy. Treatment with prednisone and\neventually methotrexate was started but she was lost to follow-up for 19 months\nbefore reestablishing care at our institution.\n\nShe presented with new indurated tender skin lesions and worsening pain and edema on\nher extremities, since last seen. She also reported subjective fever and weight loss\n(30 lbs in 4 months). On physical examination, she had extensive erythematous\nsubcutaneous papules and nodules with a background of gray hyperpigmentation on her\narms and legs (Figure 1),\nand few scattered tender superficial erythematous nodules on the face and abdomen.\nMadarosis and hypotrichosis of arms and legs were seen. Decreased light touch\n(monofilament 0.2 gr) in the left arm and loss of protective pain sensation (10 gr\nmonofilament) in both feet with glove-stocking pattern were noted. The remainder of\nher examination was unremarkable. The white blood cells count was 10.3\ncells/cm3 (neutrophil predominance) and hemoglobin was 10.8 mg/dL.\nRoutine chemistries were normal. A 4-mm punch biopsy taken from the right forearm\nrevealed foamy macrophages in the dermis with an intense neutrophilic infiltrate\nextending into the subcutaneous fat (Figure 2A). A lower magnification view (x4)\nshowed intense inflammatory cell infiltrate that outlined the dermal vasculature and\nextended into the subcutaneous fat. There was a perivascular mixed inflammatory\ninfiltrate and fibrinoid necrosis of small vessels. Fite stain showed beaded and\ngranular acid-fast bacilli within the histiocytes and focally within cutaneous nerve\ntwigs (Figure 2B).\nPolymerase chain reaction for M leprae DNA was positive. Tissue\nculture was negative for bacteria and fungi. The biopsy was reviewed by the US\nNational Hansen’s Disease Program in Carville, Louisiana. Compared with a biopsy\nfrom 2015, the inflammatory infiltrates were diminished and the bacilli had a\ndegenerating appearance. These findings were consistent with appropriate response to\nantimycobacterial therapy. Treatment with thalidomide 100 mg daily was initiated\nwith improvement in the appearance of the skin lesions (Figure 3). A repeat biopsy performed 6 months\nlater showed lack of neutrophilic infiltrates and decreased number of acid-fast\nbacilli. Monthly skin scrapings from affected sites showed progressively decreased\nbacterial load.\n\nFigure 1. Image of the anterior forearms. Multiple nodules on anterior forearms,\nhypotrichosis, and areas of hyperpigmentation. Some lesions had inflammatory\nappearance, which are typical for active lesions in the setting of erythema\nnodosum leprosum.\n\nFigure 2. (A) Hematoxylin and eosin stain of punch biopsy of forearms. Foamy\nmacrophages (red arrow) in the dermis with an intense neutrophilic\ninfiltrate (black arrow) forming abscesses (40×). (B) Fite stain of punch\nbiopsy of the forearms. It shows acid-fast organisms (1000×) with beaded,\ngranular and degenerated appearance within histiocytes (red arrow). Tissue\npolymerase chain reaction (PCR) was positive for Mycobacterium\nleprae DNA. A positive PCR result does not mean viable bacteria\nare present.\n\nFigure 3. Image of the anterior forearms post-treatment. Decreased nodularity and\nhyperpigmentation of the skin after 6 months of treatment with\nthalidomide.\n\nDiscussion\nThe distinction between persistent infection (disease progression while on treatment\nor relapse posttreatment) and immunologic reactions in leprosy can be challenging.\nPersistent infection is less common and often reflects poor adherence or incomplete\ntreatment. Antimycobacterial drug resistance can also occur, but it is rare. In\npersistent infection, skin biopsy typically shows a rising bacterial load. The\npresence of bacilli, however, does not always equate to active disease. In heavily\ninfected lepromatous leprosy patients, dead bacilli can remain in the tissues and\nnerves for up to 10 years.2 These individuals have macrophage dysfunction, which contributes to a slow\nclearance of mycobacteria. Viability testing can play a role in the evaluation of\npatients with persistent bacilli. The method frequently used is the mouse footpad\ntechnique. This method is time consuming, expensive, labor-intensive, and lacks\nsensitivity and specificity of comparable bacterial cultures. However, there is no\naccepted alternative for cultivating M leprae/leprosum.3 Another method to assess treatment response is the comparison of skin\nbiopsies performed at regular (1-2 year) intervals and evaluating reduction of\ninflammation and decline of bacilli in the tissues. In our patient, persistent\ninfection was unlikely due to the decrease and degeneration of mycobacteria observed\non skin biopsy after prolonged treatment.\n\nThere are 2 types of immunological reactions in leprosy: Type 1 reaction\n(T1R)/reversal reaction and T2R/erythema nodosum leprosum. T1R typically occurs in\npatients with borderline disease, while T2R occurs in patients with lepromatous\ndisease. These reactions can be seen in up to 50% of patients1 and there is no temporal correlation to treatment.4 In our patient, T2R was diagnosed based on a compatible clinical presentation\nand the presence of leukocytoclastic vasculitis and panniculitis with neutrophilia\nin skin biopsy. The characteristic biopsy findings in T2R are infiltration of\nneutrophils superimposed on chronic inflammation and detection of M\nleprae by staining or polymerase chain reaction methods. Neutrophils\nare rare in all other types of leprosy lesions. In addition, patients with\nimmunologic reactions typically respond to systemic corticosteroid and other forms\nof immunosuppression, unlike those with persistent infection.5\n\nConclusion\nDue to migration and globalization, leprosy will continue to be reported in the\nUnited States. In 2015 alone, 178 new cases were reported.6 Clinicians should be aware of the potential complications associated with\nthis infection including persistent infection and immunologic reactions. A high\nindex of suspicion and accurate interpretation of skin biopsy results are essential.\nThe US National Hansen’s Disease Program provides consultation services and assists\nclinicians in the diagnosis, treatment, and monitoring of challenging cases.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the\nresearch, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or\npublication of this article.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual\ncases.\n\nInformed Consent: Written informed consent was obtained from the patient for their anonymized\ninformation to be published in this article.\n==== Refs\nReferences\n1 \nWalker SL Lockwood DN. \nThe clinical and immunological features of\nleprosy\n. Br Med Bull .\n2006 ;77-78 :103 -121\n.17090777 \n2 \nShetty VP Suchitra K Uplekar MW Antia NH. \nPersistence of Mycobacterium leprae in the\nperipheral nerve as compared to the skin of multidrug-treated leprosy\npatients\n. Lepr Rev .\n1992 ;63 :329 -336\n.1479872 \n3 \nLevy L Ji B. \nThe mouse foot-pad technique for cultivation of\nMycobacterium leprae\n. Lepr\nRev .\n2006 ;77 :5 -24\n.16715686 \n4 \nScollard DM Martelli CM Stefani MM , et al\nRisk factors for leprosy\nreactions in three endemic countries\n. Am J Trop Med\nHyg .\n2015 ;92 :108 -114\n.25448239 \n5 \nEichelmann K Gonzalez SEG Salas-Alanis JC Ocampo-Candiani J. \nLeprosy. An update: definition, pathogenesis, classification,\ndiagnosis, and treatment\n. Actas\nDermosifiliogr .\n2013 ;104 :554 -563\n.23870850 \n6 \nUS Health Resources and Services Administration .\nNational Hansen’s Disease (Leprosy) Program caring and curing\nsince 1894\n. Accessed May 2, 2020 \nhttps://www.hrsa.gov/hansens-disease/index.html\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2324-7096", "issue": "8()", "journal": "Journal of investigative medicine high impact case reports", "keywords": "Mycobacterium leprae; erythema nodosum leprosum; leprosy; type 2 immunological reaction", "medline_ta": "J Investig Med High Impact Case Rep", "mesh_terms": "D001706:Biopsy; D004487:Edema; D004893:Erythema Nodosum; D005260:Female; D006801:Humans; D007917:Leprostatic Agents; D015440:Leprosy, Lepromatous; D008875:Middle Aged; D011241:Prednisone; D012867:Skin", "nlm_unique_id": "101624758", "other_id": null, "pages": "2324709620927884", "pmc": null, "pmid": "32462938", "pubdate": "2020", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "25448239;16715686;23870850;1479872;17090777", "title": "Persistent Infection Versus Type 2 Immunological Reaction in Lepromatous Leprosy.", "title_normalized": "persistent infection versus type 2 immunological reaction in lepromatous leprosy" }

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PERSISTENT INFECTION VERSUS TYPE 2 IMMUNOLOGICAL REACTION IN LEPROMATOUS LEPROSY. 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{ "abstract": "BACKGROUND\nPlatinum agents are essential for treating gynecological malignancies, particularly ovarian cancer. However, multiple carboplatin doses may cause hypersensitivity reactions (HSRs). Carboplatin desensitization prevents life-threatening HSRs and promotes the successful completion of planned chemotherapy.\n\n\nMETHODS\nSince January 2010, carboplatin desensitization was performed at our institution. Solutions with 1/1000, 1/100, and 1/10 dilutions of carboplatin and an undiluted solution were prepared in 250 mL of 5% glucose. Each solution was administered as a 1-h intravenous infusion (4-step 4-h protocol). This retrospective analysis was approved by the institutional review board.\n\n\nRESULTS\nFrom January 2010 to December 2013, 20 patients with gynecological malignancies (median age 62 years, range 43-74 years) received desensitization treatment. The International Federation of Gynecology and Obstetrics stages at presentation were I, II, III, and IV in 1, 1, 15, 13 patients, respectively. During first-line and second-line treatments, 3 and 17 patients, respectively, experienced carboplatin-induced HSRs. The median carboplatin cycle number was 11 (range 2-16). In the first desensitization cycle, 17 (85%) patients completed treatment without adverse events, 2 experienced Grade 1 HSRs but completed treatment, and 1 experienced Grade 3 HSR and discontinued treatment. The first desensitization cycle completion rate was 95%. Of 83 desensitization cycles administered, 79 (95.2%) were completed. No treatment-related deaths occurred.\n\n\nCONCLUSIONS\nMost patients completed the planned chemotherapy. Our protocol could be conducted safely with shorter duration and simpler procedures than previous protocols. Carboplatin desensitization seems beneficial for patients with a history of carboplatin-induced HSRs; however, the risk of HSR recurrence still remains. Desensitization should therefore be performed only by well-trained staff.", "affiliations": "Department of Medical Oncology, Hyogo Cancer Center, 13-70 Kitaoji-cho, Akashi, Hyogo, 673-8558, Japan, ntakase@hp.pref.hyogo.jp.", "authors": "Takase|Naoto|N|;Matsumoto|Koji|K|;Onoe|Takuma|T|;Kitao|Akihito|A|;Tanioka|Maki|M|;Kikukawa|Yoshitaka|Y|;Yamaguchi|Satoshi|S|;Fujiwara|Kiyoshi|K|;Negoro|Shunichi|S|", "chemical_list": "D017671:Platinum Compounds; D016190:Carboplatin", "country": "Japan", "delete": false, "doi": "10.1007/s10147-014-0731-1", "fulltext": null, "fulltext_license": null, "issn_linking": "1341-9625", "issue": "20(3)", "journal": "International journal of clinical oncology", "keywords": null, "medline_ta": "Int J Clin Oncol", "mesh_terms": "D000328:Adult; D000368:Aged; D016190:Carboplatin; D003888:Desensitization, Immunologic; D004342:Drug Hypersensitivity; D005260:Female; D005833:Genital Neoplasms, Female; D006801:Humans; D008875:Middle Aged; D017671:Platinum Compounds; D012189:Retrospective Studies", "nlm_unique_id": "9616295", "other_id": null, "pages": "566-73", "pmc": null, "pmid": "25030546", "pubdate": "2015-06", "publication_types": "D016428:Journal Article", "references": "8175010;15547181;22870105;12953086;11870165;12798707;16054201;12826431;15977213;22640034;11528251;1999708;22690725;19501233;20886011;19823066;12860964;20299757;18502492;16966687;10561172", "title": "4-step 4-h carboplatin desensitization protocol for patients with gynecological malignancies showing platinum hypersensitivity: a retrospective study.", "title_normalized": "4 step 4 h carboplatin desensitization protocol for patients with gynecological malignancies showing platinum hypersensitivity a retrospective study" }

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"18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypersensitivity", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cold sweat", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "TAKASE N, MATSUMOTO K, ONOE T, KITAO A, TANIOKA M, KIKUKAWA Y, ET AL. 4-STEP 4-H CARBOPLATIN DESENSITIZATION PROTOCOL FOR PATIENTS WITH GYNECOLOGICAL MALIGNANCIES SHOWING PLATINUM HYPERSENSITIVITY: A RETROSPECTIVE STUDY. INT-J-CLIN-ONCOL 2015; 20(3):566-573.", "literaturereference_normalized": "4 step 4 h carboplatin desensitization protocol for patients with gynecological malignancies showing platinum hypersensitivity a retrospective study", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20150730", "receivedate": "20150730", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11325137, "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" }, { "companynumb": "JP-MYLANLABS-2015M1023772", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": "091063", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "UTERINE CANCER", "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": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "UTERINE CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TAKASE N, MATSUMOTO K, ONOE T, KITAO A, TANIOKA M, KIKUKAWA Y, ET AL. 4-STEP 4-H CARBOPLATIN DESENSITIZATION PROTOCOL FOR PATIENTS WITH GYNECOLOGICAL MALIGNANCIES SHOWING PLATINUM HYPERSENSITIVITY: A RETROSPECTIVE STUDY. INT-J-CLIN-ONCOL 2015; 20(3):566-573.", "literaturereference_normalized": "4 step 4 h carboplatin desensitization protocol for patients with gynecological malignancies showing platinum hypersensitivity a retrospective study", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20150804", "receivedate": "20150715", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11272418, "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": "JP-MYLANLABS-2015M1023773", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": "091063", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "OVARIAN CANCER STAGE II", "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": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "OVARIAN CANCER STAGE II", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypersensitivity", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Paraesthesia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pruritus", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dyspepsia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TAKASE N, MATSUMOTO K, ONOE T, KITAO A, TANIOKA M, KIKUKAWA Y, ET AL. 4-STEP 4-H CARBOPLATIN DESENSITIZATION PROTOCOL FOR PATIENTS WITH GYNECOLOGICAL MALIGNANCIES SHOWING PLATINUM HYPERSENSITIVITY: A RETROSPECTIVE STUDY. INT-J-CLIN-ONCOL 2015; 20(3):566-573.", "literaturereference_normalized": "4 step 4 h carboplatin desensitization protocol for patients with gynecological malignancies showing platinum hypersensitivity a retrospective study", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20150804", "receivedate": "20150715", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11272478, "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": "JP-MYLANLABS-2015M1023167", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXTROSE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "250ML OF 5%", "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": "GLUCOSE" }, { "actiondrug": null, "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": "1", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": "091063", "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": "CARBOPLATIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "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": "DEXAMETHASONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "GRANISETRON" }, "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": "GRANISETRON" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RANITIDINE\\RANITIDINE 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": "RANITIDINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Palpitations", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cold sweat", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypersensitivity", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Faecal incontinence", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "TAKASE N, MATSUMOTO K, ONOE T, KITAO A, TANIOKA M, KIKUKAWA Y, ET AL. 4-STEP 4-H CARBOPLATIN DESENSITIZATION PROTOCOL FOR PATIENTS WITH GYNECOLOGICAL MALIGNANCIES SHOWING PLATINUM HYPERSENSITIVITY: A RETROSPECTIVE STUDY. INT-J-CLIN-ONCOL 2015; 20(3):566-573.", "literaturereference_normalized": "4 step 4 h carboplatin desensitization protocol for patients with gynecological malignancies showing platinum hypersensitivity a retrospective study", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20150804", "receivedate": "20150713", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11267426, "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": "JP-MYLANLABS-2015M1023799", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": "091063", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "OVARIAN CANCER STAGE III", "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": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "OVARIAN 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": "PACLITAXEL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TAKASE N, MATSUMOTO K, ONOE T, KITAO A, TANIOKA M, KIKUKAWA Y, ET AL. 4-STEP 4-H CARBOPLATIN DESENSITIZATION PROTOCOL FOR PATIENTS WITH GYNECOLOGICAL MALIGNANCIES SHOWING PLATINUM HYPERSENSITIVITY: A RETROSPECTIVE STUDY. INT-J-CLIN-ONCOL 2015; 20(3):566-573.", "literaturereference_normalized": "4 step 4 h carboplatin desensitization protocol for patients with gynecological malignancies showing platinum hypersensitivity a retrospective study", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20150804", "receivedate": "20150715", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11272479, "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": "JP-MYLANLABS-2015M1023163", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "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": "DEXAMETHASONE." }, { "actiondrug": null, "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": "1", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": "091063", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ENDOMETRIAL CANCER 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": "RANITIDINE\\RANITIDINE 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": "RANITIDINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ENDOMETRIAL CANCER 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": "PACLITAXEL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "GRANISETRON" }, "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": "GRANISETRON" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXTROSE" }, "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": "GLUCOSE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cold sweat", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypersensitivity", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Palpitations", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TAKASE N, MATSUMOTO K, ONOE T, KITAO A, TANIOKA M, KIKUKAWA Y, ET AL. 4-STEP 4-H CARBOPLATIN DESENSITIZATION PROTOCOL FOR PATIENTS WITH GYNECOLOGICAL MALIGNANCIES SHOWING PLATINUM HYPERSENSITIVITY: A RETROSPECTIVE STUDY. INT-J-CLIN-ONCOL 2015; 20(3):566-573.", "literaturereference_normalized": "4 step 4 h carboplatin desensitization protocol for patients with gynecological malignancies showing platinum hypersensitivity a retrospective study", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20150723", "receivedate": "20150713", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11267413, "safetyreportversion": 3, "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\nSinus arrest, atrio-ventricular block, supraventricular, and ventricular arrhythmias have been reported in patients with sleep apnea syndrome. The arrhythmias usually occur during sleep and contribute to the cardiovascular morbidity and mortality, and the treatment of sleep apnea usually results in the resolution of the brady- arrhythmias. Weight loss, continuous positive airway pressure (CPAP), oral appliances, and upper airway surgery are the recommended treatments, however, compliance and efficacy are issues.\n\n\nMETHODS\nA 58-year-old Arab man presented with recurrent presyncope. He was subsequently diagnosed with sleep apnea associated with frequent and significant sinus pauses. He presented a treatment challenge because he refused continuous positive airway pressure and pacemaker, however, he was successfully treated with theophylline.\n\n\nCONCLUSIONS\nFrequent and significant sinus pause associated with sleep apnea was successfully treated with theophylline in our patient when the standard treatment of care was refused.", "affiliations": "Section of Adult Cardiology, Cardiovascular Department, King Faisal Specialist Hospital & Research Center, P.O. Box 40047, Jeddah, 21499, Kingdom of Saudi Arabia. amindaoulah@yahoo.com.;Internal Medicine Department, University of Alabama Huntsville Regional Medical Campus, Huntsville, Alabama, USA. dr.sara.ocheltree@gmail.com.;Section of Pulmonology, Internal Medicine Department, King Faisal Specialist Hospital & Research Center, Jeddah, Kingdom of Saudi Arabia. salemalfaifi@hotmail.com.;Section of Infectious Disease, Internal Medicine Department, King Faisal Specialist Hospital & Research Center, Jeddah, Kingdom of Saudi Arabia. waleedamasaib@hotmail.com.;Heart and Vascular Institute, Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates. alsheikhali@gmail.com.;Department of Family Medicine, McMaster University, Hamilton, Ontario, Canada. farhan.asrar@medportal.ca.;Baystate Medical Center, Tufts University School of Medicine, Springfield, Massachusetts, USA. amir.lotfi@tufts.edu.", "authors": "Daoulah|Amin|A|;Ocheltree|Sara|S|;Al-Faifi|Salem M|SM|;Ahmed|Waleed|W|;Alsheikh-Ali|Alawi A|AA|;Asrar|Farhan|F|;Lotfi|Amir|A|", "chemical_list": "D013806:Theophylline", "country": "England", "delete": false, "doi": "10.1186/s13256-015-0596-6", "fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 59610.1186/s13256-015-0596-6Case ReportSleep apnea and severe bradyarrhythmia – an alternative treatment option: a case report Daoulah Amin amindaoulah@yahoo.com Ocheltree Sara dr.sara.ocheltree@gmail.com Al-Faifi Salem M salemalfaifi@hotmail.com Ahmed Waleed waleedamasaib@hotmail.com Alsheikh-Ali Alawi A alsheikhali@gmail.com Asrar Farhan farhan.asrar@medportal.ca Lotfi Amir amir.lotfi@tufts.edu Section of Adult Cardiology, Cardiovascular Department, King Faisal Specialist Hospital & Research Center, P.O. Box 40047, Jeddah, 21499 Kingdom of Saudi Arabia Internal Medicine Department, University of Alabama Huntsville Regional Medical Campus, Huntsville, Alabama USA Section of Pulmonology, Internal Medicine Department, King Faisal Specialist Hospital & Research Center, Jeddah, Kingdom of Saudi Arabia Section of Infectious Disease, Internal Medicine Department, King Faisal Specialist Hospital & Research Center, Jeddah, Kingdom of Saudi Arabia Heart and Vascular Institute, Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates Department of Medicine, Tufts University School of Medicine, Boston, MA USA Department of Family Medicine, McMaster University, Hamilton, Ontario Canada Health & Counselling Centre, University of Toronto, Mississauga, Ontario Canada Baystate Medical Center, Tufts University School of Medicine, Springfield, Massachusetts USA 15 5 2015 15 5 2015 2015 9 11328 10 2014 24 4 2015 © Daoulah et al.; licensee BioMed Central. 2015This 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.Introduction\nSinus arrest, atrio-ventricular block, supraventricular, and ventricular arrhythmias have been reported in patients with sleep apnea syndrome. The arrhythmias usually occur during sleep and contribute to the cardiovascular morbidity and mortality, and the treatment of sleep apnea usually results in the resolution of the brady- arrhythmias. Weight loss, continuous positive airway pressure (CPAP), oral appliances, and upper airway surgery are the recommended treatments, however, compliance and efficacy are issues.\n\nCase presentation\nA 58-year-old Arab man presented with recurrent presyncope. He was subsequently diagnosed with sleep apnea associated with frequent and significant sinus pauses. He presented a treatment challenge because he refused continuous positive airway pressure and pacemaker, however, he was successfully treated with theophylline.\n\nConclusion\nFrequent and significant sinus pause associated with sleep apnea was successfully treated with theophylline in our patient when the standard treatment of care was refused.\n\nKeywords\nBradycardiaSinus arrestSleep apneaTheophyllineissue-copyright-statement© The Author(s) 2015\n==== Body\nIntroduction\nSleep apnea-associated bradyarrhythmias contribute to the cardiovascular mortality and morbidity of sleep apnea [1-4] and treatment of sleep apnea usually results in resolution of bradyarrhythmias [3]. To date, weight loss, continuous positive airway pressure (CPAP), oral appliances, and upper airway surgery are the recommended treatments; however, compliance and efficacy are issues [5,6]. Our patient presented a treatment challenge because he had significant sinus pauses associated with sleep apnea, but he refused recommended treatment. Theophylline, used to treat brady-arrhythmia in different settings, was introduced as an alternative treatment option and was successful in treating our patient.\n\nCase presentation\nA 58-year-old Arab man was referred to our electrophysiology clinic with monthly episodes of presyncope for the last 3 months. Despite two episodes of presyncope per year for 3 years, he had not sought medical advice. He had multiple comorbidities including coronary artery disease status post coronary artery bypass surgery (CABG), type 2 diabetes mellitus, dyslipidemia, and class III obesity (body mass index 41) with a neck circumference of 45cm and modified Mallampati score of 4.\n\nAfter his CABG, aspirin, atorvastatin, and metformin were restarted, with the addition of metoprolol tartrate 25mg twice daily. More frequent episodes of presyncope occurred. An electrocardiogram revealed normal sinus rhythm with normal PR, QRS and QTc intervals. Transthoracic echocardiography demonstrated a normal left ventricular systolic function and 24-hour ambulatory Holter monitoring recorded multiple sinus pauses occurring from 11:22 p.m. until 11:46 a.m. with a maximum pause of 22 seconds occurring at 11:45:33 a.m. (see Figure 1). During this observation, there were no episodes of presyncope.Figure 1 Holter recording displaying a prolonged sinus pause. A sample from the Holter recording displaying a non-conducted P-wave (small black arrow) preceded by a sinus pause of 2.7 seconds (large black arrow) and followed by sinus arrest of 22 seconds with junctional escape beats (between the horizontal start and end arrows). The gray arrows point to sinus bradycardia and black arrowhead points to the first P-wave, after the return of sinus rhythm. Holter revealing a non-conducted P-wave (small black arrow) followed by sinus arrest (horizontal arrows).\n\n\n\nHe was admitted to our hospital for further workup. Despite discontinuation of metoprolol for 1 week, his telemetry revealed multiple episodes of sinus pause, observed during daytime sleepiness or snoring episodes. Obstructive sleep apnea (OSA) was suspected and a sleep study demonstrated both central and OSA: Epworth score 7, sleep latency of 17 minutes, Apnea–Hypopnea Index (AHI) of 98/hour, arousal index of 49/hour and lowest oxygen saturation at 78% on room air (Table 1).Table 1 \nSymptoms reported, Holter monitor, theophylline levels and polysomnography results at presentation and during follow up\n\n\n\t\nSymptoms\n\t\nWeight (kg)\n\t\n24-hour Holter monitor\n\t\nTheophylline level\n*\n\t\nPolysomnography\n\t\n\nMax sinus pause (seconds)\n\t\nTotal number of sinus pauses\n\t\nMin/max/Average HR (beats/minute)\n\t\nPrior to presentation (2008 until 2011)\tPresyncope twice a year for 3 years\t115\t–\t–\t–\tNot on treatment\t–\t\nAt presentation (September 2011)\tPresyncope once a month for 3 months\t119\t22\t71\t49/119/85\tNot on treatment\tEpworth score 7\t\nSleep latency of 17 minutes\t\nAHI of 98/hour\t\nArousal index of 49/hour\t\nLowest oxygen saturation at 78% on room air\t\n5-month follow up\tNone\t120\t6\t18\t61/125/93\t11.11\tNot done\t\n6-month follow up\tNone\t122\t5\t5\t68/124/94\t13.0\tNot done\t\n7-month follow up\tNone\t126\tNone\tNone\t71/128/92\t14.4\tEpworth score of 11\t\nSleep latency of 28 minutes\t\nAHI of 96/hour\t\nArousal index of 43/hour\t\nLowest oxygen saturation at 78% on room air\t\n14-month follow up\tNone\t123\tNone\tNone\t69/123/90\t11.4\tNot done\t\n19-month follow up\tNone\t129\t2.9\t3\t67/115/82\t14.6\tEpworth score of 11\t\nSleep latency of 48.5 minutes\t\nAHI of 83/hour\t\nArousal index of 42.8/hour\t\nLowest oxygen saturation at 75% on room air\t\n29-month follow up\tNone\t130\tNone\tNone\t65/110/81\tNot done\tNot done\t\nAHI = Apnea–Hypopnea Index; HR = Heart rate; Max = Maximum; Min = Minimum.\n\n\n*Therapeutic level is between 10 and 20mcg/mL in plasma [4].\n\n\n\nOvernight CPAP was started and the telemetry showed sinus bradycardia with a minimum heart rate of 30 beats per minute with infrequent pauses of less than 3 seconds. However he refused to continue to use the CPAP upon discharge. In addition, he was offered a pacemaker and he refused. A trial of theophylline 200mg twice daily was initiated and he was discharged from our hospital and encouraged to initiate a weight reduction program.\n\nAt follow up, he had no further episode of presyncope with infrequent short or no pauses at therapeutic theophylline levels (Table 1). A follow-up sleep study revealed improvement in the central element of his sleep apnea, however, his AHI did not significantly improve; such results are expected with theophylline therapy (Table 1).\n\nDiscussion\nSleep apnea syndrome has been associated with cardiovascular complications including hypertension [1], heart failure [2] and cardiac arrhythmia [3]. Observational studies have shown that treating sleep apnea syndrome can decrease blood pressure [1], reduce cardiac arrhythmia [3] and decrease cardiovascular mortality [4]. Noninvasive positive pressure ventilation effectively decreases the incidence of sleep apnea-associated arrhythmia [3]; however, not all patients can tolerate it and compliance is an issue [5]. We report the case of a patient who presented with presyncope most likely secondary to sleep apnea-induced brady-arrhythmia. He was started on beta-blockers after his CABG, which could have made his brady-arrhythmia worse and contributed to increasing presyncope. However, while he was an in-patient and off his metoprolol he continued to have significant sinus pause. He did not tolerate CPAP and refused a pacemaker so, as a last resort, theophylline treatment was started and he reported complete resolution of his symptoms. A Holter monitor documented a decrease in both the frequency and duration of sinus pauses. We initiated theophylline based on its effectiveness in treating brady-arrhythmia in the setting of post-cardiac transplant [6] and spinal cord injury [7]. The mechanism of brady-arrhythmia in sleep apnea syndrome is hypothesized to be due to the activation of the diving reflex by hypoxemia and apnea, with reflex activation of the cardiac vagal nerve. This induces severe nocturnal bradyarrhythmias, especially during rapid eye movement sleep [8]. Theophylline is a nonselective phosphodiesterase inhibitor that also competitively blocks adenosine receptors resulting in central nervous system and cardiovascular stimulation. Theophylline also increases the respiratory drive and it has been used in patients with central sleep apnea due to left ventricular dysfunction before CPAP and is still recommended in patients who cannot tolerate CPAP [9]. For OSA, theophylline has been shown to mildly reduce obstructive events but is associated with sleep disruption and therefore it is not recommended [9]. The limitations and side effects of theophylline result from its narrow therapeutic index, traditionally between 10 and 20mcg/mL [4] in plasma. Theophylline is metabolized in the liver through the cytochrome P450 system and consequently is implicated in several drug interactions with commonly prescribed drugs, which may increase serum concentrations of theophylline [10].\n\nConclusions\nWe report a case of treating sleep apnea-induced brady-arrhythmia with theophylline when standard treatment of care was refused. Further studies are needed to determine the safety and efficacy of theophylline for treating sleep apnea-induced bradyarrhythmias to ensure the benefits outweigh the risks.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nAHIApnea–Hypopnea Index\n\nCABGCoronary artery bypass surgery\n\nCPAPContinuous positive airway pressure\n\nOSAObstructive sleep apnea\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nAD was the major contributor and provided care to the patient. AD also conceived the case report, collected information and wrote the manuscript. SO, SMAF AAAA and AL contributed in writing the manuscript and developing the table and figure. WA assisted with data collection. FA contributed in the preparation, editing and revision of the manuscript. All authors have read and approved the final manuscript.\n\nAcknowledgement\nThe lead author would like to acknowledge Dr. James Stewart and Dr. Ciaran M. Dixon for their assistance in proofreading the manuscript.\n\nThe work was conducted in the Section of Adult Cardiology, Cardiovascular Department, King Faisal Specialist Hospital & Research Center-Jeddah, Kingdom of Saudi Arabia.\n==== Refs\nReferences\n1. Dhillon S Chung S Fargher T Huterer N Shapiro C Sleep apnea, hypertension, and the effects of continuous positive airway pressure Am J Hypertens. 2005 18 594 600 10.1016/j.amjhyper.2004.11.031 15882540 \n2. Naughton M The link between obstructive sleep apnea and heart failure: underappreciated opportunity for treatment Curr Cardiol Rep. 2005 7 211 5 10.1007/s11886-005-0079-2 15865863 \n3. Simantirakis EN Schiza SI Marketou ME Chrysostomakis SI Chlouverakis GI Klapsinos NC Severe bradyarrhythmias in patients with sleep apnoea: the effect of continuous positive airway pressure treatment: a long-term evaluation using an insertable loop recorder Eur Heart J 2004 25 1070 6 10.1016/j.ehj.2004.04.017 15191779 \n4. Buchner NJ Sanner BM Borgel J Rump LC Continuous positive airway pressure treatment of mild to moderate obstructive sleep apnea reduces cardiovascular risk Am J Respir Crit Care Med. 2007 176 1274 80 10.1164/rccm.200611-1588OC 17673692 \n5. Zozula R Rosen R Compliance with continuous positive airway pressure therapy: assessing and improving treatment outcomes Curr Opin Pulm Med. 2001 7 391 8 10.1097/00063198-200111000-00005 11706314 \n6. Qaseem A Holty JEC Owens DK Dallas P Starkey M Shekelle P A clinical practice guideline from the American College of Physicians Ann Intern Med. 2013 159 471 83 \n7. Bertolet BD Eagle DA Conti JB Mills RM Belardinelli L Bradycardia after heart transplantation: reversal with theophylline J Am Coll Cardiol 1996 28 396 9 10.1016/0735-1097(96)00162-3 8800116 \n8. Sakamoto T Sadanaga T Okazaki T Sequential use of aminophylline and theophylline for the treatment of atropine-resistant bradycardia after spinal cord injury: a case report J Cardiol 2007 49 91 6 17354583 \n9. Javaheri S Parker TJ Wexler L Liming JD Lindower P Roselle GA Effect of theophylline on sleep-disordered breathing in heart failure N Engl J Med 1996 335 562 7 10.1056/NEJM199608223350805 8678934 \n10. Giembycz MA Corrigan CJ Seybold J Newton R Barnes PJ Identification of cyclic AMP phosphodiesterases 3, 4 and 7 in human CD41 and CD81 T-lymphocytes: role in regulating proliferation and the biosynthesis of interleukin-2 Br J Pharmacol. 1996 118 1945 58 10.1111/j.1476-5381.1996.tb15629.x 8864528\n\n", "fulltext_license": "CC BY", "issn_linking": "1752-1947", "issue": "9()", "journal": "Journal of medical case reports", "keywords": null, "medline_ta": "J Med Case Rep", "mesh_terms": "D001919:Bradycardia; D006801:Humans; D008297:Male; D008875:Middle Aged; D009765:Obesity; D017286:Polysomnography; D012891:Sleep Apnea Syndromes; D013806:Theophylline; D016312:Treatment Refusal", "nlm_unique_id": "101293382", "other_id": null, "pages": "113", "pmc": null, "pmid": "25975802", "pubdate": "2015-05-15", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "15191779;15865863;8864528;8800116;8678934;15882540;11706314;24061345;17673692;17354583", "title": "Sleep apnea and severe bradyarrhythmia--an alternative treatment option: a case report.", "title_normalized": "sleep apnea and severe bradyarrhythmia an alternative treatment option a case report" }

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{ "abstract": "Multiple sclerosis is the most common neurological disease of young adults that causes major disability. In Romania, it is estimated that this disease has a prevalence of 35-40 per 100,000 inhabitants. It is a disease that begins at the age of 20-40 years and is 2-3 times more common in women than in men. More than half of patients with MS develop the disease in their fertile period of life; therefore, MS patients use contraceptive methods while being under our treatment. Since several therapeutic options have been implemented with good efficiency in the disease stabilization, increasingly more patients begin to wonder about the possibility of having a child and about the possible risks of pregnancy. The evolution during pregnancy and the lactation period has been favorable, with lower relapses and side effects comparable to those in the general population. In addition, babies born to mothers with MS have not had a significantly different mean gestational age or birth weight compared to babies born to healthy mothers.", "affiliations": "Head of Neurology, \"Carol Davila\" University of Medicine and Pharmacy, Colentina Clinical Hospital, No. 19-21 Stefan cel Mare Avenue, 020125 Bucharest, Romania.;Department of Neurology, Colentina Clinical Hospital, No. 19-21 Stefan cel Mare Avenue, 020125 Bucharest, Romania.", "authors": "Buraga|Ioan|I|0000-0002-5223-7929;Popovici|Roxana-Elena|RE|", "chemical_list": "D007155:Immunologic Factors", "country": "United States", "delete": false, "doi": "10.1155/2014/513160", "fulltext": "\n==== Front\nScientificWorldJournalScientificWorldJournalTSWJThe Scientific World Journal2356-61401537-744XHindawi Publishing Corporation 10.1155/2014/513160Review ArticleMultiple Sclerosis and Pregnancy: Current Considerations http://orcid.org/0000-0002-5223-7929Buraga Ioan \n1\nPopovici Roxana-Elena \n2\n*\n1Head of Neurology, “Carol Davila” University of Medicine and Pharmacy, Colentina Clinical Hospital, No. 19-21 Stefan cel Mare Avenue, 020125 Bucharest, Romania\n2Department of Neurology, Colentina Clinical Hospital, No. 19-21 Stefan cel Mare Avenue, 020125 Bucharest, Romania*Roxana-Elena Popovici: doctor_roxi@yahoo.co.ukAcademic Editors: V. M. Rivera and E. J. Thompson\n\n2014 7 4 2014 2014 51316029 11 2013 24 12 2013 Copyright © 2014 I. Buraga and R.-E. Popovici.2014This 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.Multiple sclerosis is the most common neurological disease of young adults that causes major disability. In Romania, it is estimated that this disease has a prevalence of 35–40 per 100,000 inhabitants. It is a disease that begins at the age of 20–40 years and is 2-3 times more common in women than in men. More than half of patients with MS develop the disease in their fertile period of life; therefore, MS patients use contraceptive methods while being under our treatment. Since several therapeutic options have been implemented with good efficiency in the disease stabilization, increasingly more patients begin to wonder about the possibility of having a child and about the possible risks of pregnancy. The evolution during pregnancy and the lactation period has been favorable, with lower relapses and side effects comparable to those in the general population. In addition, babies born to mothers with MS have not had a significantly different mean gestational age or birth weight compared to babies born to healthy mothers.\n==== Body\n1. Introduction\n\nMS is the most common neurological disease of young adults that causes major disability. In Romania, it is estimated that this disease has a prevalence of 35–40 per 100,000 inhabitants. It is a disease that begins at the age of 20–40 years and is 2-3 times more common in women than in men. More than half of patients with MS develop the disease in the fertile period of life while being under treatment, and, therefore, they have to use contraceptive methods to avoid pregnancy.\n\nBefore 1950, most women with MS were counseled to avoid pregnancy because it was thought the disease could be worsened. Over the past 40 years, many studies have been done on hundreds of women with MS, and they have almost all reached the opposite conclusion that pregnancy reduces the number of MS exacerbations, especially in the third trimester.\n\nIn a large prospective study of 254 pregnant women with multiple sclerosis, the rate of relapse was 0.7 ± 0.9 per woman per year in the year before pregnancy, 0.5 ± 1.3 during the first trimester, 0.6 ± 1.6 during the second trimester, and 0.2 ± 1.0 during the third. This statistic shows that the frequency of relapses has decreased during pregnancy, especially during the third trimester, but the same study shows an increased rate of 1.2 ± 2.0 during the first three months postpartum which then returned to the prepregnancy rate [1].\n\nMore than half of patients with MS develop the disease in the fertile period of life during treatment, and they have to use various contraceptives. The effectiveness of disease-modifying therapy has made more and more patients want their first child, in view of a significant decrease in the annual relapse rate and periods of stable disease.\n\nThere have been several cases of patients with MS who were registering a stabilized trend, from both clinical and imaging point of view, when approaching the age of 30 and, therefore, willing for a scheduled pregnancy to be developed in optimal conditions without adverse effects on the mother or newborn.\n\nThe current advice is to discontinue disease-modifying treatment (DMT) prior to conception, although studies, which have considered this aspect, have found only minor adverse effects of interferons (IFN) and no effect of glatiramer acetate (GA) [2, 3].\n\n2. Our Clinical Experience\nColentina Clinical Hospital is one of the largest centers of MS in the country. At the moment, we have a total of 427 patients under the treatment program with interferons (Avonex, Rebif, and Betaferon) or GA. Of all patients, 129 are men and 298 are women and 68.7% (205 patients) are at fertility age (18–40 years).\n\nOur recommendation supports early initiation of immunomodulatory therapy in order to achieve stabilization of the disease. This stabilization occurs after a minimum of 3 years and a maximum of 5 years. During this period, some patients have given up the desire to have children because of the disease. Lately, increasingly more patients begin to wonder about the possibility of having a child and about the possible risks.\n\nWe have 21 patients that have interrupted immunomodulatory treatment when they made the decision to have a child and 18 patients who have discontinued the treatment in the first trimester of pregnancy.\n\nWe have a total of 34 healthy children, including one twin pregnancy; one birth defect (foramen ovale); one stillbirth and 3 spontaneous abortions; mothers whose babies were born healthy were exposed to interferon therapy as well as to GA. Birth defects occurred in a patient who discontinued the medication before becoming pregnant, stillbirth occurred in patient exposed to Betaseron, and spontaneous abortions occurred in patients exposed to Rebif (2 of them) and Avonex.\n\nOur patients had no relapses during pregnancy or breastfeeding. We restarted immunomodulatory treatment within 4 months after birth, except for one case who insisted to breastfeed for 6 months, at which time she made a relapse that increased her EDSS score by 1 point. The mean EDSS score in patients who remained pregnant was 2.1.\n\n3. The Impact of the MS Treatment on Pregnancy\nSince more and more therapeutic options have been released and implemented, we have performed a review of the impact that these drugs can have on the mother and the developing fetus. To achieve this, we reviewed information from the pregnancy registries about various therapies and the latest publications on the topic.\n\nThe interferons (Avonex, Betaseron, and Rebif) are all “Category C” drugs, meaning they caused some harm to fetuses in animal studies [4]. The Avonex Pregnancy Exposure Registry analyzed women with MS who were exposed to intramuscular (IM) IFNbeta-1a, approximately 1 week prior to conception or during the first trimester of pregnancy. Of the 306 outcomes, there were 272 live births, 28 spontaneous abortions, 5 induced abortions, and 1 stillbirth. The rate of spontaneous abortions (SAB) of 10.5% was comparable to the rate in the general population of 15%. Birth defects (spina bifida, Down syndrome, diaphragmatic hernia, duodenal atresia, hypospadias, club foot, trisomy 8, nuchal translucency, pyloric stenosis, and hydronephrosis) were reported in 17 infants and were consistent with those observed in the general population [5].\n\nThe Betaseron Pregnancy Registry was a follow-up study, with 86 live births, 2 stillbirths, and 11 SABs. The prevalence of SAB was 11.5%, with no significant difference from the 16% estimation for the general population. Stillbirths occurred in black women with both comorbidities and a history of prior SAB. There were 5 cases of birth defects (Down syndrome, hemangioma, polydactyly, ventricular septal defect, hip dysplasia, and patent foramen ovale), all exposed to interferon beta-1b during the first trimester of gestation, but the prevalence was not significantly different from the general population [6].\n\nOther studies have demonstrated the association of changes in other parameters such as lower birth weight [7], shorter gestational period [8], or higher SAB rates [9] in interferon beta-exposed pregnancies.\n\nGlatiramer acetate (Copaxone) is the only DMT with an FDA pregnancy “Category B” drug, meaning it did not cause harm to fetuses in animal studies. GA does not cross the placental barrier and it may be considered compatible with breastfeeding, because it is hard to believe that an amino acid polymer like GA could get entirely absorbed through an infant's gastrointestinal mucosa [10]. In a study on 44 women, only 7 patients discontinued GA, 9 remained on GA but discontinued when pregnant, and 28 remained on GA. The results were 28 normal children and 3 ongoing, one minor congenital anomaly, two pregnancies with Down syndrome who were terminated, one ectopic pregnancy, and 3 spontaneous abortions. These results suggest that GA may be safely continued during pregnancy [11].\n\nThere are studies that compared pregnancies under interferon-beta and under glatiramer acetate. The obstetric complications rates were similar for women who were exposed and who were not exposed to DMT. There has been one case of prematurity during the use of GA, but this was a patient that had three previous illegally provoked abortions. Another non-drug-related adverse event was a case of bone malformations in a mother exposed to GA [12]. No pattern of malformation was assigned to the first line MS drug (IFN-beta and GA) [13, 14]. Birth weight did not differ significantly from controls in pregnancies exposed to GA. There was a smaller difference between children whose mothers were or were not exposed to DMT and no significant difference between the heights of the children whose mothers had been exposed to GA or IFN [7, 8]. The relapse rate in mothers exposed in the first 8 weeks of pregnancy to DMT was significantly lower during pregnancy and after delivery and less EDSS progression was recorded in comparison with patients that were not exposed [12, 15].\n\nPatients with a more aggressive disease may be treated with natalizumab (Tysabri) or fingolimod (Gilenya). Given abnormalities seen in animal studies, there have been observed abnormalities that advise stopping the medication 2 or 3 months before conception. Natalizumab is a Category C drug and a reduction in pregnancy rates was observed in guinea pigs. No adverse effects were reported on male fertility [16]. Natalizumab crosses the placenta in the second trimester and is secreted in small amounts in the human milk [17]. The results from the Tysabri Pregnancy Exposure Registry showed a spontaneous abortions rate of 11.2% in 23 pregnancies, with no significant differences when compared with the general population. In 35 women exposed to natalizumab during accidental pregnancies, 28 healthy neonates and one child with 6 fingers were born and five early miscarriages were recorded [18].\n\nFingolimod (pregnancy Category C) is teratogenic in rats, with congenital abnormalities reported [19, 20]. In the fingolimod clinical trial program, 34 pregnancies resulted in 13 healthy infants, 1 with a tibia malformation believed to be unrelated to treatment, 5 spontaneous abortions, 9 elective ones, and 6 ongoing pregnancies [21]. Fingolimod crosses the placenta and is secreted in breast milk. It is currently advised that patients with MS cease fingolimod for at least 2 months before getting pregnant. This is because fingolimod remains in the blood for at least 2 months after stopping the treatment.\n\nDimethyl fumarate (BG-12) is a pending approval pregnancy category. There was no teratogenicity or evidence of infertility found in rats and rabbits. Cell hyperplasia in the testis was observed in male rats at all doses, but with no effect on fertility. In females, there were no consequent effects on fertility [22]. In an older study on rats, a dosage of 508 mg/kg induced death, 356 mg/kg induced delay of ossification, and 178 mg/kg increased embryo absorption [23]. There were 34 pregnant subjects who received BG-12 with 65% live births compared with 64% in placebo-treated Subjects, 9% spontaneous abortion rate and no fetal abnormalities, consistent with the expected rate in the general population (12–22%). For the time being, it is still unknown if dimethyl fumarate crosses the placenta or is secreted in breast milk [24].\n\nMitoxantrone is a Category D drug that causes growth retardation and premature births in animals [25]. Patients should not become pregnant while taking mitoxantrone and they should wait at least 6 months after discontinuation [10]. Placental transfer of mitoxantrone is limited; it is secreted in milk and contraindicated when breastfeeding [4].\n\nTeriflunomide is a Category X drug that causes teratogenicity in animals. It is contraindicated in pregnant women or with childbearing potential, who are not using reliable contraception. Teriflunomide crosses the placenta and is detected in rat milk, following a single oral dose [26].\n\nLaquinimod is in the category of pending approval. Animal studies demonstrated fetal malformation in rats, but not in rabbits [27]. Women with childbearing potential are advised to use effective contraception and no breastfeeding is recommended [28].\n\nDaclizumab, a monoclonal anti-CD25 antibody is a Category C drug, with no fetal malformation observed in monkeys, but with an increase in prenatal loss. Very low concentrations of daclizumab are secreted in the breast milk of lactating monkey. Recommendations are to use contraception and to avoid breastfeeding [29].\n\nShort courses of steroids have been regarded as safe in pregnancy [30], in the second and third trimesters of pregnancy. Steroids cross the placental barrier and may increase the risk of cleft palate and low birth weight when used in the first trimester. Prednisone, prednisolone, and methylprednisolone can be administered with low levels of fetal exposure and may be preferred for use during pregnancy [31].\n\nA promising treatment in the period around childbirth is intravenous immunoglobulins (IVIg). They appear to have no significant side effects on pregnancy and to reduce relapse rates [32, 33].\n\n4. Breastfeeding\nBreastfeeding should be encouraged, because there is no risk of disease transmission through breast milk. If the mother should receive a drug, it must be known that it is possible to be excreted in milk.\n\nMS itself does not pose any obstacles to breastfeeding. Women who breastfed exclusively had significantly lower postpartum disease activity compared with women who did not breastfeed exclusively or did not breastfeed at all [15, 34]. A possible explanation might be that only exclusive breastfeeding on demand suppresses ovarian function, with high prolactin levels [35]. In experimental settings, high levels of prolactin were shown to promote remyelination [36]. Breastfeeding mothers are advised not to start DMT after birth, as there are no reliable data available on drug transfer into milk and the effects on newborns [37]. For the women who do not want to breastfeed, the recommendation is to start DMT as soon as possible after birth, because of the delayed onset of efficacy for IFN-beta and GA [38].\n\nFragoso et al. reported on 9 mothers who breastfed for a mean period of 3.6 months while taking GA. No significant ill effects were observed in those children during or after breastfeeding [39]. Hellwig and Gold followed 3 mothers taking GA and one taking IFN-beta during breastfeeding without any noticeable problems [14].\n\n5. Difficulties during Pregnancy\nDuring pregnancy, there can be apparent worsening of preexisting dysfunction or the occurrence of new events. Women who have walking impairments may find these getting worse during late pregnancy, as the patient becomes heavier and their center of gravity shifts. Excess weight can decrease motility already affected by the process of demyelination more or less extensive at the corticospinal fibers. Increased use of assistive devices to walk or the use of a wheelchair may be advisable at these times.\n\nPreexisting dysfunctions may be of motor sphincter, digestive track, sensory activity, and fatigue and seem to be due to the state of pregnancy associated with weight gain. Bladder and bowel problems, which occur in all pregnant women, may be aggravated in women with MS who have preexisting urinary or bowel dysfunction. The presence of localized spinal demyelinating plaques associated with the uterus impact on thoracic-abdominopelvic cavity can generate or amplify urgency, constipation, and mild ventilatory dysfunction [40].\n\n6. Difficulties at Birth\nLabor and delivery are usually the same as in other women and no special management is needed. But in some cases, the obstetrician and the anesthetist must choose the safest option for the mother and fetus, taking into consideration the existing neurological dysfunction.\n\nMS has no contraindications, neither for natural birth nor for caesarean section. Both epidurals and anesthesia for caesarean births are safe in women with MS. Neither breastfeeding nor epidural analgesia has got worse disability in the postpartum period [1]. Special consideration may have to be taken for the minority of people with MS who are severely disabled or have respiratory problems.\n\n7. The Impact of Pregnancy on MS Activity\nDuring pregnancy, the evolution of our patients has been positive, with a much lower relapse rate. These observations are confirmed by a 10-year follow-up study that found a lower relapse rate in women with pregnancies after disease onset, compared to those without pregnancies after MS onset [41]. A prospective five-year study compared the rate of progression in disability between childless women, women who had onset of MS after childbirth, and women who had onset before or during their pregnancy. The rates of disability, including wheelchair dependence, increased most rapidly in women with no children [42] and the risk of conversion to secondary progressive MS was lower [43].\n\nThere have been many studies examining the impact of pregnancy on MS. They all show that pregnancy appears to have a positive protective influence, with relapse rates going down, especially during the third trimester. The reasons are unknown, but it is believed that hormone fluctuations levels in pregnancy could have a role. The hormone involved in altering the immune system is estrogen. During pregnancy, estrogen levels rise and are the highest in the last trimester. This is considered to suppress the activity of the immune system, consequently decreasing the disease activity. After the birth, estrogen levels rapidly drop and the immune system returns to its usual function and MS resumes its work [44].\n\nAnother explanation for the association of pregnancy with spontaneous remission and the postpartum period with exacerbations arises from an immunologic point of view. The fetal placental unit secretes cytokines such as interleukin-10, resulting in an increased number of T helper 2 cells instead of T helper 1. The tolerance of the fetus by the mother may be explained through this mechanism. An inversion of this cytokine balance occurs at birth and it could be regarded as a graft-rejection process [45].\n\n8. Disease Transmission and Fertility\nIt is known that multiple sclerosis is not directly inherited like other genetic diseases, and the patients are usually informed about the transmission incidence. The evidence shows that if the mother or father has MS, risk of getting the disease is 3–5% compared to the general population, where the probability is only 0.2%. If both parents have MS, the risk increases to 29.5%.\n\nThere are currently no genetic or prenatal tests, nor even tests on newborn, able to determine the probability of this circumstance. The risk in the general population is one out of every 800 children. In conclusion, although having a parent with MS increases the risk, the transmission incidence rate is still very small.\n\nHaving multiple sclerosis (MS) does not seem to affect fertility in male or female in any significant way. The standard immunomodulation agents for MS do not affect fertility itself. Mitoxantrone, an FDA-approved medication for progressive MS, may affect fertility in the same way that other chemotherapies do.\n\nAlthough MS has not been shown to affect fertility, approximately 15% of all couples have trouble conceiving. There have been 3 studies focused on this issue. It seems that one type of the medications used, GnRH agonists, may increase the relapse rate. This effect is not seen with GnRH antagonists. This increase in relapse rates is present for at least 3 months following treatment [46]. Failure of in vitro fertilization (IVF) was also shown to be associated with an increased relapse [47]. Treatment with IFN and, particularly, GA appears safe in the perinatal period and indication is to continue treatment when having IVF.\n\n9. Conclusion\nIncreasingly more women with multiple sclerosis want to have a baby. The decision to continue or discontinue the disease-modifying treatment belongs to the patient, together with her neurologist and her obstetrician. Patients must know all aspects of the adverse effects of therapy on themselves and on pregnancy and be aware of the benefits of continuing treatment during pregnancy.\n\nThe rate of relapse declines in pregnant women, especially in the third trimester, but before returning to the prepregnancy rate, the risk of relapse increases during the first three months postpartum.\n\nDisease-modifying therapy has not proven a 100% safe administration throughout pregnancy or while breastfeeding, which is why we need a larger number of studies to assess the safety profile. According to statistics and studies having been conducted so far, GA seems to be the only available treatment that patients can trust in case pregnancy occurs under therapy and it can be used with certain safety.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n==== Refs\n1 Confavreux C Hutchinson M Hours MM Cortinovis-Tourniaire P Moreau T Rate of pregnancy-related relapse in multiple sclerosis The New England Journal of Medicine 1998 339 5 285 291 2-s2.0-0032581445 9682040 \n2 Giannini M Portaccio E Ghezzi A Pregnancy and fetal outcomes after Glatiramer Acetate exposure in patients with multiple sclerosis: a prospective observational multicentric study BMC Neurology 2012 12 article 124 \n3 Amato MP Portaccio E Ghezzi A Pregnancy and fetal outcomes after interferon-β exposure in multiple sclerosis Neurology 2010 75 20 1794 1802 2-s2.0-78650016412 21079181 \n4 Ferrero S Pretta S Ragni N Multiple sclerosis: management issues during pregnancy European Journal of Obstetrics & Gynecology and Reproductive Biology 2004 115 3 9 15223156 \n5 Tomczyk S Wallace K Liu S Sperling B Pregnancy outcomes from the Avonex (interferon beta-1a) pregnancy exposure registry Proceedings of the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis 2012 \n6 Coyle PK Sinclair S Scheuerle AE Thorpe JM Albano J Rametta M Final results from the Betaseron (interferon beta-1b) Pregnancy Registry \n7 Weber-Schoendorfer C Schaefer C Multiple sclerosis, immunomodulators, and pregnancy outcome: a prospective observational study Multiple Sclerosis 2009 15 9 1037 1042 2-s2.0-69149096504 19692433 \n8 Patti F Cavallaro T Lo Fermo S Is in utero early-exposure to interferon beta a risk factor for pregnancy outcomes in multiple sclerosis? Journal of Neurology 2008 255 8 1250 1253 2-s2.0-60049097384 18677640 \n9 Boskovic R Wide R Wolpin J Bauer DJ Koren G The reproductive effects of beta interferon therapy in pregnancy: a longitudinal cohort Neurology 2005 65 6 807 811 2-s2.0-25444454284 16186517 \n10 Briggs GG Freeman RK Yaffe SJ Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk 2011 9th edition Philadelphia, Pa, USA Lippincott, Williams & Wilkins \n11 Miller AE Rustgi S Farrell C Use of glatiramer acetate during pregnancy: offering women a choice Multiple Sclerosis 2012 18 supplement 4 \n12 Fragoso YD Boggild M Macias-Islas MA Carra A Schaerer KD The effects of long-term exposure to disease-modifying drugs during pregnancy in multiple sclerosis Clinical Neurology and Neurosurgery 2013 115 2 154 159 22633835 \n13 Sandberg-Wollheim M Alteri E Moraga MS Kornmann G Pregnancy outcomes in multiple sclerosis following subcutaneous interferon beta-1a therapy Multiple Sclerosis 2011 17 4 423 430 2-s2.0-79954602080 21220368 \n14 Hellwig K Gold R Glatiramer acetate and interferon-beta throughout gestation and postpartum in women with multiple sclerosis Journal of Neurology 2011 258 3 502 503 2-s2.0-79953775914 20878174 \n15 Hellwig K Haghikia A Rockhoff M Gold R Multiple sclerosis and pregnancy: experience from a nationwide database in Germany Therapeutic Advances in Neurological Disorders 2012 5 5 247 253 22973421 \n16 Wehner NG Skov M Shopp G Rocca MS Clarke J Effects of natalizumab, an α 4 integrin inhibitor, on fertility in male and female guinea pigs Birth Defects Research B—Developmental and Reproductive Toxicology 2009 86 2 108 116 2-s2.0-65549091168 \n17 Biogen Idec Inc. Tysabri (natalizumab) prescribing information 2012, http://www.tysabri.com/pdfs/I61061-13_PI.pdf \n18 Hellwig K Haghikia A Gold R Pregnancy and natalizumab: results of an observational study in 35 accidental pregnancies during natalizumab treatment Multiple Sclerosis 2011 17 8 958 963 2-s2.0-80052007513 21613333 \n19 GILENYA Summary of product characteristics http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002202/WC500104528.pdf \n20 GILENYA Prescribing Information http://www.pharma.us.novartis.com/cs/www.pharma.us.novartis.com/product/pi/pdf/gilenya.pdf \n21 Collins W Francis G Koren G Lack of interaction between fingolimod (FTY720) and oral contraceptives, and pregnancy experience in the clinical program of fingolimod in multiple sclerosis Proceedings of the 63rd annual meeting of the American Academy of Neurology April 2011 Honolulu, Hawaii P07. 184 \n22 Gold R Phillips JT Havrdova E BG-12 (dimethyl fumarate) and pregnancy: preclinical and clinical data from the clinical development program Proceedings of the 65th Annual Meeting of the American Academy of Neurology March 2013 San Diego, Calif, USA \n23 Wei Q Runrong G Xiangdong S Studies on teratogenicity of dimethyl fumarate Journal of Hygiene Research 1990 19 28 31 \n24 TECFIDERA Summary of product characteristics http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002601/WC500162069.pdf \n25 Immunex Corporation. Novantrone New Drug Application Pharmacology Review Part 2 2012, http://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21120.pdf_Novantrone_Pharmr_P2.pdf \n26 Genzyme Corporation, a Sanofi company. Aubagio (teriflunomide) prescribing information 2012, http://products.sanofi.us/aubagio/aubagio.pdf \n27 Björk A Jönsson S Fex T Quinoline derivatives. Patent 6593343, USA, 2002 \n28 Thöne J Gold R Laquinimod: a promising oral medication for the treatment of relapsing-remitting multiple sclerosis Expert Opinion on Drug Metabolism and Toxicology 2011 7 3 365 370 2-s2.0-79951918131 21306281 \n29 ZENAPAX Summary of product characteristics http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000198/WC500057604.pdf \n30 Hviid A Mølgaard-Nielsen D Corticosteroid use during pregnancy and risk of orofacial clefts Canadian Medical Association Journal 2011 183 7 796 804 21482652 \n31 Hoes JN Jacobs JWG Boers M EULAR evidence-based recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases Annals of the Rheumatic Diseases 2007 66 12 1560 1567 2-s2.0-36749001123 17660219 \n32 Hellwig K Beste C Schimrigk S Chan A Immunomodulation and postpartum relapses in patients with multiple sclerosis Therapeutic Advances in Neurological Disorders 2009 2 1 7 11 2-s2.0-77949598928 21180639 \n33 Achiron A Kishner I Dolev M Effect of intravenous immunoglobulin treatment on pregnancy and postpartum-related relapses in multiple sclerosis Journal of Neurology 2004 251 9 1133 1137 2-s2.0-4644350358 15372259 \n34 Pakpoor J Disanto G Melanie VL Hellwig K Giovannoni G Sreeram VR Breastfeeding and multiple sclerosis relapses: a meta-analysis Journal of Neurology 2012 259 10 2246 2248 22619059 \n35 McNeilly AS Lactational control of reproduction Reproduction, Fertility and Development 2001 13 7-8 583 590 2-s2.0-0035572994 \n36 Gregg C Shikar V Larsen P White matter plasticity and enhanced remyelination in the maternal CNS Journal of Neuroscience 2007 27 8 1812 1823 2-s2.0-33847200751 17314279 \n37 Coyle PK Christie S Fodor P Multiple sclerosis gender issues: clinical practices of women neurologists Multiple Sclerosis 2004 10 5 582 588 2-s2.0-4444230646 15471377 \n38 Comi G Filippi M Wolinsky JS European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging-measured disease activity and burden in patients with relapsing multiple sclerosis Annals of Neurology 2001 49 3 290 297 2-s2.0-0035091667 11261502 \n39 Fragoso YD Finkelsztejn A Kaimen-Maciel DR Long-term use of glatiramer acetate by 11 pregnant women with multiple sclerosis: a retrospective, multicentre case series CNS Drugs 2010 24 11 969 976 2-s2.0-77957850617 20806993 \n40 Ford H Trigwell P Johnson M The nature of fatigue in multiple sclerosis Journal of Psychosomatic Research 1998 45 1 33 38 2-s2.0-0032127602 9720853 \n41 Roullet E Verdier-Taillefer M-H Amarenco P Gharbi G Alperovitch A Marteau R Pregnancy and multiple sclerosis: a longitudinal study of 125 remittent patients Journal of Neurology Neurosurgery and Psychiatry 1993 56 10 1062 1065 2-s2.0-0027362720 \n42 D’hooghe MB Haentjens P Nagels G D’Hooghe T De Keyser J Menarche, oral contraceptives, pregnancy and progression of disability in relapsing onset and progressive onset multiple sclerosis Journal of Neurology 2012 259 5 855 861 2-s2.0-80053651731 21993617 \n43 Runmarker B Andersen O Pregnancy is associated with a lower risk of onset and a better prognosis in multiple sclerosis Brain 1995 118 1 253 261 2-s2.0-0028923117 7895009 \n44 Soldan SS Retuerto AIA Sicotte NL Voskuhl RR Immune modulation in multiple sclerosis patients treated with the pregnancy hormone estriol Journal of Immunology 2003 171 11 6267 6274 2-s2.0-0344153820 \n45 Wegmann TG Lin H Guilbert L Mosmann TR Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunology Today 1993 14 7 353 356 2-s2.0-0027207375 8363725 \n46 Hellwig K Schimrigk S Beste C Müller T Gold R Increase in relapse rate during assisted reproduction technique in patients with multiple sclerosis European Neurology 2009 61 2 65 68 2-s2.0-56749184083 19039223 \n47 Michel L Foucher Y Vukusic S Increased risk of multiple sclerosis relapse after in vitro fertilisation Journal of Neurology, Neurosurgery & Psychiatry 2012 83 796 802\n\n", "fulltext_license": "CC BY", "issn_linking": "1537-744X", "issue": "2014()", "journal": "TheScientificWorldJournal", "keywords": null, "medline_ta": "ScientificWorldJournal", "mesh_terms": "D005260:Female; D006801:Humans; D007155:Immunologic Factors; D015994:Incidence; D038622:Internationality; D009103:Multiple Sclerosis; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D012307:Risk Factors; D016896:Treatment Outcome", "nlm_unique_id": "101131163", "other_id": null, "pages": "513160", "pmc": null, "pmid": "24977202", "pubdate": "2014", "publication_types": "D016428:Journal Article; D017418:Meta-Analysis; D016454:Review", "references": "22693287;22633835;21306281;21220368;19692433;20878174;19039223;8410003;15471377;21613333;22973421;21180639;11999309;18677640;19283862;15223156;9682040;20806993;17314279;24821713;16186517;7895009;23088447;11261502;21993617;15372259;21079181;21482652;22619059;14634144;9720853;17660219;8363725", "title": "Multiple sclerosis and pregnancy: current considerations.", "title_normalized": "multiple sclerosis and pregnancy current considerations" }

[ { "companynumb": "DE-BIOGEN-2011BI019799", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "NATALIZUMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "125104", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RELAPSING-REMITTING MULTIPLE SCLEROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TYSABRI" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "NATALIZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "125104", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": "20091020", "drugenddateformat": "102", "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20061010", "drugstartdateformat": "102", "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TYSABRI" } ], "patientagegroup": null, "patientonsetage": "28", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Maternal exposure during pregnancy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Abortion spontaneous", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Heart sounds abnormal", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20091103" } }, "primarysource": { "literaturereference": "BURAGA I, DAVILA C, POPOVICI R. MULTIPLE SCLEROSIS AND PREGNANCY: CURRENT CONSIDERATIONS. THE SCIENTIFIC WORLD JOURNAL. 2014 APR 07?.", "literaturereference_normalized": "multiple sclerosis and pregnancy current considerations", "qualification": "1", "reportercountry": "RO" }, "primarysourcecountry": "DE", "receiptdate": "20210223", "receivedate": "20210223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18931997, "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" }, { "companynumb": "DE-BIOGEN-2011BI019806", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "NATALIZUMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "125104", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": "20091203", "drugenddateformat": "102", "drugindication": "RELAPSING-REMITTING MULTIPLE SCLEROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20071015", "drugstartdateformat": "102", "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TYSABRI" } ], "patientagegroup": null, "patientonsetage": "30", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Maternal exposure during pregnancy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Abortion spontaneous", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20100208" } }, "primarysource": { "literaturereference": "BURAGA J, POPOVICI R. MULTIPLE SCLEROSIS AND PREGNANCY: CURRENT CONSIDERATIONS. THE SCIENTIFIC WORLD JOURNAL. 2014 APR 07?2014:.", "literaturereference_normalized": "multiple sclerosis and pregnancy current considerations", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "DE", "receiptdate": "20210301", "receivedate": "20210301", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18955871, "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": "A 50-year-old woman presented to our dermatology clinic with pruritic lesions on her hands that had appeared 24 hours earlier. The clinical manifestations had started 24 hours after taking 100 mg of doxycycline for acute bronchitis. She had no history of allergic disease or allergic reactions to drugs. The dermatologic examination revealed multiple erythematous, purplish annular patches with overlying bullae with hemorrhagic content on both palms (Figure 1). The patient had no fever, and the rest of the physical examination did not reveal any abnormalities. Results of laboratory tests were within normal limits. A skin biopsy was performed, showing hydrophic degenerations of the basal membrane, a superficial perivascular infiltrate consisting of lymphocytes and eosinophils, and red blood cells in the dermis (Figure 2). A pharmacovigilance investigation was conducted, and doxycycline was confirmed as the agent responsible for the bullous fixed drug eruption (FDE) in our patient.", "affiliations": "Department of Dermatology, Tunis, Tunisia; anissa_zaouak@yahoo.fr.;Department of Dermatology, Tunis, Tunisia.;Department of Dermatology, Tunis, Tunisia.;Department of Anatomopathology, Tunis, Tunisia.;Department of Anatomopathology, Tunis, Tunisia.;Habib Thameur Hospital; and the National Center of Pharmacovigilance, Tunis, Tunisia.;Department of Dermatology, Tunis, Tunisia.;Department of Dermatology, Tunis, Tunisia.", "authors": "Zaouak|Anissa|A|;Bacha|Takoua|T|;Jrad|Meriem|M|;Jouini|Raja|R|;Salah|Meriem Belhaj|MB|;Sahnoun|Rym|R|;Hammami|Houda|H|;Fenniche|Samy|S|", "chemical_list": "D000900:Anti-Bacterial Agents; D004318:Doxycycline", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1540-9740", "issue": "16(3)", "journal": "Skinmed", "keywords": null, "medline_ta": "Skinmed", "mesh_terms": "D000900:Anti-Bacterial Agents; D004318:Doxycycline; D003875:Drug Eruptions; D005260:Female; D006801:Humans; D008875:Middle Aged; D012872:Skin Diseases, Vesiculobullous", "nlm_unique_id": "101168327", "other_id": null, "pages": "202-203", "pmc": null, "pmid": "29989543", "pubdate": "2018", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Bullous Fixed Drug Eruption Caused by Doxycycline.", "title_normalized": "bullous fixed drug eruption caused by doxycycline" }

[ { "companynumb": "TN-BAUSCH-BL-2019-018125", "fulfillexpeditecriteria": "1", "occurcountry": "TN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DOXYCYCLINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "65281", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXYCYCLINE." } ], "patientagegroup": null, "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dermatitis bullous", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Fixed eruption", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ZAOUAK A, BACHA T, JRAD M, JOUINI R, SALAH M, SAHNOUN R, HAMMAMI H, FENNICHE S. BULLOUS FIXED DRUG ERUPTION CAUSED BY DOXYCYCLINE. SKINMED. 2018?16(3):202-203.", "literaturereference_normalized": "bullous fixed drug eruption caused by doxycycline", "qualification": "1", "reportercountry": "TN" }, "primarysourcecountry": "TN", "receiptdate": "20190708", "receivedate": "20190628", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16497808, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20191004" }, { "companynumb": "TN-CHARTWELL PHARMA-2052557", "fulfillexpeditecriteria": "1", "occurcountry": "TN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXYCYCLINE HYCLATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "062505", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXYCYCLINE HYCLATE." } ], "patientagegroup": null, "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dermatitis bullous", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ZAOUAK A, BACHA T, JRAD M, JOUINI R, SALAH MB, SAHNOUN R, HAMMAMI H, FENNICHE S. BULLOUS FIXED DRUG ERUPTION CAUSED BY DOXYCYCLINE. SKINMED. 2018 JUN 1?16(3):202?203. PMID: 29989543", "literaturereference_normalized": "bullous fixed drug eruption caused by doxycycline", "qualification": "3", "reportercountry": "TN" }, "primarysourcecountry": "TN", "receiptdate": "20180723", "receivedate": "20180723", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15179178, "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": "TN-PFIZER INC-2019256661", "fulfillexpeditecriteria": "1", "occurcountry": "TN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DOXYCYCLINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "050006", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRONCHITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXYCYCLINE MONOHYDRATE" } ], "patientagegroup": null, "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Fixed eruption", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dermatitis bullous", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ZAOUAK, A.. BULLOUS FIXED DRUG ERUPTION CAUSED BY DOXYCYCLINE. SKINMED: DERMATOLOGY FOR THE CLINICIAN. 2018?16 (3):202-203", "literaturereference_normalized": "bullous fixed drug eruption caused by doxycycline", "qualification": "1", "reportercountry": "TN" }, "primarysourcecountry": "TN", "receiptdate": "20190813", "receivedate": "20190708", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16541369, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191004" } ]

{ "abstract": "BACKGROUND\nVedolizumab (VDZ), a humanised monoclonal antibody that selectively inhibits alpha4-beta7 integrins is approved for use in adult moderate to severe ulcerative colitis (UC) patients.\n\n\nOBJECTIVE\nTo assess the efficacy and safety of VDZ in the real-world management of UC in a large multicenter cohort involving two countries and to identify predictors of achieving remission.\n\n\nMETHODS\nA retrospective review of Australian and Oxford, United Kingdom data for UC patients. Clinical response at 3 mo, endoscopic remission at 6 mo and clinical remission at 3, 6 and 12 mo were assessed. Cox regression models and Kaplan Meier curves were performed to assess the time to remission, time to failure and the covariates influencing them. Safety outcomes were recorded.\n\n\nRESULTS\nThree hundred and three UC patients from 14 centres in Australia and United Kingdom, [60% n = 182, anti-TNF naïve] were included. The clinical response was 79% at 3 mo with more Australian patients achieving clinical response compared to Oxford (83% vs 70% P = 0.01). Clinical remission for all patients was 56%, 62% and 60% at 3, 6 and 12 mo respectively. Anti-TNF naive patients were more likely to achieve remission than exposed patients at all the time points (3 mo 66% vs 40% P < 0.001, 6 mo 73% vs 46% P < 0.001, 12 mo 66% vs 51% P = 0.03). More Australian patients achieved endoscopic remission at 6 mo compared to Oxford (69% vs 43% P = 0.01). On multi-variate analysis, anti-TNF naïve patients were 1.8 (95%CI: 1.3-2.3) times more likely to achieve remission than anti-TNF exposed (P < 0.001). 32 patients (11%) had colectomy by 12 mo.\n\n\nCONCLUSIONS\nVDZ was safe and effective with 60% of UC patients achieving clinical remission at 12 mo and prior anti-TNF exposure influenced this outcome.", "affiliations": "Centre for Inflammatory Bowel Diseases, St John of God Hospital, Subiaco 6008, Western Australia, Australia.;Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom.;Inflammatory Bowel Disease Research Group, Queensland institute of Medical Research, Herston 4006, Queensland, Australia.;Department of Gastroenterology, Mater Hospital, Brisbane 4101, Queensland, Australia.;Department of Gastroenterology, Mater Hospital, South Brisbane 4101, Queensland, Australia.;Department of Gastroenterology, Eastern Health, Box Hill 3128, Victoria, Australia.;Department of Gastroenterology, Eastern Health, Box Hill 3128, Victoria, Australia.;Department of Gastroenterology, Fiona Stanley Hospital, Murdoch 6150, Western Australia, Australia.;Department of Gastroenterology, Austin Health, Heidelberg 3084, Victoria, Australia.;Department of Gastroenterology, Austin Health, Heidelberg 3084, Victoria, Australia.;Department of Gastroenterology, Mater Hospital, South Brisbane 4101, Queensland, Australia.;Department of Gastroenterology, St Vincent's Hospital, Fitzroy 3065, Victoria, Australia.;Department of Gastroenterology, St Vincent's Hospital, Fitzroy 3065, Victoria, Australia.;Department of Gastroenterology, Northern Health, Epping 3076, Victoria, Australia.;Department of Gastroenterology, The Alfred Hospital, Melbourne 3004, Victoria, Australia.;Department of Gastroenterology, St Vincent's Hospital, Darlinghurst 2010, New South Wales, Australia.;Department of Gastroenterology, Flinders Medical Centre, Bedford Park 5042, South Australia, Australia.;Department of Gastroenterology, Liverpool Hospital, Sydney 2170, New South Wales, Australia.;Department of Gastroenterology, Liverpool Hospital, Sydney 2170, New South Wales, Australia.;Department of Gastroenterology, Royal Adelaide Hospital & University of Adelaide, Adelaide 5000, South Australia, Australia.;Department of Gastroenterology, Royal Adelaide Hospital & University of Adelaide, Adelaide 5000, South Australia, Australia.;Department of Gastroenterology, Townsville Hospital, Douglas 4814, Queensland, Australia.;Institute for Health Research, University of Notre Dame, Fremantle 6160, Western Australia, Australia.;Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom.;Centre for Inflammatory Bowel Diseases, St John of God Hospital, Subiaco 6008, Western Australia, Australia.", "authors": "Pulusu|Samba Siva Reddy|SSR|;Srinivasan|Ashish|A|;Krishnaprasad|Krupa|K|;Cheng|Daniel|D|;Begun|Jakob|J|;Keung|Charlotte|C|;Van Langenberg|Daniel|D|;Thin|Lena|L|;Mogilevski|Tamara|T|;De Cruz|Peter|P|;Radford-Smith|Graham|G|;Flanagan|Emma|E|;Bell|Sally|S|;Kashkooli|Soleiman|S|;Sparrow|Miles|M|;Ghaly|Simon|S|;Bampton|Peter|P|;Sawyer|Elise|E|;Connor|Susan|S|;Rizvi|Quart-Ul-Ain|QU|;Andrews|Jane M|JM|;Mahy|Gillian|G|;Chivers|Paola|P|;Travis|Simon|S|;Lawrance|Ian Craig|IC|", "chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D005765:Gastrointestinal Agents; D014409:Tumor Necrosis Factor-alpha; C543529:vedolizumab", "country": "United States", "delete": false, "doi": "10.3748/wjg.v26.i30.4428", "fulltext": "\n==== Front\nWorld J Gastroenterol\nWorld J. Gastroenterol\nWJG\nWorld Journal of Gastroenterology\n1007-9327 2219-2840 Baishideng Publishing Group Inc \n\njWJG.v26.i30.pg4428\n10.3748/wjg.v26.i30.4428\nRetrospective Cohort Study\nVedolizumab for ulcerative colitis: Real world outcomes from a multicenter observational cohort of Australia and Oxford\nPulusu Samba Siva Reddy Centre for Inflammatory Bowel Diseases, St John of God Hospital, Subiaco 6008, Western Australia, Australia\n Srinivasan Ashish Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom\n Krishnaprasad Krupa Inflammatory Bowel Disease Research Group, Queensland institute of Medical Research, Herston 4006, Queensland, Australia\n Cheng Daniel Department of Gastroenterology, Mater Hospital, Brisbane 4101, Queensland, Australia\n Begun Jakob Department of Gastroenterology, Mater Hospital, South Brisbane 4101, Queensland, Australia\n Keung Charlotte Department of Gastroenterology, Eastern Health, Box Hill 3128, Victoria, Australia\n Van Langenberg Daniel Department of Gastroenterology, Eastern Health, Box Hill 3128, Victoria, Australia\n Thin Lena Department of Gastroenterology, Fiona Stanley Hospital, Murdoch 6150, Western Australia, Australia\n Mogilevski Tamara Department of Gastroenterology, Austin Health, Heidelberg 3084, Victoria, Australia\n De Cruz Peter Department of Gastroenterology, Austin Health, Heidelberg 3084, Victoria, Australia\n Radford-Smith Graham Department of Gastroenterology, Mater Hospital, South Brisbane 4101, Queensland, Australia\n Flanagan Emma Department of Gastroenterology, St Vincent’s Hospital, Fitzroy 3065, Victoria, Australia\n Bell Sally Department of Gastroenterology, St Vincent’s Hospital, Fitzroy 3065, Victoria, Australia\n Kashkooli Soleiman Department of Gastroenterology, Northern Health, Epping 3076, Victoria, Australia\n Sparrow Miles Department of Gastroenterology, The Alfred Hospital, Melbourne 3004, Victoria, Australia\n Ghaly Simon Department of Gastroenterology, St Vincent’s Hospital, Darlinghurst 2010, New South Wales, Australia\n Bampton Peter Department of Gastroenterology, Flinders Medical Centre, Bedford Park 5042, South Australia, Australia\n Sawyer Elise Department of Gastroenterology, Liverpool Hospital, Sydney 2170, New South Wales, Australia\n Connor Susan Department of Gastroenterology, Liverpool Hospital, Sydney 2170, New South Wales, Australia\n Rizvi Quart-ul-ain Department of Gastroenterology, Royal Adelaide Hospital & University of Adelaide, Adelaide 5000, South Australia, Australia\n Andrews Jane M Department of Gastroenterology, Royal Adelaide Hospital & University of Adelaide, Adelaide 5000, South Australia, Australia\n Mahy Gillian Department of Gastroenterology, Townsville Hospital, Douglas 4814, Queensland, Australia\n Chivers Paola Institute for Health Research, University of Notre Dame, Fremantle 6160, Western Australia, Australia\n Travis Simon Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom\n Lawrance Ian Craig Centre for Inflammatory Bowel Diseases, St John of God Hospital, Subiaco 6008, Western Australia, Australia\nSchool of Medicine and Pharmacology, University of Western Australia, Crawley 6009, Western Australia, Australia. ian.lawrance@uwa.edu.au\n Author contributions: Lawrance IC is the main supervisor of the study involved in study conceptualization, funding acquisition, provision of resources, methodology design, review, editing of the manuscript and project administration; Writing up the original draft of the paper, data curation, formal analysis, manuscript editing, literature review was done by Pulusu SSR; Krishnaprasad K involved in project administration, data curation and manuscript editing; Data collection was done by Pulusu SSR, Srinivasan A, Cheng D, Keung C, Mogilevski T, Flanagan E, Sawyer E, and Rizvi Q; Data collection, project administration, supervision, manuscript revision and correction was done by Begun J, Van Langenberg D, Thin L, De Cruz P, Radford-Smith G, Bell S,, Kashkooli S, Sparrow M, Ghaly S, Bampton P, Connor S , Andrews JM, Mahy G, and Travis S; Data validation and visualization, biostatistics was done by Chivers P; all authors reviewed and approved the final manuscript.\n\nCorresponding author: Ian Craig Lawrance, FRCP (Hon), MBBS, PhD, Professor, Centre for Inflammatory Bowel Diseases, St John of God Hospital, 25 McCourt Street, Subiaco 6008, Western Australia, Australia. ian.lawrance@uwa.edu.au\n\n\n14 8 2020 \n14 8 2020 \n26 30 4428 4441\n4 4 2020 18 7 2020 30 7 2020 ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.2020This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.BACKGROUND\nVedolizumab (VDZ), a humanised monoclonal antibody that selectively inhibits alpha4-beta7 integrins is approved for use in adult moderate to severe ulcerative colitis (UC) patients.\n\nAIM\nTo assess the efficacy and safety of VDZ in the real-world management of UC in a large multicenter cohort involving two countries and to identify predictors of achieving remission.\n\nMETHODS\nA retrospective review of Australian and Oxford, United Kingdom data for UC patients. Clinical response at 3 mo, endoscopic remission at 6 mo and clinical remission at 3, 6 and 12 mo were assessed. Cox regression models and Kaplan Meier curves were performed to assess the time to remission, time to failure and the covariates influencing them. Safety outcomes were recorded.\n\nRESULTS\nThree hundred and three UC patients from 14 centres in Australia and United Kingdom, [60% n = 182, anti-TNF naïve] were included. The clinical response was 79% at 3 mo with more Australian patients achieving clinical response compared to Oxford (83% vs 70% P = 0.01). Clinical remission for all patients was 56%, 62% and 60% at 3, 6 and 12 mo respectively. Anti-TNF naive patients were more likely to achieve remission than exposed patients at all the time points (3 mo 66% vs 40% P < 0.001, 6 mo 73% vs 46% P < 0.001, 12 mo 66% vs 51% P = 0.03). More Australian patients achieved endoscopic remission at 6 mo compared to Oxford (69% vs 43% P = 0.01). On multi-variate analysis, anti-TNF naïve patients were 1.8 (95%CI: 1.3-2.3) times more likely to achieve remission than anti-TNF exposed (P < 0.001). 32 patients (11%) had colectomy by 12 mo.\n\nCONCLUSION\nVDZ was safe and effective with 60% of UC patients achieving clinical remission at 12 mo and prior anti-TNF exposure influenced this outcome.\n\nVedolizumabUlcerative colitisOutcomes\n==== Body\nCore tip: Vedolizumab (VDZ) is a gut selective anti-integrin used for treatment of Ulcerative colitis (UC). Evidence is needed to support its use in real life setting involving multiple centers and two countries to reduce physician, site and country biases. This is a retrospective review of prospectively collected database involving 303 UC patients from Australia and Oxford, United Kingdom treated with VDZ. Clinical response was observed in 79% of patients at 3 mo and clinical remission in 56%, 62% and 60% at 3 mo, 6 mo and 12 mo respectively. Anti-tumor necrosis factor (anti-TNF) naïve patients were 1.8 times more likely to achieve remission than anti-TNF exposed and 11% of patients required colectomy by 12 mo. We concluded that VDZ is a safe and effective biologic medication used for treatment of UC.\n\nINTRODUCTION\nThe aim of treatment in ulcerative colitis (UC) is to achieve sustained clinical, mucosal and histological healing[1,2]. The choice of treatment depends on several factors including induction, or maintenance, of disease remission, severity of disease, extent and location of bowel involvement, disease phenotype and individual characteristics of the drug and patient. The use of conventional medications may be limited either by a lack of efficacy (5-aminosalicylates) or side effects [steroids/azathioprine (AZA)/6 mercaptopurine (6MP)/methotrexate (MTX)][3]. Its’ use, however, is not without potential side effects including, development of opportunistic infections, reactivation of tuberculosis and an increased risk of melanoma[4].\n\nVedolizumab (VDZ), a humanised monoclonal antibody, selectively inhibits the migration of alpha4-beta7 inflammatory cells to the gastrointestinal tract, making it a biological agent without systemic immunosuppression and thus potentially reducing side-effects. In GEMINI 1, the randomised, double-blind placebo-controlled trial of VDZ in UC, the response rate for induction at week six was 47.1% with a response rate of 41.8% at week fifty two after eight-weekly VDZ treatments[5]. Patients enrolled in clinical trials, however, do not entirely represent the patients seen in routine clinical practice as demonstrated by a retrospective study where only 31% of 206 patients with moderate-to-severe inflammatory bowel disease (IBD) were eligible to participate in such a clinical trial[6].\n\nOur aim was to assess the response and remission rates to VDZ in the real world, the time taken to achieve this, mucosal healing rates, adverse/serious events, the rates of colectomy and the predictors influencing remission in the first 12 mo of VDZ therapy through a multicenter consortium in a real-world setting.\n\nMATERIALS AND METHODS\nStudy design\nThis was a multicenter retrospective review of prospectively collected data involving 14 IBD centers in Australia New Zealand inflammatory bowel disease consortium and data was also collected at a major IBD center in United Kingdom, thus reducing physician, site and country bias. All the centers involved in the study had a dedicated IBD team. In Australia, patients with UC refractory to conventional treatment, which was defined as failure of three, or more, mo of a 5-aminosalycylate and failure of three or more mo of an immunomodulator (AZA, 6MP or MTX) and 6 wk weaning dose of prednisolone that commenced at 40mg per day or more, were able to access VDZ from 2015 through the government funded pharmaceutical benefit scheme (PBS). In the United Kingdom, VDZ was given to patients at the physicians’ discretion if the conventional treatment and/or anti-tumor necrosis factor (anti-TNF) medications had failed to control the disease.\n\nConsecutive patients with UC diagnosed as per the standard criteria[7] who received at least induction VDZ therapy were considered for the study. All patients who finished VDZ induction therapy were included in the study for analysis. VDZ was given as standard intravenous (IV) induction dosing of 300mg at 0, 2 and 6 wk followed by maintenance therapy of 8 weekly IV infusions. Patients continued to take, or wean off, steroids, 5-aminosalicylates (oral and rectal therapy) as deemed appropriate by the treating physician. Patients taking immunosuppressant medications, including AZA, 6MP, MTX orally, or rectal tacrolimus, continued on these medications under the treating physicians’ preference as guided by the disease control. There were no mandated changes to a patient’s regular IBD medications. The use of steroids and/or immunomodulators and their time of cessation was recorded for analysis.\n\nA retrospective review of the IBD databases that contained prospectively-entered data included baseline patient demographics and disease characteristics classified by the Montreal classification[8], concomitant use of steroids and immunomodulator medications, prior exposure to anti-TNF medications, adverse events and colectomy rates.\n\nAssessments tools and criteria\nThe Montreal classification was used to classify UC[8]. The Partial Mayo clinical score was used to assess disease control and is composed of 3 items, which includes stool frequency, rectal bleeding and the physician global assessment which were each scored individually from 0 to 3 at baseline, 3, 6 and 12 mo. The higher the score, more severe the disease and maximum score was 9. The Mayo endoscopic score (MES) is classified into four levels of severity from 0-4 based on mucosal friability, vascular pattern, friability and erosions. Mayo 0-1 was inactive disease while Mayo 2 and Mayo 3 were mild-moderate and moderate-severe disease respectively. Ulcerative colitis endoscopic index of severity (UCEIS) is composed of 3 items, which includes vascular pattern, bleeding and erosions/ulcers with score ranging from 0-2 for vascular pattern and scores 0-3 for bleeding and erosions/ulcers with higher scores indicating severe disease and the maximum score was 9. The response and remission to VDZ was assessed clinically using partial Mayo clinical score in both Australia and the United Kingdom sites. MES was used for assessing endoscopic appearance in Australia, and the UCEIS was used in the United Kingdom.\n\nEvaluation of clinical efficiency at 3, 6 and 12 mo\nInduction: Clinical efficiency of VDZ induction therapy was assessed as either clinical response or clinical remission at 3 mo. A response to VDZ was defined as a decrease in the Partial Mayo score of ≥ 3 from baseline, while clinical remission was defined as Partial Mayo score of < 2.\n\nMaintenance\nClinical efficacy of VDZ was also assessed at 6 mo and 12 mo of VDZ therapy. The Partial Mayo score again was used to assess clinical response and clinical remission. Data was collected if VDZ was ceased due to side-effects, or loss of response (LOR) that resulted in a switch of the therapy away from VDZ, or surgery if it was required.\n\nEndoscopic assessment of disease control was undertaken after approximately 6 mo of VDZ. An MES of 0 or 1 was defined as an endoscopic remission with a score > 1 indicating active disease. An UCEIS score of 0-1 was also defined as endoscopic remission with a score > 1 indicating active disease.\n\nCorticosteroid and Immunomodulator therapy\nCorticosteroid therapy was defined as the use of any oral steroid including prednisolone and budesonide. Immunomodulator therapy includes any oral or rectal immunomodulator which includes AZA, 6MP, MTX (oral or parenteral), tacrolimus (oral or rectal), ciclosporin and mycophenylate. Corticosteroid and immunomodulator use was assessed at baseline, 3, 6 and 12 mo.\n\nSafety\nThe development of infusion reactions, adverse events and serious adverse events were all recorded. Infusion reactions were defined as any adverse event that occurred on the day, or the day after, the infusion. Adverse events were defined as any untoward medical occurrence not resulting in discontinuation of the VDZ or hospitalization. Adverse events were graded as serious if they resulted in discontinuation of VDZ, hospitalization of the patient, or patient death.\n\nStatistical analysis\nData for each patient from their first dose of VDZ to either last infusion within the study period or cessation of the VDZ were included for analysis. All statistical analysis was conducted using SPSS version 24 (IBM Corp, released 2016). Statistical significance was set at P < 0.05. Patient demographic and disease profile information was described using frequency and percent for categorically classified variables, with mean and standard deviation and median and range used to describe scale variables. VDZ treatment outcomes are described at baseline, 3, 6 and 12 mo. Sample size varied across measures and was reported accordingly.\n\nTwo Cox Regression models and Kaplan Meier curves were performed separately for each site. The first model examined time (weeks) to remission. Time to censor was calculated as the difference between the date of remission (censor event) and the date the patient started the study. The second model examined time (weeks) to failure. Failure was defined as Partial Mayo clinical score ≥ 2 or MES ≥ 2, or the need for a change in the biologic agent, or requiring colectomy. Time to censor was calculated as the difference between this date of failure (censor event) and the date the patient started the study, truncated to 60 wk. Both models examined the covariates gender, disease duration (year), smoking (non–smoker/current smoker or ex smoker), disease location, age at which VDZ was given (year), and previous immunomodulator exposure. For the failure model, a remission covariate was also included (median split ≤ 13/> 13 wk of time to remission). For both models where remission or failure occurred at the start of the study, a small constant (0.01) was added to the time to event variable. Cox model proportional hazard assumption was tested using Schoenfeld residuals with no violations. A chi square analysis was used to investigate the remission and failure censor variables with anti-TNF, and site differences across categorical variables. Disease duration, age vedolizumab started, remission time and failure time were examined for normality using Shapiro Wilk and violations were noted. Therefore site differences for these continuous variables were examined using the non-parametric alternative Mann Whitney U Test. Further Cox Regression models and Kaplan Meier curves were performed using the combined data set with site included as a variable.\n\nRESULTS\nPatient characteristics\nThree hundred and thress UC patients (Australia n = 210 and Oxford, United Kingdom, n = 93) from 15 centers (Australia n = 14) were included in the study. Of the 303 patients, patient data was available in 278 at 3 mo, 250 patients at 6 mo and 209 patients at 12 mo. Of the 303 patients, 15 patients were in remission at the start of VDZ and VDZ was commenced due to side effects to the anti-TNF agents, these patients were analysed separately at each time point (Figure 1).\n\nFigure 1 Flowchart.\n\nPatient demographics and clinical characteristics\nOf the total 303 patients, 60% (n = 182) were anti-TNF naïve and VDZ was their first biologic agent, while 40% (n = 121) had prior anti-TNF exposure with a secondary LOR in 20% (n = 61) and primary LOR in 15% (n = 45). VDZ was commenced in 5% (n = 15) of patients due to side-effects from anti-TNF therapy and these patients were in clinical remission at VDZ induction, so were analyzed separately. A total of 47% (n = 143) were female (Table 1).\n\nTable 1 Clinical characteristics of study population\n\nCharacteristic\tTotal (n = 303)\tAustralia (n = 210)\tOxford (n = 93)\t\nGender\t\t\t\t\nFemale, n (%)\t143 (47)\t95 (45)\t48 (52)\t\nMedian age VDZ given (range, yr)\t35 (16-84)\t36 (19-78)\t35 (16-84)\t\nMedian disease duration (range, yr)\t6 (0.2-48)\t7 (1-48)\t5.4 (0.2-39.2)\t\nMontreal classification, n (%)\t\t\t\t\nAge\t\t\t\t\nA1\t34 (11)\t33 (16)\t1 (1)\t\nA2\t170 (56)\t120 (57)\t50 (54)\t\nA3\t99 (33)\t57 (27)\t42 (45)\t\nLocation\t\t\t\t\nE1\t18 (6)\t15 (7)\t3 (3)\t\nE2\t114 (38)\t72 (34)\t42 (45)\t\nE3\t170 (56)\t122 (58)\t48 (52)\t\nMissing\t1\t1\t0\t\nFamily History, n (%)\t29 (12)\t22 (15)\t7 (7)\t\nFirst degree\t19\t12\t7\t\nSecond degree\t10\t10\t0\t\nNone\t212\t126\t86\t\nSmoking, n\t\t\t\t\nNever\t226\t140\t86\t\nCurrent\t9\t6\t3\t\nEx smoker\t45\t41\t4\t\nAnti-TNF naïve, n (%)\t182 (60)\t122 (58.1)\t60 (65)\t\nAnti-TNF exposed, n (%)\t121 (40)\t88 (41.9)\t33 (35)\t\nPrimary LOR\t45 (15)\t29 (13.8)\t16 (17)\t\nSecondary LOR\t61 (20)\t47 (22.4)\t14 (15)\t\nSide-effects\t15 (5)\t12 (5.7)\t3 (3.2)\t\nSteroids at VDZ initiation, n (%)\t191 (63)\t134 (64)\t57 (61.2)\t\nPrednisone\t162 (53)\t108 (51)\t54 (58)\t\nBudesonide\t29 (10)\t26 (12)\t3 (3)\t\nImmunomodulation at VDZ initiation, n (%)\t175 (58)\t135 (64)\t40 (43)\t\nAZA/6MP\t136 (45)\t108 (51)\t28 (30)\t\nMethotrexate\t19 (6)\t11 (5)\t8 (9)\t\nTacrolimus\t17 (6)\t16 (8)\t1 (1)\t\nOthers (Cyclo&Myco)\t3 (1)\t0\t3 (3)\t\nMean Partial Mayo before VDZ initiation\t5 (2-9)\t6 (2-9)\t5 (2-9)\t\nVDZ: Vedolizumab; min: Minimum; max: Maximum; TNF: Tumor necrosis factor; Primary LOR: Primary loss of response; Secondary LOR: Secondary loss of response; AZA: Azathioprine; 6MP: 6-mercaptopurine; Cyclo: Ciclosporine; Myco: Mycophenolate; Init, Initiation.\n\nThe median age at which VDZ was started was 35 years (range 16-84 years), while the median disease duration was 6 years (range 0.2-48 years) prior to the commencement of VDZ. A family history was present in 12% (n = 29) and 81% (n = 226) were non-smokers at the time of commencing VDZ. All patients were classified by the Montreal classification[8] and 56% were diagnosed with UC between the ages of 17-40 years (n = 170, A2) compared to younger than 17 years in 11% (n = 34, A1) and 33% older than 40 years (n = 99, A3). Disease extent was extensive in 56% of patients (n = 170, E3) with 38% with suffering left-sided colitis (n = 114, E2) and 6% patients with proctitis (n = 18, E1). Of all patients, 63% (n = 191) were on steroids at the commencement of VDZ, 53% (n = 162) were taking prednisone and 10% (n = 29) budesonide. 58% (n = 175) of the patients were on an immunomodulator, with the thiopurines (AZA/6MP) being the most commonly used in 45% (n = 136), followed by MTX, tacrolimus, ciclosporine and mycophenolate. The mean partial Mayo score was 5 (range 2-9) at commencement of VDZ.\n\nNo significant differences were observed between the Australian and Oxford patients for prior anti-TNF exposure (P = 0.36), sex (P = 0.3), family history (P = 0.43), and age at which VDZ was started (P = 0.35). Significant differences between the Australian and Oxford patients, however, were observed for smoking with more Oxford patients having never smoked (P < 0.001) but there was no difference in the current smokers at time of VDZ commencement. Immunomodulator usage at the commencement of VDZ was greater in Australian than Oxford patients (P < 0.001), and the disease duration in Australian patients was longer prior to VDZ commencement (P < 0.048).\n\nAssessment at 3 mo, 6 mo and 12 mo\nA total of 263 patients were not in remission at commencement of VDZ, and of these 79% (n = 208) achieved a clinical response and 56% (n = 148) achieved clinical remission by 3 mo. Three mo data was missing for 25 patients (9 Australia, 16 Oxford), and thus these were not included in the induction analysis but there was data for the clinical status of these patients at 6 and 12 mo.\n\nAt 3 mo, Australian patients were more likely to achieve response (P = 0.01), but were not more likely to achieve remission than Oxford patients (P = 0.58) (Table 2). Anti-TNF naïve patients were more likely to achieve both response (P = 0.03) and remission (P < 0.001) at 3 mo compared to patients who had prior anti-TNF exposure. Within the anti-TNF exposed group, there was no significant difference between the patients who had a primary or secondary LOR to an anti-TNF agent in achieving clinical response (P = 0.9) or remission (P = 0.8) to VDZ at 3 mo.\n\nTable 2 Response and remission at 3 mo of vedolizumab therapy\n\n\tTotal\tAustralia\tOxford\tP value\t\nResponse, n (%)\t208 (79)\t157 (83)\t51 (70)\t0.01\t\nRemission, n (%)\t148 (56)\t104 (55)\t44 (59)\t0.58\t\n\tTotal\tAnti-TNF naive\tAnti-TNF exposed\tP value\t\nResponse, n (%)\t208 (79)\t138 (83)\t70 (72)\t0.03\t\nRemission, n (%)\t148 (56)\t109 (66)\t39 (40)\t< 0.001\t\n\tAnti-TNF exposed\tPrimary LOR\tSecondary LOR\tP value\t\nResponse, n (%)\t70 (72)\t30 (73)\t40 (71)\t0.85\t\nRemission, n (%)\t39 (40)\t16 (39)\t23 (41)\t0.83\t\nVDZ: Vedolizumab; TNF: Tumor necrosis factor; Primary LOR: Primary loss of response to anti-TNF agent; Secondary LOR: Secondary loss of response to anti-TNF agent.\n\nOf the total 238 patients assessed at 6 mo, 62% (n = 147) were in remission and of the 201 patients assessed at 12 mo, 60% (n = 120) were in remission (Table 3). No significant difference was found between Australia and Oxford in the number of patients in remission at 6 mo (P = 0.3) or at 12 mo (P = 0.09). Anti-TNF naïve patients were more likely to achieve remission both at 6 mo (P < 0.001) and 12 mo (P = 0.03) than those previously exposed. Within the anti-TNF exposed group, there was no significant difference between the patients who had primary or secondary LOR to anti-TNF agents in clinical remission at 6 mo (P = 0.2) or 12 mo (P = 0.3).\n\nTable 3 Remission at 6 mo and 12 mo of vedolizumab therapy\n\n\tTotal\tAustralia\tOxford\tP value\t\nRemission at 6 mo, n (%)\t147 (62)\t110/173(64)\t37/65 (57)\t0.34\t\nRemission at 12 mo, n (%)\t120/201 (60)\t87/138 (63)\t33/65 (52)\t0.09\t\n\tTotal\tAnti-TNF naive\tAnti-TNF exposed\t\t\nRemission at 6 mo, n (%)\t147/238 (62)\t103/142 (73)\t44/96 (46)\t< 0.001\t\nRemission at 12 mo, n (%)\t120/201 (60)\t76/115 (66)\t44/86 (51)\t0.03\t\n\tAnti-TNF exposed\tPrimary LOR\tSecondary LOR\t\t\nRemission at 6 mo, n (%)\t44/96 (46)\t16/42 (38)\t28/54 (52)\t0.18\t\nRemission at 12 mo, n (%)\t44/86 (51)\t17/38 (44)\t27/48 (56)\t0.28\t\nVDZ: Vedolizumab; TNF: Tumor necrosis factor; Primary LOR: Primary loss of response to anti-TNF agent; Secondary LOR: Secondary loss of response to anti-TNF agent.\n\nOf the 15 patients who were in remission at the start of VDZ, where the indication was side effects to anti-TNF agents, 66% (n = 10/15) at 3 mo, 58% (n = 7/12) at 6 mo, 50% (n = 4/8) at 1 year were still in clinical remission.\n\nEndoscopy\nA total of 108 patients had endoscopy at 6 mo, 78 in Australia and 30 in Oxford. Of the Oxford patients, 43% (13/30) had an UCEIS of ≤ 1 indicating endoscopic remission. Of the Australian patients, 69% (54/78) had an MES of 0-1 indicating endoscopic remission. A significantly greater percentage of patients achieved endoscopic remission in Australia compared to Oxford (P = 0.01). A MES score of 0 was achieved in 31% (24/78) of the Australian cohort. A MES ≥ 2 was reported in 31% (n = 24) of Australian patients and a UCEIS ≥ 2 was reported in 57% (n = 17) of Oxford patients.\n\nTime to remission\nA total of 224 (73.9%) patients were censored as being in “remission”. While controlling for the site, univariate cox regression models for time to remission found no significant associations for gender (P = 0.3), disease duration (P = 0.6), smoking status (P = 0.9), age at which VDZ was given (P = 0.7), immunomodulator exposure (P = 0.8) and these were also not significant when considered with anti-TNF exposure. The final model included anti-TNF exposure and the site with the Log Rank (Mantel-Cox) reporting a significant difference (P < 0.001) between time-to-remission for anti-TNF exposure, with anti-TNF naïve patients 1.8 times more likely to achieve clinical remission (95%CI: 1.3-2.3) (Figure 2).\n\nFigure 2 Cumulative remission rate of anti-tumor necrosis factor naïve patients to vedolizumab therapy (vs anti-tumor necrosis factor exposed patients, P < 0.001).\n\nTime to failure\nA total of 84 (27.7%) patients were censored as ‘failure’. Controlling for site, univariate cox regression models for time-to-failure found no significant associations for gender (P = 0.4), smoking status (P = 0.3), age at which VDZ was given (P = 0.9), immunomodulator exposure (P = 0.2). These factors remained not significant when considered with anti-TNF exposure. Disease duration was significant (OR = 0.95, 95%CI: 0.93-1.00 P = 0.048), however, was no longer significant when considered with anti-TNF exposure. The final model included anti-TNF exposure and site with the Log Rank (Mantel-Cox) reporting significant difference (P = 0.011) between time-to-failure for anti-TNF groups with anti-TNF exposure patients 1.8 times more likely to lose response (95%CI: 1.16-2.75) (Figure 3).\n\nFigure 3 Cumulative loss of response of anti-tumor necrosis factor exposed patients to Vedolizumab therapy (vs anti-tumor necrosis factor naïve patients, P = 0.011).\n\nSafety\nThe tolerability of VDZ was high with only 8% (n = 25) of all patients reporting an adverse event. Infections (7%, n = 21) were by far the most common adverse event. Two patients reported a serious infection, one was Haemophagocytic syndrome due to Cytomegalovirus and another was from Klebsiella sepsis, both from Australia and both patients were on dual immunosuppression thorough out the study period. A total of 9 patients who received VDZ reported respiratory complications of whom 4 patients reported sinusitis, 2 patients an upper respiratory tract infection, one patient each of nasopharyngitis, pharyngitis and pneumonia. Gastrointestinal infections were reported in 8 patients. Clostridium difficile was the most common gastrointestinal infection (4 patients) followed by Strongyloides (one patient), Campylobacter (one patient), and Salmonella (one patient). A buttock abscess was reported in one patient. Oral thrush was reported in an Oxford patient was attributed to VDZ use. The other complications due to VDZ use reported in our cohort during the study period include rash in one patient, delayed hypersensitivity in one patient and arthralgia and headaches in another patient (Table 4). No deaths were attributed to VDZ use.\n\nTable 4 Complications of vedolizumab therapy\n\nComplication\tAustralia (n = 20)\tOxford (n = 5)\t\nRespiratory infections\tURTI (2)\tPneumonia (1)\t\nSinusitis (4)\tPharyngitis (1)\t\nNasopharyngitis (1)\t\t\nGastrointestinal Infections\tStrongyloidis (1)\tGastroenteritis (1)\t\nClostridium difficile (4)\tButtock abscess (1)\t\nCampylobacter (1)\tOral Thrush (1)\t\nSalmonella (1)\t\t\nSerious infections\tHaemophagocytic syndrome due to CMV (1)\tNA\t\nKlebsiella (1)\t\nOthers\tRash (1)\tNA\t\nDelayed hypersensitivity reaction (1)\t\nArthralgia and Headaches (1)\t\nVDZ: Vedolizumab; URTI: Upper respiratory tract infection; NA: Not applicable.\n\nA colectomy was undertaken in 11% (n = 32) patients by 12 mo. No significant difference (P = 0.25) in the number of patients requiring colectomy in Australia (n = 19/210) and Oxford (n = 13/93) was observed. Anti-TNF exposed patients (23/121) were more likely to require colectomy compared to anti-TNF naïve (9/182) by 12 mo (P = 0.0005) but when patients with primary and secondary LOR to anti-TNF agents were compared, no significant difference was noted (Table 5).\n\nTable 5 Colectomy at 12 mo of vedolizumab therapy\n\nColectomy, n\tAustralia\tOxford\tP value\t\n\t19/210\t13/93\t0.25\t\nColectomy, n\tAnti-TNF naive\tAnti-TNF exposed\tP value\t\n\t9/182\t23/121\t0.0005\t\nColectomy, n\tPrimary LOS\tSecondary LOS\tP value\t\n\t10/45\t23/61\t0.795\t\nVDZ: Vedolizumab; TNF: Tumor necrosis factor; Primary LOR: Primary loss of response; Secondary LOR: Secondary loss of response.\n\nDISCUSSION\nIn this study of 303 UC patients treated with VDZ from 15 specialist IBD centers in two countries, VDZ was noted to be both safe and effective. This study, and the GETAID studies[9], are the only studies where VDZ data is collected from multiple centers encompassing two countries, thus effectively reducing physician, site and country biases.\n\nThe key findings in this cohort were that the week 12 response in UC was 79% while remission rates were 56%, 62% and 60% at 3, 6 and 12 mo respectively. No differences were observed between the two countries in achieving remission at all time points. Anti-TNF-exposed patients, however, were almost twice as likely to lose response to VDZ compared to anti-TNF naïve patients but no difference in VDZ outcomes were observed between patients who had a primary and secondary LOR to anti-TNF agents. Adverse events were observed in 8% of patients and 11% patients required colectomy by 12 mo.\n\nOur results were comparable to prior work from other real world studies. A Swedish real world study observed that 64% of UC patients achieved clinical remission at the end of the follow-up period[10], while a French study demonstrated that 40.5% were in steroid-free clinic remission at week 54[11]. The discrepancy in the clinical response rates could be explained by the difference in clinical characteristics of the patients entering the study and also different clinical criteria (steroid-free remission in French study) used to assess the patients. Similarly, other real world data have shown that prior exposure to anti-TNF agents reduces VDZ effectiveness, but no difference in VDZ outcomes when the patients had either primary or secondary LOR to anti-TNF agents is in line with our findings[12]. The adverse event profile with VDZ treatment was also similar to what has been previously reported[13].\n\nMucosal healing in UC is associated with improved long-term clinical outcomes and STRIDE guidelines identified it as a therapeutic goal[1]. With MES as an endpoint, we report mucosal healing rates of 69% in Australian Cohort at 6 mo compared to 50% in ACT1, 46% in ACT2 at week 30 with Infliximab[14], 59% in PURSUIT at week 30 with Golimumab[15] , 25% in ULTRA2 at week 52 with adalimumab[16], 51% in GEMINI1 with VDZ at week 52[5].The high mucosal healing rates observed in our study could be due to high concomitant immunomodulator use in Australia(64%), however further prospective studies are needed to prove the role of immunomodulator use with VDZ.\n\nWe chose week 12 to assess the response and remission, in contrast to GEMINI 1 time of assessment for response at week 6[5]. This was done in accordance with Australian PBS criteria, which stipulates that patients must be in remission after induction at clinic review before applying for maintenance VDZ. It appears, however, that the full effect of VDZ may take longer than 12 wk as a longer duration of treatment is associated with a higher rate remission at 6 (62%) than at 3 mo (56%). This study thus suggests that the PBS funding criteria may need to be re-attended to benefit the patients. Compared to its predecessor Natalizumab, an alpha4 antagonist, VDZ is a more selective integrin antagonist blocking only alpha4beta7 and thus does not effect lymphocyte trafficking to central nervous system, thereby theoretically eliminating the risk of progressive multifocal leukoencephalopathy (PML), a catastrophic side effect of Natalizumab[17]. No case of PML occurred in our study or any other previous studies with VDZ[18,19].\n\nMore Australian patients compared to Oxford patients achieved clinical response at 3 mo (83% vs 70% P = 0.01) and endoscopic remission at 6 mo (69% vs 43% P = 0.01). This may be due to more patients on concomitant immunomodulation in Australia compared to Oxford (64% vs 43% at VDZ initiation). Further analysis of our data and more prospective studies need to be done to define the role of concomitant immunomodulation with VDZ.\n\nOur observed rate of VDZ efficacy at 12 mo in UC (60%) was comparable to the rates reported with anti-TNF agents[20,21]. While there are no head to head randomized control trials comparing VDZ and infliximab in UC, VDZ showed a significantly better durable clinical response (OR = 3.18, 95%CI: 1.14-9.20) and clinical remission (OR = 2.93, 95%CI: 1.03-8.28) when compared to infliximab in a network meta-analysis[22]. With no major safety concerns[23], in the treatment algorithm ladder of UC, we argue that VDZ should be considered as the first biologic when conventional treatments fail due to its gut selectivity. This is most relevant in patients at high risk of serious infections such as the elderly, those with chronic obstructive airway disease or cardiac disease. If cost allows, it should even be considered before conventional treatment such as AZA due to the same feature and with more and more biosimilars reducing the cost of biologics we may see this in future.\n\nVDZ is also an attractive option in patients who have failed prior anti-TNF agent. Anti-TNF therapy is effective for the treatment of moderate to severe UC, however a significant proportion of patients either fail to respond to anti-TNF therapy termed or lose response with time[24]. Second and third anti-TNF agents can be used in such patients, however, it is a game of diminishing returns, as Golimumab efficacy data has shown that clinical response diminishes with each subsequent anti-TNF agent[25]. Rather than giving another anti-TNF agent, VDZ provides a unique mechanism of action with gut selectivity and less side effects. VDZ does work in anti-TNF refractory IBD patients[26] and our study supports this with 51% of TNF exposed patients achieving remission at 12 mo with VDZ therapy.\n\nThere are several limitations to our study, the most significant of which is retrospective review of the data (although the data in Australia pertaining to each VDZ application to PBS was collected prospectively). Different endoscopic assessment scores were used in Australia and United Kingdom, although a significant correlation was found between the two scores in a recent study[27]. There was consistency, however, in the clinical and endoscopic outcomes across the institutions. One another limitation is we did not report the number of patients who were steroid free and on immunomodulators at different time points in our study although our aim is to look at that in future by obtaining further information from the centers.\n\nAs more and more biologic agents become available for the treatment of IBD, the role of VDZ needs to be defined. Real-world data is important in developing treatment algorithms, which will ultimately help physicians make important treatment decisions in complex IBD patients. This study has shown that VDZ is safe and effective in achieving clinical and endoscopic remission in UC patients.\n\nARTICLE HIGHLIGHTS\nResearch background\nVedolizumab (VDZ) is a gut selective anti-integrin used for treatment of ulcerative colitis (UC). Evidence needed to assess it efficacy and safety in a real world setting.\n\nResearch motivation\nEfficacy and safety of VDZ needs to be assessed, involving multiple inflammatory bowel disease (IBD) centers from two countries to reduce physician, site and country biases.\n\nResearch objectives\nIn this real world study, we aim to assess the clinical response, clinical, endoscopic remission and the factors influencing them in UC patients from Australia and Oxford in United Kingdom treated with VDZ.\n\nResearch methods\nRetrospective review of prospectively entered patient database, treated with VDZ. Three hundred and three UC patients from 14 Australian centers and Oxford (United Kingdom) were included. Clinical response and remission was assessed at 3, 6 and 12 mo using Mayo score across all centers. Endoscopic remission was assessed at 6 mo using mayo endoscopic score in Australia and ulcerative colitis endoscopic score of severity score in Oxford. Cox regression models and Kaplan Meier curves were performed to assess the time to remission, time to failure and the covariates influencing them. Safety was assessed through adverse event reporting.\n\nResearch results\nClinical response for all patients was 79% at 3 mo and number of patients achieving clinical remission increased from 3 mo (56%) to 6 mo (62%) and remained almost stable at 12 mo (60%). No significant difference was observed between the two countries in achieving clinical remission at all points and a significantly greater proportion of Australian patients achieved mucosal healing compared to Oxford, which could be due to more patients using concomitant immunomodulation in Australia. Anti-tumor necrosis factor (anti-TNF) exposed patients were almost twice more likely to lose response to VDZ compared to anti-TNF naïve patients but no difference in outcomes were observed between patients who had a primary and secondary loss of response to anti-TNF agents. The role of concomitant immunomodulation in achieving above outcomes need to be elucidated in future prospective studies.\n\nResearch conclusions\nVDZ can be safely and effectively used to treat UC patients in a real world setting. However patients who had prior anti-TNF therapy were more likely to fail compared to anti-TNF naïve patients.\n\nResearch perspective\nVDZ use was reviewed in real world setting involving multiple IBD centers from two countries. This study helps physicians find VDZ its place in the treatment algorithm of complex IBD patient management. Future prospective studies are needed to evaluate the benefit of using concomitant immunomodulation with VDZ.\n\nACKNOWLEDGEMENTS\nAustralia New Zealand inflammatory bowel disease consortium Australian centers involved in the study include St John of God Hospital Subiaco (Perth), Mater Hospital (Brisbane), Eastern Health (Melbourne), Fiona Stanley Hospital (Perth), Austin Health (Melbourne), QIMR Berghofer Medical Research Institute (Brisbane), St Vincent’s Hospital (Melbourne), Northern Health (Melbourne), The Alfred Hospital, (Melbourne), St Vincent’s Hospital (Sydney), Flinders Medical Centre (Adelaide), Liverpool Hospital (Sydney), Royal Adelaide Hospital & University of Adelaide (Adelaide), Townsville Hospital (Townsville). John Radcliffe, Oxford (United Kingdom) also contributed for the study.\n\nInstitutional review board statement: This study comes under the investigation into natural history of inflammatory bowel disease approved by South Metropolitan area health service.\n\nInformed consent statement: Patients were not required to give informed consent for the study because the data obtained and used for analysis was anonymous.\n\nConflict-of-interest statement: All authors declare no conflict of interest related to this article.\n\nSTROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.\n\nManuscript source: Unsolicited manuscript\n\nPeer-review started: April 4, 2020\n\nFirst decision: April 26, 2020\n\nArticle in press: July 30, 2020\n\nSpecialty type: Gastroenterology and hepatology\n\nCountry/Territory of origin: Australia\n\nPeer-review report’s scientific quality classification\n\nGrade A (Excellent): A\n\nGrade B (Very good): 0\n\nGrade C (Good): 0\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nP-Reviewer: Zaltman C S-Editor: Ma YJ L-Editor: A P-Editor: Ma YJ\n\nData sharing statement\nNo additional data are available.\n==== Refs\n1 Peyrin-Biroulet L Sandborn W Sands BE Reinisch W Bemelman W Bryant RV D'Haens G Dotan I Dubinsky M Feagan B Fiorino G Gearry R Krishnareddy S Lakatos PL Loftus EV Jr Marteau P Munkholm P Murdoch TB Ordás I Panaccione R Riddell RH Ruel J Rubin DT Samaan M Siegel CA Silverberg MS Stoker J Schreiber S Travis S Van Assche G Danese S Panes J Bouguen G O'Donnell S Pariente B Winer S Hanauer S Colombel JF Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): Determining Therapeutic Goals for Treat-to-Target Am J Gastroenterol 2015 110 1324 1338 26303131 \n2 Bryant RV Burger DC Delo J Walsh AJ Thomas S von Herbay A Buchel OC White L Brain O Keshav S Warren BF Travis SP Beyond endoscopic mucosal healing in UC: histological remission better predicts corticosteroid use and hospitalisation over 6 years of follow-up Gut 2016 65 408 414 25986946 \n3 Kozuch PL Hanauer SB Treatment of inflammatory bowel disease: a review of medical therapy World J Gastroenterol 2008 14 354 377 18200659 \n4 Targownik LE Bernstein CN Infectious and malignant complications of TNF inhibitor therapy in IBD Am J Gastroenterol 2013 108 1835 1842, quiz 1843 24042192 \n5 Feagan BG Rutgeerts P Sands BE Hanauer S Colombel JF Sandborn WJ Van Assche G Axler J Kim HJ Danese S Fox I Milch C Sankoh S Wyant T Xu J Parikh A GEMINI 1 Study Group Vedolizumab as induction and maintenance therapy for ulcerative colitis N Engl J Med 2013 369 699 710 23964932 \n6 Ha C Ullman TA Siegel CA Kornbluth A Patients enrolled in randomized controlled trials do not represent the inflammatory bowel disease patient population Clin Gastroenterol Hepatol 2012 10 1002 7; quiz e78 22343692 \n7 Maaser C Sturm A, Vavricka SR, Kucharzik T, Fiorino G, Annese V, Calabrese E, Baumgart DC, Bettenworth D, Borralho Nunes P, Burisch J, Castiglione F, Eliakim R, Ellul P, González-Lama Y, Gordon H, Halligan S, Katsanos K, Kopylov U, Kotze PG, Krustinš E, Laghi A, Limdi JK, Rieder F, Rimola J, Taylor SA, Tolan D, van Rheenen P, Verstockt B, Stoker J, European Crohn’s and Colitis Organisation [ECCO] and the European Society of Gastrointestinal and Abdominal Radiology [ESGAR] ECCO-ESGAR Guideline for Diagnostic Assessment in IBD Part 1: Initial diagnosis, monitoring of known IBD, detection of complications J Crohns Colitis 2019 13 144 164 30137275 \n8 Satsangi J Silverberg MS Vermeire S Colombel JF The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications Gut 2006 55 749 753 16698746 \n9 Amiot A Serrero M Peyrin-Biroulet L Filippi J Pariente B Roblin X Buisson A Stefanescu C Trang-Poisson C Altwegg R Marteau P Vaysse T Bourrier A Nancey S Laharie D Allez M Savoye G Moreau J Vuitton L Viennot S Bouguen G Abitbol V Fumery M Gagniere C Bouhnik Y OBSERV-IBD study group, the GETAID Three-year effectiveness and safety of vedolizumab therapy for inflammatory bowel disease: a prospective multi-centre cohort study Aliment Pharmacol Ther 2019 50 40 53 31165509 \n10 Eriksson C Marsal J Bergemalm D Vigren L Björk J Eberhardson M Karling P Söderman C SWIBREG Vedolizumab Study Group, Myrelid P, Cao Y, Sjöberg D, Thörn M, Karlén P, Hertervig E, Strid H, Ludvigsson JF, Almer S, Halfvarson J Long-term effectiveness of vedolizumab in inflammatory bowel disease: a national study based on the Swedish National Quality Registry for Inflammatory Bowel Disease (SWIBREG) Scand J Gastroenterol 2017 52 722 729 28362144 \n11 Amiot A Serrero M Peyrin-Biroulet L Filippi J Pariente B Roblin X Buisson A Stefanescu C Trang-Poisson C Altwegg R Marteau P Vaysse T Bourrier A Nancey S Laharie D Allez M Savoye G Moreau J Vuitton L Viennot S Aubourg A Pelletier AL Bouguen G Abitbol V Gagniere C Bouhnik Y OBSERV-IBD study group and the GETAID One-year effectiveness and safety of vedolizumab therapy for inflammatory bowel disease: a prospective multicentre cohort study Aliment Pharmacol Ther 2017 46 310 321 28593685 \n12 Shmidt E Kochhar G Hartke J Chilukuri P Meserve J Chaudrey K Koliani-Pace JL Hirten R Faleck D Barocas M Luo M Lasch K Boland BS Singh S Vande Casteele N Sagi SV Fischer M Chang S Bohm M Lukin D Sultan K Swaminath A Hudesman D Gupta N Kane S Loftus EV Jr Sandborn WJ Siegel CA Sands BE Colombel JF Shen B Dulai PS Predictors and Management of Loss of Response to Vedolizumab in Inflammatory Bowel Disease Inflamm Bowel Dis 2018 24 2461 2467 29788240 \n13 Loftus EV Jr Colombel JF Feagan BG Vermeire S Sandborn WJ Sands BE Danese S D'Haens GR Kaser A Panaccione R Rubin DT Shafran I McAuliffe M Kaviya A Sankoh S Mody R Abhyankar B Smyth M Long-term Efficacy of Vedolizumab for Ulcerative Colitis J Crohns Colitis 2017 11 400 411 27683800 \n14 Rutgeerts P Sandborn WJ Feagan BG Reinisch W Olson A Johanns J Travers S Rachmilewitz D Hanauer SB Lichtenstein GR de Villiers WJ Present D Sands BE Colombel JF Infliximab for induction and maintenance therapy for ulcerative colitis N Engl J Med 2005 353 2462 2476 16339095 \n15 Sandborn WJ Feagan BG Marano C Zhang H Strauss R Johanns J Adedokun OJ Guzzo C Colombel JF Reinisch W Gibson PR Collins J Järnerot G Rutgeerts P PURSUIT-Maintenance Study Group Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis Gastroenterology 2014 146 96 109.e1 23770005 \n16 Sandborn WJ van Assche G Reinisch W Colombel JF D'Haens G Wolf DC Kron M Tighe MB Lazar A Thakkar RB Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis Gastroenterology 2012 142 257 65.e1-3 22062358 \n17 Bloomgren G Richman S Hotermans C Subramanyam M Goelz S Natarajan A Lee S Plavina T Scanlon JV Sandrock A Bozic C Risk of natalizumab-associated progressive multifocal leukoencephalopathy N Engl J Med 2012 366 1870 1880 22591293 \n18 Feagan BG Greenberg GR Wild G Fedorak RN Paré P McDonald JW Dubé R Cohen A Steinhart AH Landau S Aguzzi RA Fox IH Vandervoort MK Treatment of ulcerative colitis with a humanized antibody to the alpha4beta7 integrin N Engl J Med 2005 352 2499 2507 15958805 \n19 Parikh A Leach T Wyant T Scholz C Sankoh S Mould DR Ponich T Fox I Feagan BG Vedolizumab for the treatment of active ulcerative colitis: a randomized controlled phase 2 dose-ranging study Inflamm Bowel Dis 2012 18 1470 1479 22147460 \n20 Bálint A Farkas K, Palatka K, Lakner L, Miheller P, Rácz I, Hegede G, Vincze Á, Horváth G, Szabó A, Nagy F, Szepes Z, Gábor Z, Zsigmond F, Zsóri Á, Juhász M, Csontos Á, Szűcs M, Bor R, Milassin Á, Rutka M, Molnár T Efficacy and Safety of Adalimumab in Ulcerative Colitis Refractory to Conventional Therapy in Routine Clinical Practice J Crohns Colitis 2016 10 26 30 26392413 \n21 Oussalah A Evesque L Laharie D Roblin X Boschetti G Nancey S Filippi J Flourié B Hebuterne X Bigard MA Peyrin-Biroulet L A multicenter experience with infliximab for ulcerative colitis: outcomes and predictors of response, optimization, colectomy, and hospitalization Am J Gastroenterol 2010 105 2617 2625 20736936 \n22 Vickers AD Ainsworth C Mody R Bergman A Ling CS Medjedovic J Smyth M Systematic Review with Network Meta-Analysis: Comparative Efficacy of Biologics in the Treatment of Moderately to Severely Active Ulcerative Colitis PLoS One 2016 11 e0165435 27776175 \n23 Bye WA Jairath V Travis SPL Systematic review: the safety of vedolizumab for the treatment of inflammatory bowel disease Aliment Pharmacol Ther 2017 46 3 15 28449273 \n24 Ben-Horin S Loss of response to anti-tumor necrosis factors: what is the next step? Dig Dis 2014 32 384 388 24969284 \n25 Taxonera C Rodríguez C Bertoletti F Menchén L Arribas J Sierra M Arias L Martínez-Montiel P Juan A Iglesias E Algaba A Manceñido N Rivero M Barreiro-de Acosta M López-Serrano P Argüelles-Arias F Gutierrez A Busquets D Gisbert JP Olivares D Calvo M Alba C Collaborators Clinical Outcomes of Golimumab as First, Second or Third Anti-TNF Agent in Patients with Moderate-to-Severe Ulcerative Colitis Inflamm Bowel Dis 2017 23 1394 1402 28671873 \n26 Shelton E Allegretti JR Stevens B Lucci M Khalili H Nguyen DD Sauk J Giallourakis C Garber J Hamilton MJ Tomczak M Makrauer F Burakoff RB Levine J de Silva P Friedman S Ananthakrishnan A Korzenik JR Yajnik V Efficacy of Vedolizumab as Induction Therapy in Refractory IBD Patients: A Multicenter Cohort Inflamm Bowel Dis 2015 21 2879 2885 26288002 \n27 Xie T Zhang T Ding C Dai X Li Y Guo Z Wei Y Gong J Zhu W Li J Ulcerative Colitis Endoscopic Index of Severity (UCEIS) versus Mayo Endoscopic Score (MES) in guiding the need for colectomy in patients with acute severe colitis Gastroenterol Rep (Oxf) 2018 6 38 44 29479441\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1007-9327", "issue": "26(30)", "journal": "World journal of gastroenterology", "keywords": "Outcomes; Ulcerative colitis; Vedolizumab", "medline_ta": "World J Gastroenterol", "mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D001315:Australia; D003093:Colitis, Ulcerative; D005765:Gastrointestinal Agents; D006801:Humans; D012189:Retrospective Studies; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha; D006113:United Kingdom", "nlm_unique_id": "100883448", "other_id": null, "pages": "4428-4441", "pmc": null, "pmid": "32874055", "pubdate": "2020-08-14", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study", "references": "16698746;22062358;28449273;22147460;26303131;27776175;24969284;27683800;16339095;29479441;24042192;28593685;23964932;23770005;15958805;28671873;29788240;31165509;30137275;22591293;26392413;28362144;25986946;20736936;26288002;18200659;22343692", "title": "Vedolizumab for ulcerative colitis: Real world outcomes from a multicenter observational cohort of Australia and Oxford.", "title_normalized": "vedolizumab for ulcerative colitis real world outcomes from a multicenter observational cohort of australia and oxford" }

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{ "abstract": "BACKGROUND\nCerebral toxoplasmosis infection presents with non-specific neurologic symptoms in immunocompromised patients. With lack of measurable adaptive immune responses and reluctance to sample affected brain tissue, expedient diagnosis to guide directed treatment is often delayed.\n\n\nMETHODS\nWe describe the use of cerebrospinal fluid polymerase chain reaction and plasma cell-free DNA technologies to supplement neuroimaging in the diagnosis of cerebral toxoplasmosis in an immunocompromised pediatric patient following allogeneic hematopoietic cell transplantation for idiopathic severe aplastic anemia. Successful cerebral toxoplasmosis treatment included antibiotic therapy for 1 year following restoration of cellular immunity with an allogeneic stem cell boost.\n\n\nCONCLUSIONS\nPlasma cell-free DNA technology provides a non-invasive method of rapid diagnosis, improving the likelihood of survival from often lethal opportunistic infection in a high risk, immunocompromised patient population.", "affiliations": "Medical School, University of Minnesota, Minneapolis, MN, USA.;Department of Pediatrics, Division of Blood and Marrow Transplantation and Cellular Therapy, University of Minnesota, Minneapolis, MN, USA.;Department of Pediatrics, Division of Infectious Diseases, University of Minnesota, Minneapolis, MN, USA.;Department of Pediatrics, Division of Infectious Diseases, University of Minnesota, Minneapolis, MN, USA.;Department of Medicine, Division of Infectious Diseases and International Medicine, University of Minnesota, Minneapolis, MN, USA.;Department of Pediatrics, Division of Blood and Marrow Transplantation and Cellular Therapy, University of Minnesota, Minneapolis, MN, USA. ebens012@umn.edu.", "authors": "Brewer|Danielle|D|;MacMillan|Margaret L|ML|;Schleiss|Mark R|MR|;Ayuthaya|Satja Issaranggoon Na|SIN|;Young|Jo-Anne|JA|;Ebens|Christen L|CL|http://orcid.org/0000-0003-2430-911X", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1186/s12879-021-06650-2", "fulltext": "\n==== Front\nBMC Infect Dis\nBMC Infect Dis\nBMC Infectious Diseases\n1471-2334\nBioMed Central London\n\n6650\n10.1186/s12879-021-06650-2\nCase Report\nDetection and treatment of cerebral toxoplasmosis in an aplastic pediatric post-allogeneic hematopoietic cell transplant patient: a case report\nBrewer Danielle 1\nMacMillan Margaret L. 2\nSchleiss Mark R. 3\nAyuthaya Satja Issaranggoon Na 3\nYoung Jo-Anne 4\nhttp://orcid.org/0000-0003-2430-911X\nEbens Christen L. ebens012@umn.edu\n\n2\n1 grid.17635.36 0000000419368657 Medical School, University of Minnesota, Minneapolis, MN USA\n2 grid.17635.36 0000000419368657 Department of Pediatrics, Division of Blood and Marrow Transplantation and Cellular Therapy, University of Minnesota, Minneapolis, MN USA\n3 grid.17635.36 0000000419368657 Department of Pediatrics, Division of Infectious Diseases, University of Minnesota, Minneapolis, MN USA\n4 grid.17635.36 0000000419368657 Department of Medicine, Division of Infectious Diseases and International Medicine, University of Minnesota, Minneapolis, MN USA\n10 9 2021\n10 9 2021\n2021\n21 94114 5 2021\n1 9 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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 in a credit line to the data.\nBackground\n\nCerebral toxoplasmosis infection presents with non-specific neurologic symptoms in immunocompromised patients. With lack of measurable adaptive immune responses and reluctance to sample affected brain tissue, expedient diagnosis to guide directed treatment is often delayed.\n\nCase presentation\n\nWe describe the use of cerebrospinal fluid polymerase chain reaction and plasma cell-free DNA technologies to supplement neuroimaging in the diagnosis of cerebral toxoplasmosis in an immunocompromised pediatric patient following allogeneic hematopoietic cell transplantation for idiopathic severe aplastic anemia. Successful cerebral toxoplasmosis treatment included antibiotic therapy for 1 year following restoration of cellular immunity with an allogeneic stem cell boost.\n\nConclusions\n\nPlasma cell-free DNA technology provides a non-invasive method of rapid diagnosis, improving the likelihood of survival from often lethal opportunistic infection in a high risk, immunocompromised patient population.\n\nKeywords\n\nToxoplasmosis\nAllogeneic hematopoietic cell transplantation\nSevere aplastic anemia\nImmune mediated cytopenia\nCell-free DNA\nCase report\nhttp://dx.doi.org/10.13039/100006108 National Center for Advancing Translational Sciences KL2TR002492 Ebens Christen L. issue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nCerebral toxoplasmosis is a rare but serious complication of allogeneic hematopoietic cell transplantation (alloHCT). Caused by the protozoan parasite Toxoplasma gondii, toxoplasmosis most often results from reactivation of latent infection in immunocompromised patients [1]. It is one of the most common opportunistic infection of the central nervous system (CNS) [2], with greatest prevalence in those with acquired immunodeficiency syndrome (AIDS) [3]. The incidence of toxoplasmosis after alloHCT ranges from 0.3 to 9% [2, 4], with variation based on population seroprevalence. Although the incidence and treatment of toxoplasmosis in adult alloHCT patients has been reported extensively, few studies have focused specifically on cerebral toxoplasmosis in pediatric patients [5–17]. Furthermore, cerebral toxoplasmosis diagnosis is usually based on a combination of radiologic imaging abnormalities and clinical symptoms such as seizures, headaches, and altered mental status, non-specific findings contributing to delays in diagnosis and treatment [18]. This case reviews the successful management of cerebral toxoplasmosis in a pediatric alloHCT patient following diagnosis with the use of cerebrospinal fluid (CSF) polymerase chain reaction (PCR) and microbial cell free DNA (cfDNA) technology.\n\nCase presentation\n\nA 13-year-old male with idiopathic severe aplastic anemia was treated with a human leukocyte antigen (HLA)-matched unrelated donor alloHCT on an Institutional Review Board-approved protocol with parental consent. His transplant course was complicated by Epstein-Barr virus (EBV) viremia (day + 21, successfully treated with rituximab), immune-mediated cytopenias versus inadequate graft function (beginning at day + 100, refractory to granulocyte-colony stimulating factor (GCSF), corticosteroids, intravenous immunoglobulin (IVIG), plasmapheresis and bortezomib), and right cervical lymphadenopathy concerning for EBV-post-transplant lymphoproliferative disease (day + 188, surgically excised, negative for infection or malignancy). With persistent pancytopenia, he required blood product transfusions and prophylactic anti-infective agents (valacyclovir, itraconazole, and intravenous pentamidine). Eight months after alloHCT, he was hospitalized locally for a severe gastrointestinal hemorrhage requiring superior mesenteric artery branch embolization.\n\nNine months after alloHCT, he was readmitted to our hospital with refractory pancytopenia. He denied night sweats and weight loss, but endorsed 2 weeks of intermittent headaches. With no financial, cultural or social barriers to care, the patient was promptly evaluated. A bone marrow biopsy was hypocellular (5–10%), with 93% donor chimerism. On day 3 of hospitalization, his severe headache recurred, accompanied by somnolence, nausea, fever, and hypertension. Head computed tomography (CT) showed a curvilinear hyperdensity at the right parietal and occipital lobe junction. Brain magnetic resonance imaging (MRI), angiogram (MRA), and venogram (MRV) revealed numerous enhancing cerebellar and cerebral lesions with punctate microhemorrhages and surrounding vasogenic edema (Fig. 1). Compared to a previous brain MRI, third and 4th ventricle sizes were increased with accompanying ependymal enhancement concerning for possible hydrocephalus. Additionally, moderate stenosis of the distal transverse sinuses bilaterally raised concern for intracranial hypertension. Clinically, he had no focal neurological deficits and a normal ophthalmologic exam. Given his history, CNS EBV infection was initially suspected.Fig. 1 Resolution of cerebral toxoplasmosis with combined antibiotics and restoration of cellular immunity. Radiologic improvements in right posterior temporal and left occipital toxoplasmosis over time (axial fluid-attenuated inversion recovery 1.5 (16.5 months) or 3-T (all other) brain MRI images, are shown with a timeline of Toxoplasma directed antibiotics, interventions for presumed immune-mediated cytopenias, CD34 + PBSC boost, and blood laboratory findings (CD4 + lymphocyte count, platelet count, and absolute neutrophil count)\n\nA lumbar puncture (LP) on hospital day 5 (alloHCT day + 304) revealed an elevated opening pressure of 38 cm H2O (normal 10–20) and CSF with 6 WBC/microliter (54% lymphocytes, 46% monocytes/macrophages), 8 RBC/microliter, glucose 39 mg/dL, and protein 112 mg/dL. Toxoplasma gondii was identified by CSF PCR and plasma cfDNA testing (5081 DNA molecules per microliter; Karius assay, Redwood City, CA), while serologies for Toxoplasma were negative. Given concurrent cytopenias and suspicion for alternative etiology, Toxoplasma therapy began only after these positive results (cfDNA testing returning in 2 days, CSF PCR in 4 days). Oral therapy with high dose pyrimethamine (200 mg loading dose followed by 75 mg once daily) with leucovorin rescue (50 mg daily) and sulfadiazine (1500 mg every 6 h daily) was initiated. While the patient was already on stress dosing hydrocortisone, three days of neuroprotective dexamethasone was provided within initiation of Toxoplasma therapy. Repeat Toxoplasma CSF PCR and plasma cfDNA testing was negative 2 weeks into treatment and remained so on future evaluations.\n\nDuring the 3rd week of toxoplasmosis therapy, the patient required intensive care including 18 days of intubation/ventilation for an acute increase in somnolence and hypertension. While head CT and ophthalmologic exams were unchanged, his LP opening pressure was again elevated at 55 cm H2O. Improvement in mental status/alertness following the LP (closing pressure of 26.5) prompted initiation of acetazolamide and serial therapeutic LPs (16 times over 58 days). Atovaquone (1500 mg twice daily) was added when an MRI at 4 weeks of therapy (day + 337 post-alloHCT) showed decreased cerebral edema but unchanged toxoplasmosis lesions.\n\nIn the context of persistent cytopenias and poor graft function despite multi-modal therapy (Fig. 1), the patient received 4 days of immunosuppressive fludarabine followed by a CD34 + selected peripheral blood stem cell boost from his previous bone marrow donor (day + 349 after alloHCT). After 6 weeks of toxoplasmosis treatment showing both clinical and radiologic response, and to avoid bone marrow suppression after his stem cell boost, sulfadiazine was transitioned to oral clindamycin 600 mg 3 times/day for chronic maintenance therapy. One month after the stem cell boost, peripheral blood donor chimerism was 100% in the CD33 + myeloid compartment and 87% in the CD3 + lymphoid compartment. Transfusion independence was achieved at 42 days, eltrombopag discontinued at 60 days, and GCSF discontinued at 100 days. Fifty-five days following his stem cell boost—3 months of hospitalization—he was discharged on maintenance pyrimethamine and clindamycin. Adherence to oral therapies was monitored by nursing while inpatient and by the patient’s mother while outpatient. The patient himself reported no intolerance or adverse toxicities.\n\nAfter 5 months of cerebral toxoplasmosis therapy, comprehensive neuropsychologic evaluations were completed. Compared to pre-alloHCT 14 months earlier, he displayed fine motor speed, dexterity and visuomotor integration deficiencies. From 6 to 12 months following cerebral toxoplasmosis diagnosis, his course was complicated by a single 30 s partial seizure. A brain MRI at 12.5 months of therapy revealed residual hypointense right posterior temporal lesions, resolution of associated vasogenic edema, and no new lesions. A bone marrow evaluation at that time was remarkable for 30–40% cellularity, trilineage hematopoiesis with no dysplasia and 98% donor contribution. With reassuring MRI findings and a CD4 count > 400 cells/microliter, toxoplasmosis therapy was discontinued. A 4 month off-therapy brain MRI was stable with no new lesions and interval improvement in mild ventriculomegaly.\n\nDiscussion and conclusions\n\nThis case demonstrates the successful diagnosis and management of cerebral toxoplasmosis in a pediatric alloHCT patient. While seroprevalence of Toxoplasma exceeds 50% in some regions of the world, in both the United States and China (where this patient resided for 3 years), Toxoplasma is less common (~ 10%) [19, 20]. As such, surveillance for Toxoplasma is not routine prior to alloHCT at our institution and the serostatus of this patient was unknown. Risk factors for opportunistic reactivation included 4–6 months of preceding cytopenias and medication-associated immunosuppression from graft-versus-host disease prophylaxis, EBV treatment, and immune-mediated cytopenia therapies. Notably, routine prophylaxis against Pneumocystis jirovecii pneumonia with trimethoprim-sulfamethoxazole (TMP-SMX) until at least 1 year post-alloHCT and recovery of CD4 + lymphocyte count to > 200 cell/mm3 additionally protects against Toxoplasma reactivation and infection. However, to avoid further myelosuppression from TMP-SMX in this patient with concurrent cytopenias, his Pneumocystis jirovecii pneumonia prophylaxis had been transitioned to pentamidine, an agent with no activity against Toxoplasma [21]. Without standard alloHCT population recommendations, toxoplasmosis treatment and duration was based on U.S. Department of Health and Human Services “Guidelines for prevention and treatment of opportunistic infection in adults and adolescents with HIV” (available at https://aidsinfo.nih.gov2019).\n\nPCR as a diagnostic tool for CSF samples of immunocompromised patients with suspected cerebral toxoplasmosis demonstrates wide variability in sensitivity [22–27]. Variations are attributable to laboratory variability, sample processing efficiency, and patient level differences in CSF protein and cellularity [27–29]. Regardless, CSF PCR remains less invasive than brain biopsy and provides rapid detection of parasite DNA. Moreover, CSF PCR expanded gene targets to detect Toxoplasma DNA [17, 28] are increasing accuracy of this methodology.\n\nMicrobial cfDNA sequencing technology provides a novel, non-invasive approach to the diagnosis of thousands of infectious organisms [30], including detection of opportunistic infection in immunocompromised hosts [31, 32]. However, cfDNA studies to date are limited by small sample sizes, lack of control groups, and cohort heterogeneity. Clinical indications for this novel approach remain to be clearly established. There is no published medical literature reporting the use of cfDNA to identify cerebral toxoplasmosis in an immunocompromised host. Prior to CSF PCR and plasma cfDNA sequencing results, the infectious differential diagnosis for our teenage alloHCT patient’s brain lesions included a broad group of neurotropic viruses, fungi and parasites. In our case, cfDNA sequencing provided rapid evidence of cerebral toxoplasmosis despite negative blood serologies and ophthalmologic examination. Thus, cfDNA sequencing emerges as a useful adjunct to diagnosis for toxoplasmosis, particularly when tissue diagnosis is not feasible [33].\n\nOf note, while Toxoplasma serologies are often useful to assess for prior or current immune response to infection, they are unreliable before adequate immune reconstitution after alloHCT. This particularly patient was profoundly immune suppressed from treatment of immune mediated cytopenias after alloHCT and had recently undergone plasmapheresis, further reducing the likelihood of production of circulating antibodies. Interpretation of positive serologies, had they been found, would also be challenging as he had recently received IVIG.\n\nWhile mortality of cerebral toxoplasmosis in post-alloHCT patients is reported from 38 to 67% [34], little is known about long term sequelae in adult or pediatric survivors [14]. While promptly initiated on antibiotics, our patient only displayed definitive clinical improvement after a CD34 + stem cell boost restored the cellular immunity essential for Toxoplasma clearance. Clinical and radiographic signs of recovery persisted at follow-up 4 months following completion of maintenance antibiotics. Future studies exploring the incidence and outcomes of cerebral toxoplasmosis in pediatric post-alloHCT patients are needed.\n\nPatient perspective\n\nFortunately during the time I was most ill as a patient I don’t really remember how I felt in the hospital and only have hazy memories. However, as I began to heal I do have memories of some nurses that especially helped me laugh during this time. I also remember enjoying integrative healing therapies in the form of music, aromatherapy, and massages. I am currently doing great, finishing my Freshman year of high school, playing in fantasy sports leagues, and also relieved to not be on clindamycin anymore.\n\nAbbreviations\n\nHCT Allogeneic hematopoietic cell transplantation\n\nCNS Central nervous system\n\nAIDS Acquired immunodeficiency syndrome\n\nCSF Cerebrospinal fluid\n\nPCR Polymerase chain reaction\n\nHLA Human leukocyte antigen\n\nEBV Epstein-Barr virus\n\nGCSF Granulocyte colony stimulating factor\n\nIVIG Intravenous immunoglobulin\n\nCT Computed tomography\n\nMRI Magnetic resonance imaging\n\nLP Lumbar puncture\n\nCMV Cytomegalovirus\n\ncfDNA Cell free DNA\n\nTMP-SMX Trimethoprim-sulfamethoxazole\n\nAcknowledgements\n\nWe thank our patient and his family for their patience and perseverance during his complicated alloHCT and cerebral toxoplasmosis course.\n\nAuthors’ contributions\n\nDB and CLE contributed to conception of the report and drafted the manuscript, DB, MLM, SIN, MRS, JY, and CLE all contributed to data analysis and critical revision of the manuscript, CLE interpreted data and created the figure. All authors read and approved the final manuscript.\n\nFunding\n\nThis research was supported by the National Institutes of Health’s National Center for Advancing Translational Sciences, Grants KL2TR002492, funding research effort for CLE. The content is the sole responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health’s National Center for Advancing Translational Sciences which had no role in study design, data collection, analysis, interpretation or writing of the manuscript.\n\nAvailability of data and materials\n\nData sharing is not applicable to this article as no datasets were generated or analyzed during the current study. All relevant data are herein included.\n\nDeclarations\n\nEthics approval and consent to participate\n\nThe patient’s care was provided on a University of Minnesota IRB approved allogeneic hematopoietic cell transplant protocol.\n\nConsent for publication\n\nVerbal and written consent for publication of de-identified clinical data was obtained from the patient’s parent with the patient’s assent.\n\nCompeting interests\n\nThe authors report no competing interests.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Martino R Cordonnier C European Group for B, Marrow Transplantation Infectious Diseases Working P Toxoplasmosis following allogeneic hematopoietic stem cell transplantation Bone Marrow Transpl 2003 31 7 617 618 10.1038/sj.bmt.1703914\n2. 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Gajurel K Dhakal R Montoya JG Toxoplasma prophylaxis in haematopoietic cell transplant recipients: a review of the literature and recommendations Curr Opin Infect Dis 2015 28 4 283 292 10.1097/QCO.0000000000000169 26098500\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2334", "issue": "21(1)", "journal": "BMC infectious diseases", "keywords": "Allogeneic hematopoietic cell transplantation; Case report; Cell-free DNA; Immune mediated cytopenia; Severe aplastic anemia; Toxoplasmosis", "medline_ta": "BMC Infect Dis", "mesh_terms": "D000741:Anemia, Aplastic; D002648:Child; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D009894:Opportunistic Infections; D016781:Toxoplasmosis, Cerebral; D014184:Transplantation, Homologous", "nlm_unique_id": "100968551", "other_id": null, "pages": "941", "pmc": null, "pmid": "34507535", "pubdate": "2021-09-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "22627571;24103000;1543952;30742071;22548804;19072243;30017314;10828877;10382957;15184533;30941906;19709704;8054907;27191201;19433092;26098500;25240445;18194354;12692632;6381682;12729998;17645187;10194081;25581774;10921953;28664700;31823860;15880132;28604668;16333839;7854375;31814964;16441450;30040610", "title": "Detection and treatment of cerebral toxoplasmosis in an aplastic pediatric post-allogeneic hematopoietic cell transplant patient: a case report.", "title_normalized": "detection and treatment of cerebral toxoplasmosis in an aplastic pediatric post allogeneic hematopoietic cell transplant patient a case report" }

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indication", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Brewer D, MacMillan ML, Schleiss MR, Ayuthaya SIN, Young J-A, Ebens CL.. Detection and treatment of cerebral toxoplasmosis in an aplastic pediatric post-allogeneic hematopoietic cell transplant patient: a case report.. 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Detection and treatment of cerebral toxoplasmosis in an aplastic pediatric post-allogeneic hematopoietic cell transplant patient: a case report. 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"drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Injection", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Infection prophylaxis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PENTAMIDINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "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": "FLUDARABINE" } ], "patientagegroup": null, "patientonsetage": "13", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cerebral toxoplasmosis", "reactionmeddraversionpt": "25.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Somnolence", "reactionmeddraversionpt": "25.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hydrocephalus", "reactionmeddraversionpt": "25.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Partial seizures", "reactionmeddraversionpt": "25.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cerebellar microhaemorrhage", "reactionmeddraversionpt": "25.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Cerebral microhaemorrhage", "reactionmeddraversionpt": "25.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Vasogenic cerebral oedema", "reactionmeddraversionpt": "25.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Transverse sinus stenosis", "reactionmeddraversionpt": "25.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Cerebral ventricle dilatation", "reactionmeddraversionpt": "25.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Fine motor delay", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fine motor skill dysfunction", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Motor dysfunction", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Brewer D, MacMillan ML, Schleiss MR, Ayuthaya SIN, Young J-A, Ebens CL. Detection and treatment of cerebral toxoplasmosis in an aplastic pediatric post-allogeneic hematopoietic cell transplant patient: a case report. BMC-Infect-Dis 2021;21:No. 1.", "literaturereference_normalized": "detection and treatment of cerebral toxoplasmosis in an aplastic pediatric post allogeneic hematopoietic cell transplant patient a case report", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220425", "receivedate": "20220425", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20744132, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 2, "transmissiondate": "20220721" }, { "companynumb": "US-MLMSERVICE-20220513-3558250-1", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090828", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Antifungal prophylaxis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BORTEZOMIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Immune-mediated cytopenia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BORTEZOMIB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "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": "RITUXIMAB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "IMMUNE GLOBULIN NOS" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Immune-mediated cytopenia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMMUNE GLOBULIN NOS" } ], "patientagegroup": null, "patientonsetage": "13", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myelosuppression", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Brewer D, MacMillan ML, Schleiss MR, Ayuthaya SIN, Young JA, Ebens CL.. Detection and treatment of cerebral toxoplasmosis in an aplastic pediatric post-allogeneic hematopoietic cell transplant patient: a case report.. 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"2" }, { "reactionmeddrapt": "Vasogenic cerebral oedema", "reactionmeddraversionpt": "25.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hydrocephalus", "reactionmeddraversionpt": "25.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Transverse sinus stenosis", "reactionmeddraversionpt": "25.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Partial seizures", "reactionmeddraversionpt": "25.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cerebral ventricle dilatation", "reactionmeddraversionpt": "25.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Fine motor delay", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fine motor skill dysfunction", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Motor dysfunction", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Brewer D, MacMillan ML, Schleiss MR, Ayuthaya SIN, Young J-A, Ebens CL. Detection and treatment of cerebral toxoplasmosis in an aplastic pediatric post-allogeneic hematopoietic cell transplant patient: a case report. 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{ "activesubstancename": "PENTAMIDINE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Infection prophylaxis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PENTAMIDINE" } ], "patientagegroup": "4", "patientonsetage": "13", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cerebral toxoplasmosis", "reactionmeddraversionpt": "25.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Gastrointestinal haemorrhage", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Brewer D, MacMillan M, Ebens C, Schleiss M, Ayuthaya S, Young J. Detection and treatment of cerebral toxoplasmosis in an aplastic pediatric post?allogeneic hematopoietic cell transplant patient: a case report. BMC Infect Dis. 2021;21(1):941-941. doi:10.1186/s12879-021-06650-2", "literaturereference_normalized": "detection and treatment of cerebral toxoplasmosis in an aplastic pediatric post allogeneic hematopoietic cell transplant patient a case report", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220426", "receivedate": "20220426", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20750343, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20220720" } ]

{ "abstract": "Post-traumatic stress disorder (PTSD) is a pathological response to trauma characterized by frequent recollections, recurrent nightmares, and flashbacks of the traumatic event(s). To date, the precise mechanisms underlying the development of PTSD remain unknown. Several studies have suggested that antiepileptic drugs, such as gabapentin and lamotrigine, may be effective in the treatment of PTSD symptoms. We report on a 15-year-old Japanese female junior high school student who developed PTSD symptoms following repeated teasing from male classmates. Additionally, we underscore the beneficial effects of treatment with gabapentin and lamotrigine on flashbacks and nightmares. This patient developed PTSD symptoms after repeated teasing from male classmates at school. Her flashbacks and nightmares were treated with a combination of gabapentin and lamotrigine. After recovery, treatment with lamotrigine alone controlled her symptoms. Our observations suggest that a process of sensitization may be involved in the development of PTSD symptoms. Additionally, gabapentin and/or lamotrigine were effective in the treatment of flashbacks and nightmares in this patient. Thus, doctors should consider using these anti-epileptic drugs as an alternative approach to treating PTSD symptoms.", "affiliations": "Yonago Medical Corporation, Yonago Clinic, Yonago, Japan.;Yonago Medical Corporation, Yonago Clinic, Yonago, Japan.;Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.", "authors": "Kishimoto|Akira|A|;Goto|Yurie|Y|;Hashimoto|Kenji|K|", "chemical_list": null, "country": "Korea (South)", "delete": false, "doi": "10.9758/cpn.2014.12.3.240", "fulltext": "\n==== Front\nClin Psychopharmacol NeurosciClin Psychopharmacol NeurosciCPNClinical Psychopharmacology and Neuroscience1738-10882093-4327Korean College of Neuropsychopharmacology 10.9758/cpn.2014.12.3.240Case ReportPost-traumatic Stress Disorder Symptoms in a Female Patient Following Repeated Teasing: Treatment with Gabapentin and Lamotrigine and the Possible Role of Sensitization Kishimoto Akira 1Goto Yurie 1Hashimoto Kenji 21 Yonago Medical Corporation, Yonago Clinic, Yonago, Japan.2 Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.Address for correspondence: Akira Kishimoto, MD, PhD. Yonago Medical Corporation, Yonago Clinic, 80-1 Bakuro-machi 3-Chome, Yonago 683-0052, Japan. Tel: +81-859-34-1201, Fax: +81-859-35-5023, ak-feb8@sea.chukai.ne.jp12 2014 26 12 2014 12 3 240 242 25 4 2014 21 6 2014 14 7 2014 Copyright© 2014, Korean College of Neuropsychopharmacology2014This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Post-traumatic stress disorder (PTSD) is a pathological response to trauma characterized by frequent recollections, recurrent nightmares, and flashbacks of the traumatic event(s). To date, the precise mechanisms underlying the development of PTSD remain unknown. Several studies have suggested that antiepileptic drugs, such as gabapentin and lamotrigine, may be effective in the treatment of PTSD symptoms. We report on a 15-year-old Japanese female junior high school student who developed PTSD symptoms following repeated teasing from male classmates. Additionally, we underscore the beneficial effects of treatment with gabapentin and lamotrigine on flashbacks and nightmares. This patient developed PTSD symptoms after repeated teasing from male classmates at school. Her flashbacks and nightmares were treated with a combination of gabapentin and lamotrigine. After recovery, treatment with lamotrigine alone controlled her symptoms. Our observations suggest that a process of sensitization may be involved in the development of PTSD symptoms. Additionally, gabapentin and/or lamotrigine were effective in the treatment of flashbacks and nightmares in this patient. Thus, doctors should consider using these anti-epileptic drugs as an alternative approach to treating PTSD symptoms.\n\nFlashbackGabapentinLamotrigineNightmarePost-traumatic stress disordersSensitization\n==== Body\nINTRODUCTION\nPost-traumatic stress disorder (PTSD) is a pathological response to trauma characterized by frequent recollections, recurrent nightmares, and images or flashbacks of the trauma(s). These symptoms are frequently associated with insomnia, irritability, impaired concentration, and increased vigilance.1) The primary treatment options for people with PTSD are psychotherapy (e.g., exposure therapy, cognitive restricting, and stress inoculation training), medication, or a combination of both. The U.S. Food and Drug Administration has approved two medications, sertraline and paroxetine, for treating adults with PTSD. Additionally, other medications, including benzodiazepines, antipsychotics, and other antidepressants, have also been used as potential therapeutic drugs, although there is little information about their effectiveness for PTSD.1) Nonetheless, new therapeutic drugs for PTSD are needed, because the efficacy of current medications is limited.\n\nSeveral clinical studies have suggested that the anti-epileptic drug, gabapentin, an analogue of γ-aminobutyric acid (GABA), may have beneficial effects on several PTSD symptoms.2,3,4,5) Furthermore, a double-blind, placebo-controlled study showed that, compared with a placebo, another antiepileptic drug, lamotrigine, which functions as a voltage-sensitive sodium channel blocker, improved the re-experiencing and avoidance/numbing symptoms of patients with PTSD.6) Whereas the precise mechanisms underlying PTSD symptoms remain unknown, these findings suggest that antiepileptic drugs, such as gabapentin and lamotrigine, may act as potential therapeutic drugs for this disorder.7,8)\n\nHere, we describe the development of PTSD symptoms in a female junior high school student after repeated teasing from male classmates. Additionally, we also report on the beneficial effects of gabapentin and lamotrigine for controlling PTSD symptoms, such as nightmares and flashbacks.\n\nCASE\nA15-year-old Japanese female patient was diagnosed with psychosomatic disorder (F-459), mixed anxiety and depressive disorder (F-41.2), and PTSD (F-43.1) according to International Classification of Diseases, 10th edition (ICD-10) criteria. During her first grade of junior high school, she was repeatedly teased by a male classmate, \"S.\" When this teasing intensified, she received counseling at school and was then diagnosed with insomnia. She began to exhibit psychological and physical symptoms, such as stomach aches, headaches, and insomnia. At this point, she no longer felt able to attend school. She was then admitted to our clinic, reporting \"I feel too heavy-hearted to go to school,\" and \"The school staff and school counselors do not listen to my complaints about the teasing.\" Additionally, she displayed psychotic symptoms such as, \"I see the faces of the boys who teased me before go to bed,\" \"I mistake night and day,\" and \"Objects look distorted to me.\" At this time, she was not diagnosed with PTSD. Her score on the 17-item Hamilton Depression Rating Scale (HDRS) was 8, and she showed mild depressive symptoms and anxiety. She was treated with the hypnotic drug flunitrazepam (2 mg) as well as an analgesic drug and she attended our clinic on a regular basis. However, the teasing continued. She reported \"I fear their unbearable behavior toward me.\" She was unable to attend school due to her psychosomatic symptoms, which were brought on by the teasing. At this point, we decided to make a criminal report to the police. This news was broadcast on television and published in newspapers. One week later, she visited the clinic and reported \"I have not been teased by 'S,' and I can go to school.\" At this time, she did not show depressive symptoms, and her score on the HDRS was 2.\n\nTwo weeks after returning to school, she was the target of intense teasing from student \"A,\" a friend of \"S.\" After 1-2 weeks, her vomiting, stomach aches, and headaches returned. This was followed by repeated nightmares and flashbacks. The flashbacks occurred between five and ten times per day, with a duration of approximately 30 min. Additionally, she experienced physical symptoms, such as palpitations, trembling, vomiting, and fear and was unable to return to school. At this stage, she was diagnosed with PTSD, as she had four of the five symptoms needed for this diagnosis. She was started on gabapentin (400 mg). Her PTSD symptoms disappeared 3 days later, and she was able to return to school. Four months later, she agreed to be questioned by the police, and her flashbacks and nightmares re-emerged. The antiepileptic drug lamotrigine (25 mg) was then added to her therapy, and the number of flashbacks decreased. After 2 weeks of treatment, the number of flashbacks and nightmares had been reduced by approximately 50%. The dose of lamotrigine was therefore increased to 50 mg, and the incidence of flashbacks and nightmares began to decrease gradually, finally disappearing by the third week. After graduating from junior high school, she entered high school and enjoyed her school life. During this time, she was treated with flunitrazepam (2 mg), lamotrigine (50 mg), and fluvoxamine (150 mg). Her encounters with students \"S\" and \"A,\" who had teased her in junior high school, were not accompanied by flashbacks or nightmares. Therefore, gabapentin and fluvoxamine were discontinued. The remaining two drugs, lamotrigine and flunitrazepam, have been maintained due to her positive response. She is currently enjoying her life in high school and is free from flashbacks and nightmares.\n\nWritten informed consent for publication of this case report was obtained from the patient and her parent.\n\nDISCUSSION\nWe report on a female student who developed PTSD symptoms after repeated teasing from male classmates at school. The precise mechanisms underlying the PTSD symptoms experienced by this patient are undefined. It is well known that exposure to traumatic stress is a requirement for the development of PTSD and that the amygdala plays a key role in fear and other emotional processes.9,10,11) Furthermore, repeated exposure to the same stressor results in a progressive reduction in response magnitude, and this is thought to be mediated by structures such as the prefrontal cortex, paraventricular thalamus, and amygdala. However, exposure to a new stressor after either homotypic or heterotypic stressors causes an exaggerated response or sensitization, which may be mediated by enhanced activity in the basolateral amygdala, paraventricular thalamus, or locus coeruleus.12) It has also been suggested that neuronal plasticity, such as amygdala kindling and sensitization, are models of PTSD.13) Taken together, it is likely that this type of neuronal plasticity may have been involved in the developmental course of the PTSD symptoms experienced by this patient.\n\nHere, we report a case showing the beneficial effects of gabapentin and lamotrigine on a female patient with PTSD. Inhibitory neurotransmission via GABA receptors in the amygdala is important for fear conditioning and, potentially, for regulating the process of fear learning.11) It has also been reported that lamotrigine reduces GABA-mediated neurotransmission in the rat amygdala, suggesting that the GABAergic system may play a role in its mechanism of action.14) Although it is unclear how these two antiepileptic drugs, gabapentin and lamotrigine, alleviate PTSD symptoms, it seems that their modulation of GABA receptors may facilitate their actions in this regard. In this case, lamotrigine monotherapy was effective in the treatment of PTSD, as the removal of gabapentin did not lead to a worsening of symptoms in this patient. It has been reported recently that lamotrigine eliminated aggression in a patient with treatment-resistant PTSD.15) This implies that lamotrigine may be useful for treating aggression and aggression-related symptoms in PTSD. Overall, it is highly likely that lamotrigine may be clinically effective in the treatment of PTSD, although further placebo-controlled, double-blind studies using large samples are necessary.\n\nIn conclusion, we documented the development of PTSD symptoms in a female subject who had experienced repeated teasing in school. Her clinical course implicates the operation of sensitization in the development of PTSD symptoms. Furthermore, this case suggests that the antiepileptic medications, gabapentin and lamotrigine, may be beneficial in the treatment of PTSD. Nonetheless, more detailed, randomized, double-blind studies should be performed to confirm the efficacy of gabapentin and lamotrigine for PTSD.\n==== Refs\nNational Institute of Mental Health Post-traumatic stress disorder (PTSD). U.S. Department of Health and Human Services, National Institutes of Health. NIH Publication No. 08 6388 cited 2014 Apr 1 Available from Http: http://www.nimh.nih.gov/health/topics/post-traumatic-stress-disorderptsd/index.shtml \n2 Berigan TR Gabapentin and PTSD J Clin Psychiatry 2002 63 744 12197459 \n3 Hamner MB Brodrick PS Labbate LA Gabapentin in PTSD: a retrospective, clinical series of adjunctive therapy Ann Clin Psychiatry 2001 13 141 146 11791951 \n4 Malek-Ahmadi P Gabapentin and posttraumatic stress disorder Ann Pharmacother 2003 37 664 666 12708942 \n5 Stein MB Kerridge C Dimsdale JE Hoyt DB Pharmacotherapy to prevent PTSD: Results from a randomized controlled proof-of-concept trial in physically injured patients J Trauma Stress 2007 20 923 932 18157888 \n6 Hertzberg MA Butterfield MI Feldman ME Beckham JC Sutherland SM Connor KM A preliminary study of lamotrigine for the treatment of posttraumatic stress disorder Biol Psychiatry 1999 45 1226 1229 10331117 \n7 Aurora RN Zak RS Auerbach SH Casey KR Chowdhuri S Karippot A Standards of Practice Committee American Academy of Sleep Medicine Best practice guide for the treatment of nightmare disorder in adults J Clin Sleep Med 2010 6 389 401 20726290 \n8 Bajor LA Ticlea AN Osser DN The Psychopharmacology Algorithm Project at the Harvard South Shore Program: an update on posttraumatic stress disorder Harv Rev Psychiatry 2011 19 240 258 21916826 \n9 Phelps EA LeDoux JE Contributions of the amygdala to emotion processing: from animal models to human behavior Neuron 2005 48 175 187 16242399 \n10 Yehuda R LeDoux J Response variation following trauma: a translational neuroscience approach to understanding PTSD Neuron 2007 56 19 32 17920012 \n11 Johansen JP Cain CK Ostroff LE LeDoux JE Molecular mechanisms of fear learning and memory Cell 2011 147 509 524 22036561 \n12 Herman JP Neural control of chronic stress adaptation Front Behav Neurosci 2013 7 61 23964212 \n13 Grillon C Southwick SM Charney DS The psychobiological basis of posttraumatic stress disorder Mol Psychiatry 1996 1 278 297 9118351 \n14 Shiah IS Yatham LN Gau YC Baker GB Effect of lamotrigine on plasma GABA levels in healthy humans Prog Neuropsychopharmacol Biol Psychiatry 2003 27 419 423 12691776 \n15 Kozarić-Kovačić D Eterović M Lamotrigine abolished aggression in a patient with treatment-resistant posttraumatic stress disorder Clin Neuropharmacol 2013 36 94 95 23673912\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1738-1088", "issue": "12(3)", "journal": "Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology", "keywords": "Flashback; Gabapentin; Lamotrigine; Nightmare; Post-traumatic stress disorders; Sensitization", "medline_ta": "Clin Psychopharmacol Neurosci", "mesh_terms": null, "nlm_unique_id": "101207332", "other_id": null, "pages": "240-2", "pmc": null, "pmid": "25598830", "pubdate": "2014-12", "publication_types": "D016428:Journal Article", "references": "9118351;11791951;23964212;12708942;18157888;22036561;21916826;17920012;10331117;12197459;16242399;20726290;12691776;23673912", "title": "Post-traumatic Stress Disorder Symptoms in a Female Patient Following Repeated Teasing: Treatment with Gabapentin and Lamotrigine and the Possible Role of Sensitization.", "title_normalized": "post traumatic stress disorder symptoms in a female patient following repeated teasing treatment with gabapentin and lamotrigine and the possible role of sensitization" }

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{ "abstract": "Peripheral T-cell lymphomas (PTCLs) are a group of heterogeneous T-cell malignancies representing 5%-10% of aggressive lymphomas. The prognosis is poor for patients with relapsed/refractory (R/R) disease, with a median overall survival of less than 6 months and no standardized treatments. We discuss the role of the phosphatidylinositol 3-kinase (PI3K) γδ inhibitor duvelisib as bridge to allotransplantation in a patient with R/R PTCL.\nCase report.\nA 55-year-old woman diagnosed with relapsed nodal PTCL with T-follicular helper phenotype received PI3K γδ inhibitor duvelisib in the context of the phase II PRIMO clinical trial. After two cycles at a dose of 75 mg twice daily, the patient achieved complete response (CR), which was subsequently consolidated with human leukocyte antigen fully matched unrelated donor allotransplantation. No major toxicities were recorded during the duvelisib treatment period or during hospitalization for allotransplantation. At the latest follow-up, the patient was alive and still in CR 10 months posttransplant.\nDuvelisib should be further explored as a bridge to allotransplantation in patients with R/R PTCL, given the success and low toxicity in our patient.", "affiliations": "IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia \"Seràgnoli,\" Bologna, Italy.;IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia \"Seràgnoli,\" Bologna, Italy.;IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia \"Seràgnoli,\" Bologna, Italy.;IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia \"Seràgnoli,\" Bologna, Italy.;Hematology Unit, ASST Monza Ospedale San Gerado, Monza, Italy.;IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia \"Seràgnoli,\" Bologna, Italy.", "authors": "Lolli|Ginevra|G|;Casadei|Beatrice|B|;Pellegrini|Cinzia|C|;Argnani|Lisa|L|;Cocito|Federica|F|;Zinzani|Pier Luigi|PL|https://orcid.org/0000-0002-2112-2651", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1177/03008916211027219", "fulltext": null, "fulltext_license": null, "issn_linking": "0300-8916", "issue": "107(6)", "journal": "Tumori", "keywords": "Duvelisib; T-follicular helper phenotype; allotransplantation; peripheral T-cell lymphoma; refractory", "medline_ta": "Tumori", "mesh_terms": null, "nlm_unique_id": "0111356", "other_id": null, "pages": "NP105-NP107", "pmc": null, "pmid": "34167407", "pubdate": "2021-12", "publication_types": "D016428:Journal Article", "references": null, "title": "Duvelisib as bridge to allotransplantation in refractory peripheral T-cell lymphoma with T-follicular helper phenotype: case report.", "title_normalized": "duvelisib as bridge to allotransplantation in refractory peripheral t cell lymphoma with t follicular helper phenotype case report" }

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"drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mucosal inflammation", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arthralgia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Paraesthesia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20200101" } }, "primarysource": { "literaturereference": "Lolli G, Casadei B, Pellegrini C, Argnani 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Duvelisib as bridge to allotransplantation in refractory peripheral T-cell lymphoma with T-follicular helper phenotype: case report.. 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RECEIVED TWO 28-DAY CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "Peripheral T-cell lymphoma unspecified stage III", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": "202003", "drugstartdateformat": "610", "drugstructuredosagenumb": "75", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DUVELISIB" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DUVELISIB" }, "drugadditional": "4", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Peripheral T-cell lymphoma unspecified recurrent", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DUVELISIB" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "THIOTEPA" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "2020", "drugenddateformat": "602", "drugindication": "Bone marrow conditioning regimen", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2020", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THIOTEPA" } ], "patientagegroup": "5", "patientonsetage": "55", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arthralgia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Paraesthesia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mucosal inflammation", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20200101" } }, "primarysource": { "literaturereference": "Lolli G, Casadei B, Pellegrini C, Argnani L, Cocito F, Zinzani PL. Duvelisib as bridge to allotransplantation in refractory peripheral T-cell lymphoma with T-follicular helper phenotype: case report. Tumori 2021;107(6):NP105-NP107.", "literaturereference_normalized": "duvelisib as bridge to allotransplantation in refractory peripheral t cell lymphoma with t follicular helper phenotype case report", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20220210", "receivedate": "20220127", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20383941, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20220423" } ]

{ "abstract": "OBJECTIVE\nThe use of continuous intravenous terbutaline treatment in severe asthma attacks has been hampered by the lack of well-powered clinical trials where effects of such treatment are described in detail. Here, we aimed to provide a descriptive report on the largest cohort of severe pediatric asthma patients treated with terbutaline.\n\n\nMETHODS\nThe study was conducted in a pediatric intensive care unit in a large metropolitan tertiary care university hospital on 124 patients receiving terbutaline infusion. To stratify the effect of, and determine any age-related differences of, terbutaline, the patients were divided into 3 age groups (0-6 years, 7-12 years, and 13-18 years). Clinical response and the potential harmful effects of terbutaline infusion were determined.\n\n\nRESULTS\nThere were significant reductions in systolic (varying between 86% and 93% of the baseline) and diastolic blood pressures (varying between 74% and 86% of the baseline level). However, the values returned to baseline level shortly after discontinuation of infusion. Terbutaline increased heart rates in all groups shortly after initiation (9%-13% above baseline), which returned to below baseline levels 1 hour after discontinuation. Serum potassium levels were also reduced in all patients compared to their baseline values after initiation of terbutaline infusion. However, none of the subjects required potassium replacement.\n\n\nCONCLUSIONS\nThe results indicate that overall, terbutaline infusion was well tolerated without irreversible adverse effects of the treatment. Although hemodynamic and metabolic disturbances occurred, these were clinically easily managed and posed little risk in emergency department or pediatric intensive care unit.", "affiliations": "From the Division of Pediatric Critical Care Medicine, Cohen Children's Medical Center of New York, New Hyde Park, NY.", "authors": "Doymaz|Sule|S|;Schneider|James|J|", "chemical_list": "D001993:Bronchodilator Agents; D013726:Terbutaline; D011188:Potassium", "country": "United States", "delete": false, "doi": "10.1097/PEC.0000000000000677", "fulltext": null, "fulltext_license": null, "issn_linking": "0749-5161", "issue": "34(5)", "journal": "Pediatric emergency care", "keywords": null, "medline_ta": "Pediatr Emerg Care", "mesh_terms": "D000293:Adolescent; D001249:Asthma; D001794:Blood Pressure; D001993:Bronchodilator Agents; D002648:Child; D002675:Child, Preschool; D005260:Female; D006339:Heart Rate; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D015278:Intensive Care Units, Pediatric; D008297:Male; D011188:Potassium; D012189:Retrospective Studies; D013726:Terbutaline; D016896:Treatment Outcome", "nlm_unique_id": "8507560", "other_id": null, "pages": "299-302", "pmc": null, "pmid": "26959519", "pubdate": "2018-05", "publication_types": "D016428:Journal Article", "references": null, "title": "Safety of Terbutaline for Treatment of Acute Severe Pediatric Asthma.", "title_normalized": "safety of terbutaline for treatment of acute severe pediatric asthma" }

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{ "abstract": "The use of opioids for patients with chronic noncancer pain has increased dramatically, and with increasing use there is increasing concern about the potential for abuse and addiction during long-term treatment. Clinicians should avoid viewing formal or subjective risk assessment as a means of classifying patients into 2 distinct categories: compliant patients and substance abusers. The provider who perceives a patient as compliant may have a complacent attitude toward aberrant drug-related behavior, presuming that these signs reflect inadequately controlled pain, to be addressed by dose escalation. The provider who perceives a patient as a substance abuser may refuse to provide treatment for pain, leaving the patient to seek either illicit drugs or prescribed treatment from another provider. In fact, in seemingly compliant patients, any noncompliant use of opioids presents a safety risk regardless of the explanations offered. Even in known or suspected drug abusers, chronic pain warrants the use of adequate pharmacotherapy, although treatment in such cases may exclude drugs with high abuse potential. Thus, all aberrant drug-related behavior should be addressed within a treatment plan that combines adequate pain care with suitable interventions for the aberrant behavior, following current best practice strategies. This approach is consistent with the approach taken with other health conditions, such as diabetes or hypertension, for which it is understood that noncompliance with therapy presents a risk of harm.", "affiliations": "Neurologist and Director, Wasser Pain Management Centre, Mount Sinai Hospital, Toronto, ON, Canada. allan.gordon@utoronto.ca.", "authors": "Gordon|Allan|A|;Cone|Edward J|EJ|;DePriest|Anne Z|AZ|;Axford-Gatley|Robert A|RA|;Passik|Steven D|SD|", "chemical_list": "D000701:Analgesics, Opioid", "country": "England", "delete": false, "doi": "10.3810/pgm.2014.09.2810", "fulltext": null, "fulltext_license": null, "issn_linking": "0032-5481", "issue": "126(5)", "journal": "Postgraduate medicine", "keywords": null, "medline_ta": "Postgrad Med", "mesh_terms": "D000701:Analgesics, Opioid; D059350:Chronic Pain; D006801:Humans; D009293:Opioid-Related Disorders; D011320:Primary Health Care; D018570:Risk Assessment", "nlm_unique_id": "0401147", "other_id": null, "pages": "159-66", "pmc": null, "pmid": "25295660", "pubdate": "2014-09", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review", "references": null, "title": "Prescribing opioids for chronic noncancer pain in primary care: risk assessment.", "title_normalized": "prescribing opioids for chronic noncancer pain in primary care risk assessment" }

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{ "abstract": "Intravenous thrombolysis (IVT) is an accepted therapy in patients with acute ischemic stroke presenting within 3-4.5 hours of symptom onset. Selection of the patient for thrombolysis depends on the careful assessment for the risk of post thrombolysis symptomatic haemorrhage (6.2-8.9%) which may be fatal. Atrial myxomas which are the commonest tumors of the heart are associated with stroke due to tumor/clot embolism. There are very few case reports of IVT and its outcome in patients with atrial myxoma with stroke. Some have reported successful thrombolysis, while others have reported intracerebral bleeding. In this report we describe our experience of IVT in atrial myxoma patient with ischemic stroke and review the relevant literature.", "affiliations": "Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India.;Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India.;Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India.;Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India.", "authors": "Kulkarni|Girish Baburao|GB|;Yadav|Ravi|R|;Mustare|Veerendrakumar|V|;Modi|Sailesh|S|", "chemical_list": null, "country": "India", "delete": false, "doi": "10.4103/0972-2327.144038", "fulltext": "\n==== Front\nAnn Indian Acad NeurolAnn Indian Acad NeurolAIANAnnals of Indian Academy of Neurology0972-23271998-3549Medknow Publications & Media Pvt Ltd India AIAN-17-45510.4103/0972-2327.144038Case ReportIntravenous thrombolysis in a patient with left atrial myxoma with acute ischemic stroke Kulkarni Girish Baburao Yadav Ravi Mustare Veerendrakumar Modi Sailesh Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, IndiaFor correspondence: Dr. Girish Baburao Kulkarni, Associate Professor, Department of Neurology, National Institute of Mental Health and Neurosciences, Hosur Road, Bangalore - 560 029, Karnataka, India. E-mail: gbk5000@rediffmail.comOct-Dec 2014 17 4 455 458 04 2 2014 08 5 2014 14 5 2014 Copyright: © Annals of Indian Academy of Neurology2014This 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.Intravenous thrombolysis (IVT) is an accepted therapy in patients with acute ischemic stroke presenting within 3-4.5 hours of symptom onset. Selection of the patient for thrombolysis depends on the careful assessment for the risk of post thrombolysis symptomatic haemorrhage (6.2-8.9%) which may be fatal. Atrial myxomas which are the commonest tumors of the heart are associated with stroke due to tumor/clot embolism. There are very few case reports of IVT and its outcome in patients with atrial myxoma with stroke. Some have reported successful thrombolysis, while others have reported intracerebral bleeding. In this report we describe our experience of IVT in atrial myxoma patient with ischemic stroke and review the relevant literature.\n\nCerebral hemorrhageintravenous thrombolysisleft atrial myxomarecombinant tissue plasminogen activator\n==== Body\nIntroduction\nAtrial myxomas are the most common tumors of the heart and may be associated with embolism to different organs.[1] At least 25% of patients with left atrial myxoma present with ischemic neurologic events secondary to embolism.[23] The embolic source may be composed of tumor tissue itself, blood clot or both.[45] Intracerebral hemorrhages can also occur due to rupture of cerebral aneurysms associated with cardiac myxomas.[6]\n\nIntravenous thrombolytic therapy (IVT) with recombinant tissue plasminogen activator (rt-PA) is the recommended treatment for patients with acute ischemic stroke (AIS) who present within the window period. An exhaustive list of contraindications is to be checked before rt-PA is administered to reduce the chances of cranial and extra cranial bleeding. However, the guidelines do not discuss the treatment AIS in a patient with atrial myxoma.[789] Only a small number of cases of atrial myxoma with AIS treated with thrombolytic therapy have been reported. Some studies have reported good outcome whereas others have reported bleeding or no improvement.[10111213141516171819] In addition, cardiac myxomas are rarely associated with intracranial aneurysms in which case the aneurysm may rupture.[6] In this report, we share our experience of a patient with AIS associated with left atrial myxoma (LAM) in whom IVT was administered and review the relevant literature.\n\nCase Report\nA 69-year-old lady diabetic and hypertensive on treatment presented with sudden onset of vertigo followed by weakness of left upper and lower limbs of 1.5 hours duration. She had associated dysarthria and deviation of angle of mouth to the right side. There was no history of loss of consciousness, visual symptoms, seizures, headache, hiccoughs, and dysphagia. No previous history suggestive of transient ischemic attacks, stroke, intracerebral hemorrhage, neck pain, trauma. She was diagnosed to have left atrial myxoma (LAM; based on cardiac magnetic resonance imaging, MRI [Figure 1], and echocardiogram) 13 months prior to the presentation and was not on any therapy. She had declined the surgical treatment of the tumor when it was diagnosed. At presentation, her vitals were stable, all peripheral pulses were felt, and no bruits were heard. Auscultation over chest revealed no murmurs. Neurologically, the patient was conscious, oriented, had severe dysarthria, no nystagmus, pupils were 2-mm reactive to light; she had gaze preference to right, left upper motor neuron facial palsy with 0/5 power in left sided limbs. Sensory system and right-sided limbs (motor, cerebellar) were normal. Deep tendon reflexes were normal except ankle jerks, which were sluggish bilaterally. Right plantar reflex was flexor while left was extensor. National Institutes of Health Stroke Scale (NIHSS) score at admission was 14, and modified Rankin score (mRS) was 4.\n\nFigure 1 Magnetic resonance imaging of the heart (a, b) showing left atrial myxoma (arrow)\n\nInvestigations revealed hemoglobin -10.9 gm/dl, total count -6000/cmm, platelet count -2,37,000/cmm, prothrombin time - normal, blood glucose -255 mg/dl, urea -39 mg/dl, creatinine -1.2 mg/dl, Na -141 meq/l. A non-contrast computerized tomographic (CT) scan done at presentation [Figure 2] was normal. A clinical diagnosis stroke was made; the site of lesion being on right side above the nucleus of the facial nerve, may be in subcortical or brainstem region with no additional localizing signs. Patient and relatives were explained about the treatment options available and the risk and benefit of thrombolysis, and consent was obtained for intravenous thrombolytic therapy (IVT). Patient was shifted to the stroke unit. As there were no contraindications for IVT and she being in the window period, 0.9 mg/kg of rt-PA was started according to the standard guidelines. About 15 minutes after starting the treatment, the patient started improving, and by the end of procedure, the patient had only minimal left-sided limb weakness, slight dysarthria, and facial weakness. The NIHSS score at the end of thrombolysis was 5, with mRS being 1. Patient was closely monitored during the procedure and later, in the stroke unit as per the protocol. There were no complications and the blood pressure was normal throughout the procedure.\n\nFigure 2 Computerized tomographic scan (a, b) of the patient at presentation being normal\n\nFive hours after the completion of the thrombolysis, she developed vomiting and became drowsy and then lapsed into altered sensorium. Examination revealed blood pressure of 184/100 mm of Hg, and pulse rate of 86/min. Neurologically, she was in altered sensorium, not opening eyes to stimuli, responding to commands, or verbalizing. Her right pupil was 3 mm not reacting, left 2 mm reacting to light. There was vertical dysconjugation (right eye lower than the left), and dolls eye movements restricted in vertical directions. She was moving her right upper and lower limb minimally to pain, not moving left upper and lower limb even to deep painful stimuli; NIHSS score was 31 and mRS was 5. She worsened in sensorium and developed respiratory difficulty so she was intubated and connected to mechanical ventilator. Clinical possibility of post IVT bleed was considered localizing to the right side above midbrain. Patient underwent plain CT scan which revealed [Figure 3] hemorrhage in the right thalamus and upper midbrain (right more than left) with intraventricular extension and mild hydrocephalus.\n\nFigure 3 Computerized tomographic scan (a, b) of the patient six hours after thrombolysis showing brainstem and thalamic hematoma with mild hydrocephalus\n\nPatient was treated with anti-edema measures and other supportive measures as per the guidelines for the management of post thrombolysis bleed. Cardiac echocardiogram showed well-defined heterogeneous mobile mass in the left atrium measuring 2.3 × 2.7 × 1.8 cm, attached to the roof of left atrium and prolapsing across the mitral valve with attached thrombus suggestive of LAM with thrombus. Troponin I was negative, lipid profile — normal, serum homocysteine - normal, glycosylated hemoglobin was (HbA1C): 9.8% suggestive of poor control of her diabetes. Magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) of the brain done 30 days after the event showed resolving late sub-acute hematoma in right thalamus with extension to right upper midbrain with hypointense rim with vessles being normal [Figure 4].\n\nFigure 4 Magnetic resonance imaging of brain done after about one month showing T1 (a), T2 (b) resolving hematoma. Magnetic resonance angiogram (c) showing no abnormality in vertebral and basilar arteries\n\nShe was on ventilator for 25 days, then gradually improved in neurological status and was weaned off from the ventilator. At the time of discharge (70 days post stroke), the patient has residual deficits in the form of moderate weakness of left upper limb and mild weakness of left lower limb, with pupil of 3 mm, bilateral equal and reactive to light. The NIHSS score was 8, and mRS was 4. Subsequently, she has been on regular follow-up from last two years. Except for mild distal left hand weakness, she is leading a normal life. She has been under care of a cardiologist for LAM and has declined surgery.\n\nDiscussion\nA 69-year-old hypertensive and diabetic female with associated left atrial myxoma presented with symptoms and signs suggestive of stroke within 1.5 hours of onset. A CT scan done at presentation was normal; after obtaining informed consent, the patient was given intravenous thrombolysis. The initial anatomical localization of the ischemic lesion was on the right side above facial nucleus but the exact location whether it was in brainstem or subcortical white matter was difficult to localize clinically. At presentation before thrombolysis, CT scan was normal and MRI/MRA was not done. During thrombolysis, the patient has made significant improvement at the end of one hour. After five hours, the patient had developed right rostral midbrain bleed with dramatic clinical deterioration. Subsequently, MRI/MRA done 30 days later confirmed CT findings. It is possible that the bleed is at the area of infract per se and because of larger area of involvement with bleed other localizing signs developed. Prior MRI at presentation might have confirmed our hypothesis. There was no evidence of aneurysms in MRA.\n\nAtrial myxomas are the most common cardiac tumors (3rd to 6th decade), and 75% of them are located in the left atrium.[1] Patients can present with embolic events or sudden death and are estimated to responsible for 0.5% of all ischemic strokes if they are located in the left atrium.[23] The causes of stroke, as previously stated, in a case of LAM can be ischemic due to tumor, thromboembolism, both, or rarely hemorrhagic stroke due to intracerebral and subarachnoid hemorrhage caused by rupture of intracranial aneurysm.[456] In our patient, sudden onset of deficits with peaking of the weakness at onset and improving post-thrombolysis with normal CT suggest thromboembolism rather than ruptured aneurysm. It is supported by echocardiogram, which showed LAM with thrombus and also favoring embolic origin from the tumor rather than lacunar infarct in the brain stem. These tumors may be asymptomatic prior to the event, and whenever detected, surgical removal is the treatment of choice. Our patient had refused to undergo surgery when it was detected during routine evaluation prior to this event.\n\nThere are reports of only 10 cases of LAM with ischemic stroke, who have undergone thrombolysis[10111213141516171819] in the literature. Compared to others, our patient was an elderly woman who was already a known case of LAM with associated hypertension and diabetes. Out of 10 patients, six of them have undergone IVT and four of them improved, one did not improve and one developed intracranial hemorrhage. Among four patients who underwent intra-arterial thrombolysis (IA), three of them improved and one did not improve. Pre-thrombolysis MRI was not available in all the patients.\n\nOne author has suggested intra-arterial thrombolysis with super selective catherization, which will help in reducing the total drug infused and theoretically identify associated aneurysms, if any.[10] The availability of an experienced person for the procedure and round the clock functioning of the cath lab in a given hospital are major hurdles.\n\nConclusion\nCerebral infarction associated with myxoma is rare, and the number of cases reported is very small for detailed analysis of the effectiveness and safety of IV thrombolysis with rt-PA in such patients. IVT may be considered for relatively young patients with left atrial myxoma who present with an ischemic stroke within three hours of onset. In elderly patients, especially 65 years or older with other risk factors, caution must be exercised due to associated risk of hemorrhage.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\n1 Reynen K Cardiac myxomas N Engl J Med 1995 333 1610 7 7477198 \n2 Lee VH Connolly HM Brown RD Jr Central nervous system manifestations of cardiac myxoma Arch Neurol 2007 64 1115 20 17698701 \n3 Knepper LE Biller J Adams HP Jr Bruno A Neurologic manifestations of atrial myxoma. A 12-year experience and review Stroke 1988 19 1435 40 3188128 \n4 Wold LE Lie JT Cardiac myxomas: A clinicopathologic profile Am J Pathol 1980 101 219 40 7446701 \n5 Burke AP Virmani R Cardiac myxoma. A clinicopathologic study Am J Clin Pathol 1993 100 671 80 8249916 \n6 Sabolek M Bachus-Banaschak K Bachus R Arnold G Storch A Multiple cerebral aneurysms as delayed complication of left cardiac myxoma: A case report and review Acta Neurol Scand 2005 111 345 50 15876333 \n7 Adams HP Jr delZoppo G Alberts MJ Bhatt DL Brass L Furlan A Guidelines for the early management of adults with ischemic stroke: A guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Counsil, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdiscriplinary Working Groups: The American Academy of Neurology affirms the value of this guidelines as an educational tool for neurologists Stroke 2007 38 1655 711 17431204 \n8 Langhorne P Diener HC Hennerici M Ferro J Sivenius J Wahlgren NG European Stroke Initiative Executive Committee; EUSI Writing Committee European stroke initiative recommendations for stroke management-update Cerebrovasc Dis 2003 16 311 7 14584488 \n9 The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group Tissue plasminogen activator for acute ischemic stroke N Engl J Med 1995 333 1581 87 7477192 \n10 Chong JY Vraniak P Etienne M Sherman D Elkind MS Intravenous thrombolytic treatment of acute ischemic stroke associatedwith left atrial myxoma: A case report J Stroke Cerebrovasc Dis 2005 14 39 41 17903996 \n11 Sugawara T Takahashi A So K Yoshimoto T Suzuki J Suzuki Y A case of cerebral embolism caused by atrial myxoma — superselective fibrinolytic therapy No Shinkei Geka 1987 15 1321 6 3448502 \n12 Bekavac I Hanna JP Wallace RC Powers J Ratliff NB Furlan AJ Intra arterial thrombolysis of embolic proximal middle cerebral artery occlusion from presumed atrial myxoma Neurology 1997 49 618 20 9270611 \n13 Yamanome T Yoshida K Miura K Ogawa A Super selective fibrinolysis for a middle cerebral artery embolism caused by a left atrial myxoma: Case report No Shinke Geka 2000 28 653 8 \n14 Ibrahim M Iliescu C Safi HJ Buja ML McPherson DD Fuentes F Biatrial myxoma and cerebral ischemia successfully treated with intravenous thrombolytic therapy and surgical resection Tex Heart Inst J 2008 35 193 5 18612442 \n15 Nagy CD Levy M Mulhearn TJ 4th Shapland M Sun H Yuh DD Safe and effective intravenous thrombolysis for acute ischemic stroke caused by left atrial myxoma J Stroke Cerebrovasc Dis 2009 18 398 402 19717026 \n16 Ong CT Chang RY Intravenous thrombolysis of occlusion in the middle cerebral and retinal arteries from presumed ventricular myxoma Stroke Res Treat 2011 735057 \n17 Nishimura H Nakajima T Ukita T Tsuji HM Miyake H Ohmura T A case of acute cerebral infarction associated with left atrial myxoma treated by intravenous tissue plasminogen activator Jpn J Stroke 2010 32 156 62 \n18 Abe M Kohama A Takeda T Ishikawa A Yamada Y Kawase Y Effective intravenous thrombolytic therapy in a patient with cerebral infarction associated with left atrial myxoma Intern Med 2011 50 2401 5 22001475 \n19 Sun MC Tai HC Lee CH Intravenous thrombolysis for embolic stroke due to cardiac myxoma Case Rep Neurol 2011 3 21 6 21468176\n\n", "fulltext_license": "CC BY-NC-SA", "issn_linking": "0972-2327", "issue": "17(4)", "journal": "Annals of Indian Academy of Neurology", "keywords": "Cerebral hemorrhage; intravenous thrombolysis; left atrial myxoma; recombinant tissue plasminogen activator", "medline_ta": "Ann Indian Acad Neurol", "mesh_terms": null, "nlm_unique_id": "101273955", "other_id": null, "pages": "455-8", "pmc": null, "pmid": "25506173", "pubdate": "2014-10", "publication_types": "D002363:Case Reports", "references": "14584488;17903996;21468176;17698701;7477192;7477198;17431204;3448502;9270611;10920828;8249916;3188128;21151657;7446701;19717026;18612442;22001475;15876333", "title": "Intravenous thrombolysis in a patient with left atrial myxoma with acute ischemic stroke.", "title_normalized": "intravenous thrombolysis in a patient with left atrial myxoma with acute ischemic stroke" }

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{ "abstract": "Experimental studies in animals suggest that arterial hypertension may be a specific risk factor predisposing to anthracycline cardiotoxicity. The aim was determination of the effect of pre-existing arterial hypertension on the development of early left ventricular systolic dysfunction (LVSD) directly after rituximab, cyclophosphamide, doxorubicin, vincristin, prednisone ([R]-CHOP) chemotherapy in patients with lymphomas.The study included 208 patients with non-Hodgkin's lymphoma receiving conventional doxorubicin. LVSD was defined as a decrease of left ventricular ejection fraction below 50% and at least by 10 percentage points from baseline value. Patients with pre-existing hypertension more frequently developed new LVSD (19.7% vs. 6.6%; P = .004), pitting edema of the ankles (23.9% vs. 9.5%; P = .005), and nycturia (21.1% vs. 7.3%; P = .004) compared with patients without hypertension. As a consequence, the hypertension subgroup suffered from more delays of subsequent chemotherapy cycles (26.8% vs. 14.6%; P = .03), more reductions of doxorubicin doses (18.3% vs. 8.8%; P = .05), and premature discontinuations of chemotherapy (16.9% vs. 7.3%; P = .03). On logistic regression analyses, hypertension was one of the most important risk factors for developing new LVSD after (R)-CHOP chemotherapy.Arterial hypertension confers a significant risk of early LVSD in lymphoma patients treated with (R)-CHOP chemotherapy, interfering with its recommended schedule of administration.", "affiliations": "Department of Pulmonary Circulation and Thromboembolic Diseases, Centre of Postgraduate Medical Education, Otwock, Poland. Electronic address: s.szmit@gmail.com.;Department of Hematology, Jagiellonian University, Krakow, Poland.;Department of Propedeutic Oncology, Medical University of Gdansk and Gdynia Oncology Center, Gdynia, Poland.;Department of Hematology, Oncology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland.;Internal Medicine and Oncology Clinic, Silesian Medical University, Katowice, Poland.;Department of Hematology, University of Medical Sciences, Poznan, Poland.;Department of Hematology, Jagiellonian University, Krakow, Poland.;Department of Pulmonary Circulation and Thromboembolic Diseases, Centre of Postgraduate Medical Education, Otwock, Poland.", "authors": "Szmit|Sebastian|S|;Jurczak|Wojciech|W|;Zaucha|Jan Maciej|JM|;Drozd-Sokołowska|Joanna|J|;Spychałowicz|Wojciech|W|;Joks|Monika|M|;Długosz-Danecka|Monika|M|;Torbicki|Adam|A|", "chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1878-7436", "issue": "8(11)", "journal": "Journal of the American Society of Hypertension : JASH", "keywords": "Cardiac damage; doxorubicin; prevention", "medline_ta": "J Am Soc Hypertens", "mesh_terms": "D000328:Adult; D017677:Age Distribution; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D001795:Blood Pressure Determination; D015331:Cohort Studies; D016001:Confidence Intervals; D003520:Cyclophosphamide; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006973:Hypertension; D015994:Incidence; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011241:Prednisone; D012189:Retrospective Studies; D018570:Risk Assessment; D000069283:Rituximab; D012720:Severity of Illness Index; D017678:Sex Distribution; D018709:Statistics, Nonparametric; D013997:Time Factors; D018487:Ventricular Dysfunction, Left; D014750:Vincristine", "nlm_unique_id": "101312518", "other_id": null, "pages": "791-9", "pmc": null, "pmid": "25455004", "pubdate": "2014-11", "publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Pre-existing arterial hypertension as a risk factor for early left ventricular systolic dysfunction following (R)-CHOP chemotherapy in patients with lymphoma.", "title_normalized": "pre existing arterial hypertension as a risk factor for early left ventricular systolic dysfunction following r chop chemotherapy in patients with lymphoma" }

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"drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Coronary artery disease", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SZMIT S, JURCZAK W, ZAUCHA J, DROZD-SOKOLOWSKA J, SPYCHALOWICZ W, JOKS M, DLUGOSZ-DANECKA M, TORBICKI A. PRE-EXISTING ARTERIAL HYPERTENSION AS A RISK FACTOR FOR EARLY LEFT VENTRICULAR SYSTOLIC DYSFUNCTION FOLLOWING (R)-CHOP CHEMOTHERAPY IN PATIENTS WITH LYMPHOMA. JOURNAL OF THE AMERICAN SOCIETY OF HYPERTENSION. 2014 JAN 01;8(11):791-799.", "literaturereference_normalized": "pre existing arterial hypertension as a risk factor for early left ventricular systolic dysfunction following r chop chemotherapy in patients with lymphoma", "qualification": "1", "reportercountry": "PL" }, "primarysourcecountry": "PL", "receiptdate": "20150908", "receivedate": "20150908", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 11471063, "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": "OBJECTIVE\nThe safety of cough and cold medication (CCM) use in children has been questioned. We describe the safety profile of CCMs in children <12 years of age from a multisystem surveillance program.\n\n\nMETHODS\nCases with adverse events (AEs) after ingestion of at least 1 index CCM ingredient (brompheniramine, chlorpheniramine, dextromethorphan, diphenhydramine, doxylamine, guaifenesin, phenylephrine, and pseudoephedrine) in children <12 years of age were collected from 5 data sources. An expert panel determined relatedness, dose, intent, and risk factors. Case characteristics and AEs are described.\n\n\nRESULTS\nOf the 4202 cases reviewed, 3251 (77.4%) were determined to be at least potentially related to a CCM, with accidental unsupervised ingestions (67.1%) and medication errors (13.0%) the most common exposure types. Liquid (67.3%), pediatric (75.5%), and single-ingredient (77.5%) formulations were most commonly involved. AEs occurring in >20% of all cases included tachycardia, somnolence, hallucinations, ataxia, mydriasis, and agitation. Twenty cases (0.6%) resulted in death; most were in children <2 years of age (70.0%) and none involved a therapeutic dose. The overall reported AE rate was 0.573 cases per 1 million units (ie, tablets, gelatin capsules, or liquid equivalent) sold (95% confidence interval, 0.553-0.593) or 1 case per 1.75 million units.\n\n\nCONCLUSIONS\nThe rate of AEs associated with CCMs in children was low. Fatalities occurred even less frequently. No fatality involved a therapeutic dose. Accidental unsupervised ingestions were the most common exposure types and single-ingredient, pediatric liquid formulations were the most commonly reported products. These characteristics present an opportunity for targeted prevention efforts.", "affiliations": "Rocky Mountain Poison and Drug Center, Denver Health and Hospital Authority, Denver, Colorado; jody.green@rmpdc.org.;Department of Pediatrics, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, Colorado.;Rocky Mountain Poison and Drug Center, Denver Health and Hospital Authority, Denver, Colorado.;Oklahoma Center for Poison and Drug Information, Oklahoma University College of Pharmacy, Oklahoma City, Oklahoma.;Faculty of Medicine, Hope Africa University, Bujumbura, Burundi.;Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri; and.;Rocky Mountain Poison and Drug Center, Denver Health and Hospital Authority, Denver, Colorado.;Departments of Pediatrics and.;Rocky Mountain Poison and Drug Center, Denver Health and Hospital Authority, Denver, Colorado.", "authors": "Green|Jody L|JL|;Wang|George Sam|GS|;Reynolds|Kate M|KM|;Banner|William|W|;Bond|G Randall|GR|;Kauffman|Ralph E|RE|;Palmer|Robert B|RB|;Paul|Ian M|IM|;Dart|Richard C|RC|", "chemical_list": "D000996:Antitussive Agents; D057985:Multi-Ingredient Cold, Flu, and Allergy Medications", "country": "United States", "delete": false, "doi": "10.1542/peds.2016-3070", "fulltext": null, "fulltext_license": null, "issn_linking": "0031-4005", "issue": "139(6)", "journal": "Pediatrics", "keywords": null, "medline_ta": "Pediatrics", "mesh_terms": "D000996:Antitussive Agents; D002648:Child; D002675:Child, Preschool; D003371:Cough; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D057985:Multi-Ingredient Cold, Flu, and Allergy Medications; D010372:Pediatrics; D012307:Risk Factors; D012449:Safety", "nlm_unique_id": "0376422", "other_id": null, "pages": null, "pmc": null, "pmid": "28562262", "pubdate": "2017-06", "publication_types": "D016428:Journal Article", "references": null, "title": "Safety Profile of Cough and Cold Medication Use in Pediatrics.", "title_normalized": "safety profile of cough and cold medication use in pediatrics" }

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"PSEUDOEPHEDRINE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SLEEP DISORDER THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PSEUDOEPHEDRINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PHENYLEPHRINE\\PHENYLEPHRINE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": 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"drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GUAIFENESIN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Ataxia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Medication error", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Psychomotor hyperactivity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hallucination", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Accidental exposure to product", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Agitation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypertension", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Extra dose administered", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Somnolence", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Confusional state", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dizziness", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dystonia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lethargy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nystagmus", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Flushing", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product administered to patient of inappropriate age", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dysarthria", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Irritability", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional product misuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mydriasis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tremor", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GREEN JL, WANG GS, REYNOLDS KM, BANNER W, BOLD GR, KAUFFMAN RE, ET AL. SAFETY PROFILE OF COUGH AND COLD MEDICATION USE IN PEDIATRICS. PEDIATRICS 04-MAY-2017?139 (6):E20163070. HALMO LS, WANG GS, REYNOLDS KM, DELVA-CLARK H, BANNER W, BOND G, ET AL. PEDIATRIC DEATHS ASSOCIATED WITH OVER-THE-COUNTER COUGH AND COLD MEDICATION EXPOSURES. CLINICAL TOXICOLOGY 50TH NORTH AMERICAN CONGRESS OF CLINICAL TOXICOLOGY, NACCT 2018 2018?56 (10):1007.", "literaturereference_normalized": "safety profile of cough and cold medication use in pediatrics", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20181126", "receivedate": "20170704", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13713972, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190204" } ]

{ "abstract": "OBJECTIVE\nTo determine risk factors associated with hepatitis C virus (HCV) treatment failure after direct acting antivirals in patients with complex treatment histories.\n\n\nMETHODS\nAll HCV mono-infected patients who received treatment at our institution were queried. Analysis was restricted to patients who previously failed treatment with boceprevir (BOC) or telaprevir (TVR) and started simeprevir (SMV) and sofosbuvir (SOF) ± ribavirin (RBV) between December 2013 and June 2014. Patients with human immunodeficiency virus (HIV)/HCV co-infection or patients who received a liver transplant in the past were excluded. Viral loads were recorded while on treatment and after treatment. Data collection continued until December, 31(st) 2014 when data analysis was initiated. Patients missing virologic outcomes data were not included in the analysis. Analysis of 35 patients who had virologic outcome data available resulted in eight patients who were viral load negative at the end of treatment with SMF/SOF but later relapsed. Data related to patient demographics, HCV infection, and treatment history was collected in order to identify risk factors shared among patients who failed treatment with SMF/SOF.\n\n\nRESULTS\nEight patients who were treated with the first generation HCV protease inhibitors BOC or TVR in combination with pegylated-interferon (PEG) and RBV who failed this triple therapy were subsequently re-treated with an off-label all-oral regimen of SMV and SOF for 12 wk, with RBV in seven cases. Treatment was initiated before the Food and Drug Administration approved a 24-wk SMV/SOF regimen for patients with liver cirrhosis. All eight patients had an end of treatment response, but later relapsed. Eight (100%) patients were male. Mean age was 56 (range, 49-64). Eight (100%) patients had previously failed PEG/RBV dual therapy at least once in addition to prior failure with triple therapy. Total number of times treated ranged from 3-6 (mean 3.8). Eight (100%) patients were male had liver cirrhosis as determined by Fibroscan or MRI. Seven (87.5%) patients had genotype 1a HCV. Seven (87.5%) patients had over 1 million IU/mL HCV RNA at the time of re-treatment.\n\n\nCONCLUSIONS\nThis study identifies factors associated with SMV/SOF treatment failure and provides evidence that twleve weeks of SMV/SOF/RBV is insufficient in cirrhotics with high-titer genotype 1a HCV.", "affiliations": "Joshua Hartman, Department of Medicine, Icahn School of Medicine at the Mount Sinai Medical Center, New York, NY 10029, United States.;Joshua Hartman, Department of Medicine, Icahn School of Medicine at the Mount Sinai Medical Center, New York, NY 10029, United States.;Joshua Hartman, Department of Medicine, Icahn School of Medicine at the Mount Sinai Medical Center, New York, NY 10029, United States.;Joshua Hartman, Department of Medicine, Icahn School of Medicine at the Mount Sinai Medical Center, New York, NY 10029, United States.;Joshua Hartman, Department of Medicine, Icahn School of Medicine at the Mount Sinai Medical Center, New York, NY 10029, United States.;Joshua Hartman, Department of Medicine, Icahn School of Medicine at the Mount Sinai Medical Center, New York, NY 10029, United States.;Joshua Hartman, Department of Medicine, Icahn School of Medicine at the Mount Sinai Medical Center, New York, NY 10029, United States.;Joshua Hartman, Department of Medicine, Icahn School of Medicine at the Mount Sinai Medical Center, New York, NY 10029, United States.", "authors": "Hartman|Joshua|J|;Bichoupan|Kian|K|;Patel|Neal|N|;Chekuri|Sweta|S|;Harty|Alyson|A|;Dieterich|Douglas|D|;Perumalswami|Ponni|P|;Branch|Andrea D|AD|", "chemical_list": "D000998:Antiviral Agents", "country": "United States", "delete": false, "doi": "10.3748/wjg.v21.i43.12430", "fulltext": null, "fulltext_license": null, "issn_linking": "1007-9327", "issue": "21(43)", "journal": "World journal of gastroenterology", "keywords": "Hepatitis C; Protease inhibitor; Relapse; Simeprevir; Sofosbuvir; Treatment failure", "medline_ta": "World J Gastroenterol", "mesh_terms": "D000998:Antiviral Agents; D004359:Drug Therapy, Combination; D016174:Hepacivirus; D006526:Hepatitis C; D006801:Humans; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D019233:Retreatment; D012307:Risk Factors; D013997:Time Factors; D017211:Treatment Failure; D014775:Virus Activation", "nlm_unique_id": "100883448", "other_id": null, "pages": "12430-8", "pmc": null, "pmid": "26604650", "pubdate": "2015-11-21", "publication_types": "D002363:Case Reports; D016428:Journal Article; D064888:Observational Study; D052061:Research Support, N.I.H., Extramural", "references": "23688081;24209977;24907225;12601358;12324553;25123381;376551;16122679;17109680;17244250;19207969;19330875;19918980;20410884;20564351;20845908;21316532;21255572;21449783;21696307;21696308;21916639;21898493;23675659;24217701;24728410", "title": "Re-re-treatment of hepatitis C virus: Eight patients who relapsed twice after direct-acting-antiviral drugs.", "title_normalized": "re re treatment of hepatitis c virus eight patients who relapsed twice after direct acting antiviral drugs" }

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RE-RE-TREATMENT OF HEPATITIS C VIRUS: EIGHT PATIENTS WHO RELAPSED TWICE AFTER DIRECT-ACTING-ANTIVIRAL DRUGS. WORLD J GASTROENTEROL 21-NOV-2015?21 (43):12430-12438.", "literaturereference_normalized": "re re treatment of hepatitis c virus eight patients who relapsed twice after direct acting antiviral drugs", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151209", "receivedate": "20151209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11815554, "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" }, { "companynumb": "US-JNJFOC-20151205079", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "SOFOSBUVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SOFOSBUVIR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SIMEPREVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "205123", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIMEPREVIR" } ], "patientagegroup": "5", "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis C", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HARTMAN J, BICHOUPAN K, PATEL N, CHEKURI S, HARTY A, DIETERICH D, ET AL. RE-RE-TREATMENT OF HEPATITIS C VIRUS: EIGHT PATIENTS WHO RELAPSED TWICE AFTER DIRECT-ACTING-ANTIVIRAL DRUGS. WORLD J GASTROENTEROLOGY 21-NOV-2015?21 (43):12430-12438.", "literaturereference_normalized": "re re treatment of hepatitis c virus eight patients who relapsed twice after direct acting antiviral drugs", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151208", "receivedate": "20151208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11811307, "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" }, { "companynumb": "US-ROCHE-1677448", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIBAVIRIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021511", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBAVIRIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PEGINTERFERON ALFA-2A" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "103964", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PEG-INTERFERON ALFA 2A" } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Depression", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HARTMAN J, BICHOUPAN K, PATEL N, CHEKURI S, HARTY A, DIETRICH D, PERUMALSWAMI P AND BRANCH A. RE-RE-TREATMENT OF HEPATITIS C VIRUS: EIGHT PATIENTS WHO RELAPSED TWICE AFTER DIRECT ACTING ANTIVIRAL DRUGS. WORLD JOURNAL OF GASTROENTEROLOGY 2015 NOV 21;21 (43):12430-12438.", "literaturereference_normalized": "re re treatment of hepatitis c virus eight patients who relapsed twice after direct acting antiviral drugs", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160816", "receivedate": "20160816", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12655687, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20161109" }, { "companynumb": "US-JNJFOC-20151205075", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "SIMEPREVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "205123", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201401", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIMEPREVIR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SOFOSBUVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201401", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SOFOSBUVIR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RIBAVIRIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201401", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBAVIRIN." } ], "patientagegroup": "5", "patientonsetage": "49", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis C", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HARTMAN J, BICHOUPAN K, PATEL N, CHEKURI S, HARTY A, DIETERICH D, ET AL. RE-RE-TREATMENT OF HEPATITIS C VIRUS: EIGHT PATIENTS WHO RELAPSED TWICE AFTER DIRECT-ACTING-ANTIVIRAL DRUGS. WORLD J GASTROENTEROL.", "literaturereference_normalized": "re re treatment of hepatitis c virus eight patients who relapsed twice after direct acting antiviral drugs", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151210", "receivedate": "20151210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11824307, "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" }, { "companynumb": "US-KADMON PHARMACEUTICALS, LLC-KAD201512-004565", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TELAPREVIR" }, "drugadditional": 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"medicinalproduct": "RIBAVIRIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PEGINTERFERON ALFA-2A OR PEGINTERFERON ALFA-2B OR PEGINTERFERON BETA-1A OR PEGINTERFERON LAMBDA-1A" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PEGYLATED INTERFERON NOS" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PEGINTERFERON ALFA-2A OR PEGINTERFERON ALFA-2B OR PEGINTERFERON BETA-1A OR PEGINTERFERON LAMBDA-1A" }, "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": "2011", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PEGYLATED INTERFERON NOS" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BOCEPREVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201211", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BOCEPREVIR" } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "No therapeutic response", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BRANCH A,HARTMAN J,BICHOUPAN K,PATEL N,CHEKURI S,HARTY A. RE-RE-TREATMENT OF HEPATITIS C VIRUS: EIGHT PATIENTS WHO RELAPSED TWICE AFTER DIRECT-ACTING-ANTIVIRAL DRUGS. WORLD J GASTROENTEROL 2015 NOV 21?21(43):12430-8.", "literaturereference_normalized": "re re treatment of hepatitis c virus eight patients who relapsed twice after direct acting antiviral drugs", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151224", "receivedate": "20151224", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 11868126, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160305" }, { "companynumb": "US-JNJFOC-20151205081", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "RIBAVIRIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2014", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBAVIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SIMEPREVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "205123", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2014", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIMEPREVIR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SOFOSBUVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2014", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SOFOSBUVIR" } ], "patientagegroup": "5", "patientonsetage": "54", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis C", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HARTMAN J, BICHOUPAN K, PATEL N, CHEKURI S, HARTY A, DIETERICH D, ET AL. RE-RE-TREATMENT OF HEPATITIS C VIRUS: EIGHT PATIENTS WHO RELAPSED TWICE AFTER DIRECT-ACTING-ANTIVIRAL DRUGS. WORLD J GASTROENTEROL 21-NOV-2015?21 (43):12430-12438.", "literaturereference_normalized": "re re treatment of hepatitis c virus eight patients who relapsed twice after direct acting antiviral drugs", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151209", "receivedate": "20151209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11815576, "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" }, { "companynumb": "US-JNJFOC-20151205077", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "SIMEPREVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "205123", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2014", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIMEPREVIR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RIBAVIRIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2014", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBAVIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SOFOSBUVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2014", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SOFOSBUVIR" } ], "patientagegroup": "5", "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis C", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HARTMAN J, BICHOUPAN K, PATEL N, CHEKURI S, HARTY A, DIETERICH D, ET AL. RE-RE-TREATMENT OF HEPATITIS C VIRUS: EIGHT PATIENTS WHO RELAPSED TWICE AFTER DIRECT-ACTING-ANTIVIRAL DRUGS. WORLD J GASTROENTEROL 21-NOV-2015?21 (43):12430-12438.", "literaturereference_normalized": "re re treatment of hepatitis c virus eight patients who relapsed twice after direct acting antiviral drugs", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151209", "receivedate": "20151209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11815556, "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" }, { "companynumb": "US-ROCHE-1677215", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PEGINTERFERON ALFA-2A" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "103964", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PEG-INTERFERON ALFA 2A" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TELAPREVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TELAPREVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBAVIRIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021511", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBAVIRIN." } ], "patientagegroup": null, "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhoidal haemorrhage", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HARTMAN J, BICHOUPAN K, PATEL N, CHEKURI S, HARTY A, DIETRICH D, PERUMALSWAMI P AND BRANCH A. RE-RE-TREATMENT OF HEPATITIS C VIRUS: EIGHT PATIENTS WHO RELAPSED TWICE AFTER DIRECT ACTING ANTIVIRAL DRUGS. WORLD JOURNAL OF GASTROENTEROLOGY 2015 NOV 21?21 (43):12430-12438.", "literaturereference_normalized": "re re treatment of hepatitis c virus eight patients who relapsed twice after direct acting antiviral drugs", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151216", "receivedate": "20151216", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11838899, "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" }, { "companynumb": "US-JNJFOC-20151202041", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "SOFOSBUVIR" }, "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": "201312", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SOFOSBUVIR" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "RIBAVIRIN" }, "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": "201312", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBAVIRIN." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "SIMEPREVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "205123", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201312", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIMEPREVIR" } ], "patientagegroup": "5", "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis C", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HARTMAN J, BICHOUPAN K, PATEL N, CHEKURI S, HARTY A, DIETERICH D, ET AL. RE-RE-TREATMENT OF HEPATITIS C VIRUS: EIGHT PATIENTS WHO RELAPSED TWICE AFTER DIRECT-ACTING-ANTIVIRAL DRUGS. WORLD J GASTROENTEROL 21-NOV-2015?21 (43):12430-12438.", "literaturereference_normalized": "re re treatment of hepatitis c virus eight patients who relapsed twice after direct acting antiviral drugs", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151210", "receivedate": "20151210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11824309, "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" }, { "companynumb": "US-ROCHE-1677449", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBAVIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021511", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBAVIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TELAPREVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TELAPREVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PEGINTERFERON ALFA-2A" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103964", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PEG-INTERFERON ALFA 2A" } ], "patientagegroup": null, "patientonsetage": "54", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HARTMAN J, BICHOUPAN K, PATEL N, CHEKURI S, HARTY A, DIETRICH D, PERUMALSWAMI P AND BRANCH A. RE-RE-TREATMENT OF HEPATITIS C VIRUS: EIGHT PATIENTS WHO RELAPSED TWICE AFTER DIRECT ACTING ANTIVIRAL DRUGS. WORLD JOURNAL OF GASTROENTEROLOGY 2015 NOV 21;21 (43):12430-12438.", "literaturereference_normalized": "re re treatment of hepatitis c virus eight patients who relapsed twice after direct acting antiviral drugs", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160816", "receivedate": "20160816", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12655680, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" }, { "companynumb": "US-JNJFOC-20151205078", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "SIMEPREVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "205123", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2014", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIMEPREVIR" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "SOFOSBUVIR" }, "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": "2014", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SOFOSBUVIR" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "RIBAVIRIN" }, "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": "2014", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBAVIRIN." } ], "patientagegroup": "5", "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis C", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HARTMAN J, BICHOUPAN K, PATEL N, CHEKURI S, HARTY A, DIETERICH D, ET AL. RE-RE-TREATMENT OF HEPATITIS C VIRUS: EIGHT PATIENTS WHO RELAPSED TWICE AFTER DIRECT-ACTING-ANTIVIRAL DRUGS. WORLD J GASTROENTEROL 21-NOV-2015?21 (43):12430-12438.", "literaturereference_normalized": "re re treatment of hepatitis c virus eight patients who relapsed twice after direct acting antiviral drugs", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151210", "receivedate": "20151210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11824310, "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" }, { "companynumb": "US-JNJFOC-20151205080", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "SIMEPREVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "205123", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2014", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIMEPREVIR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SOFOSBUVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2014", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SOFOSBUVIR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RIBAVIRIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2014", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBAVIRIN." } ], "patientagegroup": "5", "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis C", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HARTMAN J, BICHOUPAN K, PATEL N, CHEKURI S, HARTY A, DIETERICH D, ET AL. RE-RE-TREATMENT OF HEPATITIS C VIRUS: EIGHT PATIENTS WHO RELAPSED TWICE AFTER DIRECT-ACTING-ANTIVIRAL DRUGS. WORLD J GASTROENTEROL 21-NOV-2015?21 (43):12430-12438.", "literaturereference_normalized": "re re treatment of hepatitis c virus eight patients who relapsed twice after direct acting antiviral drugs", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151209", "receivedate": "20151209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11815575, "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" }, { "companynumb": "US-ROCHE-1677447", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PEGINTERFERON ALFA-2A" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "103964", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PEG-INTERFERON ALFA 2A" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIBAVIRIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021511", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBAVIRIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TELAPREVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TELAPREVIR" } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dehydration", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HARTMAN J, BICHOUPAN K, PATEL N, CHEKURI S, HARTY A, DIETRICH D, PERUMALSWAMI P AND BRANCH A. RE-RE-TREATMENT OF HEPATITIS C VIRUS: EIGHT PATIENTS WHO RELAPSED TWICE AFTER DIRECT ACTING ANTIVIRAL DRUGS. WORLD JOURNAL OF GASTROENTEROLOGY 2015 NOV 21?21 (43):12430-12438.", "literaturereference_normalized": "re re treatment of hepatitis c virus eight patients who relapsed twice after direct acting antiviral drugs", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151216", "receivedate": "20151216", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11839033, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160305" } ]

{ "abstract": "Alternating hemiplegia of childhood often manifests severe or extreme behavioral problems, the nature of which remains to be fully characterized.\n\n\n\nWe analyzed 39 consecutive patients with alternating hemiplegia of childhood for occurrence of behavioral problems and categorized those by severity: mild (not requiring intervention), moderate (requiring intervention but no risk), severe (minor risk to self, others, or both), and extreme (major risk). We then analyzed behavioral manifestations, concurrent morbidity, and medication responses in patients with severe or extreme symptoms.\n\n\n\nTwo patients had mild behavioral problems, five moderate, 10 severe, six extreme, and 16 none. Extreme cases exhibited disruptive behaviors escalating to assaults. Triggers, when present, included peer-provocation, low frustration tolerance, limits set by others, and sleep disruption. Reversible psychotic symptoms occurred in two patients: in one triggered by infection and trihexyphenidyl, and in another triggered by sertraline. Of the 16 patients with severe or extreme symptoms, 13 had concurrent neuropsychiatric diagnoses. Occurrence of severe or extreme symptoms did not correlate with age, puberty, severity of intellectual disability, or mutation status (P > 0.05). A multidisciplinary team including mental health professionals comanaged all patients with severe or extreme symptoms with either behavioral therapy, medications, or both. When considering medications prescribed to more than four patients, medicines that demonstrated efficacy or partial efficacy in more than 50% of patients were alpha-adrenergic agonists and selective-serotonin-reuptake-inhibitors.\n\n\n\nPatients with alternating hemiplegia of childhood (41%) often experience severe or extreme behavioral problems and, rarely, medication-triggered psychotic symptoms. These observations are consistent with current understanding of underlying alternating hemiplegia of childhood brain pathophysiology. Increasing awareness of these behavioral problems facilitates alternating hemiplegia of childhood management and anticipatory guidance.", "affiliations": "Division of Pediatric Neurology and Developmental Medicine, Duke Children's Health Center, Durham, North Carolina.;Division of Pediatric Neurology and Developmental Medicine, Duke Children's Health Center, Durham, North Carolina.;Division of Pediatric Neurology and Developmental Medicine, Duke Children's Health Center, Durham, North Carolina.;Division of Pediatric Neurology and Developmental Medicine, Duke Children's Health Center, Durham, North Carolina.;Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina.;Division of Child Development and Behavioral Health, Department of Pediatrics, Duke University, Durham, North Carolina.;Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina; Department of Pediatrics, Duke University, Durham, North Carolina.;Division of Pediatric Neurology and Developmental Medicine, Duke Children's Health Center, Durham, North Carolina. Electronic address: mohamad.mikati@duke.edu.", "authors": "Wallace|Keri|K|;Uchitel|Julie|J|;Prange|Lyndsey|L|;Jasien|Joan|J|;Bonner|Melanie|M|;D'Alli|Richard|R|;Maslow|Gary|G|;Mikati|Mohamad A|MA|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.pediatrneurol.2020.06.012", "fulltext": null, "fulltext_license": null, "issn_linking": "0887-8994", "issue": "111()", "journal": "Pediatric neurology", "keywords": "Aggression; Alternating hemiplegia of childhood; Behavioral problems; Psychosis; Self-harm", "medline_ta": "Pediatr Neurol", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000374:Aggression; D001526:Behavioral Symptoms; D002648:Child; D002675:Child, Preschool; D005260:Female; D006429:Hemiplegia; D006801:Humans; D008297:Male; D008875:Middle Aged; D011618:Psychotic Disorders; D016728:Self-Injurious Behavior; D012720:Severity of Illness Index; D059020:Suicidal Ideation; D014754:Violence; D055815:Young Adult", "nlm_unique_id": "8508183", "other_id": null, "pages": "5-12", "pmc": null, "pmid": "32951661", "pubdate": "2020-10", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Characterization of Severe and Extreme Behavioral Problems in Patients With Alternating Hemiplegia of Childhood.", "title_normalized": "characterization of severe and extreme behavioral problems in patients with alternating hemiplegia of childhood" }

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"reactionmeddrapt": "Psychotic disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Aggression", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Paranoia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Self-injurious ideation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hallucination, auditory", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Psychomotor hyperactivity", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Delusion", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "WALLACE K, UCHITEL J, PRANGE L, JASIEN J, MASLOW G, BONNER M, ET AL. CHARACTERIZATION OF SEVERE AND EXTREME BEHAVIORAL PROBLEMS IN PATIENTS WITH ALTERNATING HEMIPLEGIA OF CHILDHOOD. 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"drugtreatmentdurationunit": null, "medicinalproduct": "ARIPIPRAZOLE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "076920", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVETIRACETAM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ARIPIPRAZOLE" }, 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null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORAZEPAM INJECTION USP, 2 MG/ML AND 4 MG/ML" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUSPIRONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "HIGH DOSE", "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": "BUSPIRONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SERTRALINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANXIETY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SERTRALINE" } ], "patientagegroup": "5", "patientonsetage": "28", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Behaviour disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Aggression", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WALLACE K, UCHITEL J, PRANGE L, JASIEN J, BONNER, M, D^ALLI R, MASLOW, G, MIKATI M. CHARACTERIZATION OF SEVERE AND EXTREME BEHAVIORAL PROBLEMS IN PATIENTS WITH ALTERNATING HEMIPLEGIA OF CHILDHOOD. PEDIATRIC NEUROLOGY. 2020 JUN 27?111:5-12. DOI:10.1016/J.PEDIATRNEUROL.2020.06.012", "literaturereference_normalized": "characterization of severe and extreme behavioral problems in patients with alternating hemiplegia of childhood", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201016", "receivedate": "20200825", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18190196, "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" }, { "companynumb": "US-MICRO LABS LIMITED-ML2020-02567", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "FLUOXETINE HYDROCHLORIDE" 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CHARACTERIZATION OF SEVERE AND EXTREME BEHAVIORAL PROBLEMS IN PATIENTS WITH ALTERNATING HEMIPLEGIA OF CHILDHOOD.. PEDIATRIC NEUROLOGY. 2020?111:5?12.", "literaturereference_normalized": "characterization of severe and extreme behavioral problems in patients with alternating hemiplegia of childhood", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200904", "receivedate": "20200904", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18233686, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "US-DRREDDYS-USA/USA/20/0126235", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076920", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVETIRACETAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VERAPAMIL HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ALTERNATING HEMIPLEGIA OF CHILDHOOD", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VERAPAMIL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ALTERNATING HEMIPLEGIA OF CHILDHOOD", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLONIDINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BEHAVIOURAL THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONIDINE." } ], "patientagegroup": "3", "patientonsetage": "7", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Aggression", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WALLACE K, UCHITEL J, PRANGE L, JASIEN J, BONNER, M, D ALLI R, MASLOW G, MIKATI M. CHARACTERIZATION OF SEVERE AND EXTREME BEHAVIORAL PROBLEMS IN PATIENTS WITH ALTERNATING HEMIPLEGIA OF CHILDHOOD. PEDIATRIC NEUROLOGY. 2020 JUN 27?111:5-12. 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CHARACTERIZATION OF SEVERE AND EXTREME BEHAVIORAL PROBLEMS IN PATIENTS WITH ALTERNATING HEMIPLEGIA OF CHILDHOOD. 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Characterization of Severe and Extreme Behavioral Problems in Patients With Alternating Hemiplegia of Childhood. 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CHARACTERIZATION OF SEVERE AND EXTREME BEHAVIORAL PROBLEMS IN PATIENTS WITH ALTERNATING HEMIPLEGIA OF CHILDHOOD. 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PRANGE L, JASIEN J, MASLOW G, BONNER M, ET AL. CHARACTERIZATION OF SEVERE AND EXTREME BEHAVIORAL PROBLEMS IN PATIENTS WITH ALTERNATING HEMIPLEGIA OF CHILDHOOD. 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPRANOLOL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FLUOXETINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "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": "FLUOXETIN" } ], "patientagegroup": null, "patientonsetage": "14", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Aggression", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Psychotic disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Psychomotor hyperactivity", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Paranoia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Self-injurious ideation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WALLACE K, UCHITEL J, PRANGE L, JASIEN J, BONNER M, D^ALLI R, MASLOW G, MIKATI M. CHARACTERIZATION OF SEVERE AND EXTREME BEHAVIORAL PROBLEMS IN PATIENTS WITH ALTERNATING HEMIPLEGIA OF CHILDHOOD. PEDIATRIC NEUROLOGY. 2020?.", "literaturereference_normalized": "characterization of severe and extreme behavioral problems in patients with alternating hemiplegia of childhood", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20200818", "receivedate": "20200818", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18160050, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "US-OTSUKA-2020_030326", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ARIPIPRAZOLE" }, 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null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE" } ], "patientagegroup": null, "patientonsetage": "27", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Aggression", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Wallace K, Uchitel J, Prange L, Jasien J, Bonner M, Mikati MA, et al. Characterization of Severe and Extreme Behavioral Problems in Patients With Alternating Hemiplegia of Childhood. Pediatr. 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], "summary": null }, "primarysource": { "literaturereference": "WALLACE K, UCHITEL J, PRANGE L, JASIEN J, BONNER, M, D^ALLI R, MASLOW, G, MIKATI M. CHARACTERIZATION OF SEVERE AND EXTREME BEHAVIORAL PROBLEMS IN PATIENTS WITH ALTERNATING HEMIPLEGIA OF CHILDHOOD. PEDIATRIC NEUROLOGY. 2020 JUN 27?111:5-12. DOI:10.1016/J.PEDIATRNEUROL.2020.06.012", "literaturereference_normalized": "characterization of severe and extreme behavioral problems in patients with alternating hemiplegia of childhood", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201016", "receivedate": "20200825", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18190195, "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" }, { "companynumb": "US-MICRO LABS LIMITED-ML2020-02607", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ALTERNATING HEMIPLEGIA OF CHILDHOOD", "drugintervaldosagedefinition": null, "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": "VERAPAMIL HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "211370", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ALTERNATING HEMIPLEGIA OF CHILDHOOD", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VERAPAMIL HYDROCHLORIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "211954", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVETIRACETAM." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "CLONIDINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BEHAVIOURAL THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONIDINE." } ], "patientagegroup": null, "patientonsetage": "7", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Aggression", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WALLACE K, UCHITEL J, PRANGE L, JASIEN J, BONNER M, D ALLI R, MASLOW G, MIKATI M, MIKATI M, MIKATI M. CHARACTERIZATION OF SEVERE AND EXTREME BEHAVIORAL PROBLEMS IN PATIENTS WITH ALTERNATING HEMIPLEGIA OF CHILDHOOD.. PEDIATRIC NEUROLOGY. 2020?111:5?12.", "literaturereference_normalized": "characterization of severe and extreme behavioral problems in patients with alternating hemiplegia of childhood", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200905", "receivedate": "20200905", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18235661, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "US-TEVA-2020-US-1821462", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CLONIDINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BEHAVIOUR DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONIDINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VERAPAMIL HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "071019", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ALTERNATING HEMIPLEGIA OF CHILDHOOD", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VERAPAMIL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "78101", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "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." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "74569", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ALTERNATING HEMIPLEGIA OF CHILDHOOD", "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": "3", "patientonsetage": "7", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Aggression", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WALLACE K, UCHITEL J, PRANGE L, JASIEN J, MASLOW G, BONNER M, ET AL. CHARACTERIZATION OF SEVERE AND EXTREME BEHAVIORAL PROBLEMS IN PATIENTS WITH ALTERNATING HEMIPLEGIA OF CHILDHOOD. PEDIATR?NEUROL 2020?111:5?12.", "literaturereference_normalized": "characterization of severe and extreme behavioral problems in patients with alternating hemiplegia of childhood", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200901", "receivedate": "20200901", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18218871, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "US-TEVA-2020-US-1821448", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUSPIRONE HYDROCHLORIDE" }, "drugadditional": 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"Obsessive-compulsive disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anxiety", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WALLACE K, UCHITEL J, PRANGE L, JASIEN J, MASLOW G, BONNER M, ET AL. CHARACTERIZATION OF SEVERE AND EXTREME BEHAVIORAL PROBLEMS IN PATIENTS WITH ALTERNATING HEMIPLEGIA OF CHILDHOOD. 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CHARACTERIZATION OF SEVERE AND EXTREME BEHAVIORAL PROBLEMS IN PATIENTS WITH ALTERNATING HEMIPLEGIA OF CHILDHOOD. PEDIATR NEUROL. 2020?111:5?12", "literaturereference_normalized": "characterization of severe and extreme behavioral problems in patients with alternating hemiplegia of childhood", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200817", "receivedate": "20200817", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18158113, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "US-OTSUKA-2020_030325", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ARIPIPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021436", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Tablet", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Impulsive behaviour", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ARIPIPRAZOLE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHYLPHENIDATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Attention deficit hyperactivity disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPHENIDATE" } ], "patientagegroup": null, "patientonsetage": "10", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Wallace K, Uchitel J, Prange L, Jasien J, Bonner M, D^Alli R et al. Characterization of Severe and Extreme Behavioral Problems in Patients With Alternating Hemiplegia of Childhood. Pediatr Neurol. 2020;111:5-12", "literaturereference_normalized": "characterization of severe and extreme behavioral problems in patients with alternating hemiplegia of childhood", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211004", "receivedate": "20211004", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19917013, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220304" }, { "companynumb": "US-DRREDDYS-USA/USA/20/0126231", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076920", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVETIRACETAM." } ], "patientagegroup": "3", "patientonsetage": "9", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Irritability", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Agitation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional self-injury", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WALLACE K, UCHITEL, J, PRANGE, L, JASIEN, J, BONNER, M, D ALLI R, MASLOW G, MIKATI M. CHARACTERIZATION OF SEVERE AND EXTREME BEHAVIORAL PROBLEMS IN PATIENTS WITH ALTERNATING HEMIPLEGIA OF CHILDHOOD. PEDIATRIC NEUROLOGY. 2020 JUN 27?111:5-12. DOI:10.1016/J.PEDIATRNEUROL.2020.06.012", "literaturereference_normalized": "characterization of severe and extreme behavioral problems in patients with alternating hemiplegia of childhood", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201019", "receivedate": "20200825", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18190313, "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": "Chronic low back pain (LBP) is highly prevalent and costly in our society. The use of epidural steroid injections (ESIs) for the treatment of radicular LBP is very widespread and continues to rise. The most popular injection is the lumbar/sacral transforaminal epidural steroid injection (TFESI). Here, we present a serious neurological complication resulting from such a TFESI that was only reversed by timely neurosurgical intervention.\nA 49-year-old male presented with a 5-year history of progressive neurogenic claudication and right lower extremity pain/radiculopathy. He had previously received multiple lumbar ESIs and other conservative therapy. Due to a recent exacerbation of his radiculopathy associated with MRI-documented lumbosacral spondylosis, he underwent a right L5/S1 TFESI under fluoroscopic guidance. This resulted in acute right lower extremity weakness accompanied by a right-sided foot drop and sphincter dysfunction. Although the follow-up MRI was noncontributory, the EMG showed L5/S1 denervation, and the patient underwent an L4-5, L5-S1 laminectomy with discectomies at the L4-5 and L5-S1 levels. Immediately after the surgery, the patient's weakness and sensory deficits improved. Two years later, the patient continued to do well without evidence of recurrence of signs or symptoms of lumbosacral radiculopathy.\nPatients should be counseled about the risk and benefits of TFESI. Surgical treatment may be warranted in patients who develop acutely progressive worsening following these non-FDA (Food/Drug Administration) approved injections.", "affiliations": "Department of Anesthesiology, Advocate Illinois Masonic Medical Center, Chicago, Illinois, USA.;Department of Anesthesiology, Advocate Illinois Masonic Medical Center, Chicago, Illinois, USA.;Department of Anesthesiology, Advocate Illinois Masonic Medical Center, Chicago, Illinois, USA.;Department of Anesthesiology, Advocate Illinois Masonic Medical Center, Chicago, Illinois, USA.;Department of Anesthesiology, Advocate Illinois Masonic Medical Center, Chicago, Illinois, USA.", "authors": "Ghaly|Ramsis F|RF|;Zouki|Thomas|T|;Pynadath|Aby|A|;Candido|Kenneth D|KD|;Knezevic|Nebojsa Nick|NN|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.4103/sni.sni_132_18", "fulltext": "\n==== Front\nSurg Neurol IntSurg Neurol IntSNISurgical Neurology International2229-50972152-7806Medknow Publications & Media Pvt Ltd India SNI-9-15910.4103/sni.sni_132_18Pain: Case ReportTransforaminal epidural steroid injection can result in further neurological injury in a patient with severe foraminal stenosis and nerve impingement Ghaly Ramsis F. rfghaly@aol.com123*Zouki Thomas Thomas.zouki@advocatehealth.com1Pynadath Aby aby.pynadath@advocatehealth.com1Candido Kenneth D. kdcandido1@gmail.com13Knezevic Nebojsa Nick nick.knezevic@gmail.com131 Department of Anesthesiology, Advocate Illinois Masonic Medical Center, Chicago, Illinois, USA2 Ghaly Neurosurgical Associates, Aurora, Illinois, USA3 Department of Anesthesiology, University of Illinois, Chicago, Illinois, USA* Corresponding author\n2018 10 8 2018 9 15902 5 2018 18 6 2018 Copyright: © 2018 Surgical Neurology International2018This 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.Background:\nChronic low back pain (LBP) is highly prevalent and costly in our society. The use of epidural steroid injections (ESIs) for the treatment of radicular LBP is very widespread and continues to rise. The most popular injection is the lumbar/sacral transforaminal epidural steroid injection (TFESI). Here, we present a serious neurological complication resulting from such a TFESI that was only reversed by timely neurosurgical intervention.\n\nCase Description:\nA 49-year-old male presented with a 5-year history of progressive neurogenic claudication and right lower extremity pain/radiculopathy. He had previously received multiple lumbar ESIs and other conservative therapy. Due to a recent exacerbation of his radiculopathy associated with MRI-documented lumbosacral spondylosis, he underwent a right L5/S1 TFESI under fluoroscopic guidance. This resulted in acute right lower extremity weakness accompanied by a right-sided foot drop and sphincter dysfunction. Although the follow-up MRI was noncontributory, the EMG showed L5/S1 denervation, and the patient underwent an L4–5, L5–S1 laminectomy with discectomies at the L4–5 and L5–S1 levels. Immediately after the surgery, the patient's weakness and sensory deficits improved. Two years later, the patient continued to do well without evidence of recurrence of signs or symptoms of lumbosacral radiculopathy.\n\nConclusion:\nPatients should be counseled about the risk and benefits of TFESI. Surgical treatment may be warranted in patients who develop acutely progressive worsening following these non-FDA (Food/Drug Administration) approved injections.\n\nChroniccomplicationsdiscectomyforaminotomylaminectomylow back painnon-FDA (Food/Drug Administration) approvedtransforaminal epidural steroid injections\n==== Body\nINTRODUCTION\nMany patients with degenerative lumbar disc disease (DDD) are treated with non-FDA (Food/Drug Administration) approved transforaminal epidural steroid injection (TFESI). In theory, TFESIs have the advantage of resulting in greater flow into the anterior epidural space versus midline ILESI approach that predominantly results in posterior flow. However, TFESIs are correlated with various major adverse events that are typically unreported or underreported, and include: spinal cord infarction, paralysis, weakening of discs, and discitis.[256] Here, we present a patient who developed the acute onset of right lower extremity paresis/foot drop following a lumbosacral TFESI requiring emergency decompression.\n\nCASE REPORT\nA 49-year-old male presented with a 5-year history of progressive neurogenic claudication and right more than left lower extremity L4–S1 radiculopathy. The lumbar MRI showed significant disc herniations at the L4–5 and L5–S1 levels contributing to moderate central/foraminal stenosis [Figure 1]. He underwent a right L5/S1 TFESI performed under fluoroscopic guidance (e.g., injection of 3 ml water soluble, iodine-based contrast with 1 ml of 10 mg/ml dexamethasone and 1 ml of 1% PF lidocaine) [Figure 2]. Immediately following the injection, he developed right lower extremity weakness/numbness on the right and a partial right foot drop with urinary frequency. Although the repeat MRI with contrast showed no new findings, the EMG demonstrated acute denervation potentials in L5–S1 distributions. An emergent laminectomy L4–S1 and L4–5 and L5–S1 discectomies were performed; there were no indications to perform a fusion (e.g., as recommended by second opinion surgeon). Immediately postoperatively, the motor deficit improved, and at 2-year follow-up, the patient was asymptomatic.\n\nFigure 1 T2 weighted lumbar sagittal MRI view demonstrating spinal stenosis at L4-L5 and L5-S1\n\nFigure 2 PA x-ray of lumbar spine demonstrating adequate contrast spread at the right L4 nerve root\n\nDISCUSSION\nDespite the recent increase in the number of TFESI being performed, the true incidence of complications is unknown as these are largely unreported or underreported. Here we present a major neurologic deficit resulting from an L5–S1 TFESI as consequence of direct nerve root/spinal cord injury, and/or vascular injury.\n\nVascular insult\nIntra-arterial injection of particulate steroids (insoluble steroid) or direct arterial injury has been described as potential causes of devastating neurological injuries resulting from TFESI. Kennedy et al. reported two cases of bilateral lower extremity paralysis with neurogenic bowel/bladder dysfunction following lumbar TFESI.[7] They attributed these devastating injuries to an intra-arterial injection of a particulate steroid solution into a low-positioned artery of Adamkiewicz. Other experts suspect that the intravascular injection of epidural steroids is higher than detected and may be as high as 11.2% for TFESI.[3]\n\nDirect nerve injury and spinal cord injury\nIn the current case, dexamethasone, a nonparticulate steroid was used and resulted in nerve root rather than a spinal cord injury. The authors attributed this patient's neurological deficit to an acute increase in mass effect attributed to the volume of injectate resulting in ischemia. In the lumbar region, acute forceful injection of a solution into a neural foramen can lead to further entrapment of a compromised nerve root. Furthermore, an inadvertent intraneural injection cannot be ruled out. Other pathology, such an acute epidural abscess would take a longer period to become symptomatic.[4]\n\nLessons learned and avoidance of complications\nThe available literature shows conflicting results regarding the superior efficacy of TFESI versus ILESI for back pain of any cause, and further note their lack of FDA approval for safety/efficacy in the spine at any level.[18] Additionally, the complication rates for TFESI are much higher than for the interlaminar approach. Patients undergoing TFESI require surgical intervention up to 18.9% of the time within 6 months of these injections versus 4% for the interlaminar group at 1 year.[8]\n\nNotably, we would recommend TFESI be avoided when there is evidence of acute/subacute worsening of neurologic symptoms/signs. Furthermore, patients undergoing TFESI should be told about its potential risks and benefits, along with the lack of FDA approval for insufficient documentation of safety/efficacy. In all cases, one should employ the smallest dose possible, and avoid an intra-arterial injection; of interest, a negative aspiration does not guarantee that the needle is not intravascular.[1] If a patient develops any paresthesia/pain, the epidural injection should be terminated. These patients should not only be observed for longer periods postinjection, but with/without neurological worsening, should undergo immediate MRI examinations to rule out an epidural hematoma (e.g., within <24 h to avoid permanent neurological deficits/infarction) [Tables 1 and 2]. Here, our patient benefited from an emergent laminectomy and recovered full preoperative function.\n\nTable 1 Red flags for epidural steroid injection\n\nTable 2 Technical aspects while performing Epidural steroid injection\n\nCONCLUSIONS\nLumbar TFESI had no documented long-term safety/efficacy and are not FDA approved for use in the spine at any level. Furthermore, the risks/complications are typically unreported or underreported. Here we present a patient who following an L5–S1 TFESI developed acute right-lower extremity numbness/weakness/foot drop, and benefited from emergent laminectomy/surgical intervention, recovering full preoperative function.\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\nhttp://surgicalneurologyint.com/Transforaminal-epidural-steroid-injection-can-result-in-further-neurological-injury-in-a-patient-with-severe-foraminal-stenosis-and-nerve-impingement/\n==== Refs\nREFERENCES\n1 Candido KD Raghavendra MS Chinthagada M Badiee S Trepashko DW A prospective evaluation of iodinated contrast flow patterns with fluoroscopically guided lumbar epidural steroid injections: The lateral parasagittal interlaminar epidural approach versus the transforaminal epidural approach AnesthAnalg 2008 106 638 44 \n2 Chang Chien GC Candido KD Knezevic NN Digital subtraction angiography does not reliably prevent paraplegia associated with lumbar transforaminal epidural steroid injection Pain Physician 2012 15 515 23 23159970 \n3 Furman MB O’Brien EM Zgleszewski TM Incidence of intravascular penetration in transforaminal lumbosacral epidural steroid injections Spine 2000 25 2628 32 11034648 \n4 Gharibo CG Fakhry M Diwan S Kaye AD Conus medullaris infarction after a right L4 transforaminal epidural steroid injection using dexamethasone Pain Physician 2016 19 E1211 4 27906952 \n5 Houten JK Errico TJ Paraplegia after lumbosacral nerve root block: Report of three cases Spine J 2002 2 70 5 14588291 \n6 Huntoon MA Martin DP Paralysis after transforaminal epidural injection and previous spinal surgery RegAnesth Pain Med 2004 29 494 5 \n7 Kennedy DJ Dreyfuss P Aprill CN Bogduk N Paraplegia Following Image-Guided Transforaminal Lumbar Spine Epidural Steroid Injection: Two Case Reports Pain Med 2009 10 1389 94 19863744 \n8 Knezevic NN Lissounov A Candido KD Transforaminal vs interlaminar epidural steroid injections: Differences in the surgical rates and safety concerns Pain Med 2014 15 1975 6 25288305\n\n", "fulltext_license": "CC BY-NC-SA", "issn_linking": "2152-7806", "issue": "9()", "journal": "Surgical neurology international", "keywords": "Chronic; complications; discectomy; foraminotomy; laminectomy; low back pain; non-FDA (Food/Drug Administration) approved; transforaminal epidural steroid injections", "medline_ta": "Surg Neurol Int", "mesh_terms": null, "nlm_unique_id": "101535836", "other_id": null, "pages": "159", "pmc": null, "pmid": "30159203", "pubdate": "2018", "publication_types": "D002363:Case Reports", "references": "23159970;15372396;14588291;11034648;19863744;25288305;18227326;27906952", "title": "Transforaminal epidural steroid injection can result in further neurological injury in a patient with severe foraminal stenosis and nerve impingement.", "title_normalized": "transforaminal epidural steroid injection can result in further neurological injury in a patient with severe foraminal stenosis and nerve impingement" }

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TRANSFORAMINAL EPIDURAL STEROID INJECTION CAN RESULT IN FURTHER NEUROLOGICAL INJURY IN A PATIENT WITH SEVERE FORAMINAL STENOSIS AND NERVE IMPINGEMENT. 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TRANSFORAMINAL EPIDURAL STEROID INJECTION CAN RESULT IN FURTHER NEUROLOGICAL INJURY IN A PATIENT WITH SEVERE FORAMINAL STENOSIS AND NERVE IMPINGEMENT. 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TRANSFORAMINAL EPIDURAL STEROID INJECTION CAN RESULT IN FURTHER NEUROLOGICAL INJURY IN A PATIENT WITH SEVERE FORAMINAL STENOSIS AND NERVE IMPINGEMENT. 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{ "abstract": "BACKGROUND\nNeuromyelitis optica spectrum disorders (NMOSD) are a group of inflammatory central nervous system disorders characterized by optic neuritis, transverse myelitis, and anti-aquaporin 4 (AQP4) antibody production. However, it has recently been shown that some cases of typical NMOSD can be anti-AQP4 antibody-negative as well. In this study, we retrospectively investigated the disorder relapse-suppressing effect of tacrolimus (TAC) when combined with prednisolone (PSL) in anti-AQP4 antibody-positive and -negative NMOSD cases.\n\n\nMETHODS\nSubjects were NMOSD outpatients treated at our hospital in August 2016 who fulfilled the 2015 International Panel for NMO Diagnosis criteria and whose medical history before visiting our department was known; anti-myelin oligodendrocyte glycoprotein antibody-positive cases were excluded. We retrospectively investigated the annualized relapse rate (ARR) before and after combined TAC and PSL treatment in 50 NMOSD cases who had been using TAC with PSL for at least 1 year and whom we were also able to observe.\n\n\nRESULTS\nThere were 42 anti-AQP4 antibody-positive cases and 8 negative cases. Observation periods of the anti-AQP4 antibody-positive cases were 1.1 years before TAC and 5.1 years after TAC. ARR before TAC was 1.0 and 0.08 after TAC, indicating a relapse-suppression rate of 92% (p < 0.001) and clear improvement. In the anti-AQP4 antibody-negative group, the observation period was 5.6 years before and 4.1 years after TAC. ARR before TAC was 0.5 and 0.07 after TAC. The relapse-suppression rate was 86% (p < 0.05), which was obviously as effective as in the anti-AQP4 antibody-positive group. PSL dose in the anti-AQP4 antibody-positive group was 15.0 mg/day at the start of TAC and was reduced to 6.3 mg/day after 2 years (p < 0.001). The Expanded Disability Status Scale (EDSS) score decreased from 4.5 at the start of TAC to 2.0 after 2 years in the anti-AQP4 antibody-positive group (p < 0.05), which was a clear improvement.\n\n\nCONCLUSIONS\nCombined use of TAC with PSL clearly suppressed relapse of both anti-AQP4 antibody-positive and -negative NMOSD. In the anti-AQP4 antibody-positive group, both PSL dose and EDSS score decreased compared with the dose at the start of the study.", "affiliations": "Department of Neurology, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama 350-8550, Japan. Electronic address: mkoji@saitama-med.ac.jp.;Department of Neurology, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama 350-8550, Japan.;Department of Neurology, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama 350-8550, Japan.;Department of Neurology, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama 350-8550, Japan.;Department of Neurology, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama 350-8550, Japan.;Department of Neurology, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama 350-8550, Japan.;Department of Neurology, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama 350-8550, Japan.", "authors": "Kojima|Miki|M|;Oji|Satoru|S|;Tanaka|Satoru|S|;Izaki|Shoko|S|;Hashimoto|Baku|B|;Fukaura|Hikoaki|H|;Nomura|Kyoichi|K|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.msard.2019.101907", "fulltext": null, "fulltext_license": null, "issn_linking": "2211-0348", "issue": "39()", "journal": "Multiple sclerosis and related disorders", "keywords": "Annualized relapse rate; Anti-aquaporin 4 antibody; Neuromyelitis optica spectrum disorders; Prednisolone; Tacrolimus", "medline_ta": "Mult Scler Relat Disord", "mesh_terms": null, "nlm_unique_id": "101580247", "other_id": null, "pages": "101907", "pmc": null, "pmid": "31931404", "pubdate": "2019-12-26", "publication_types": "D016428:Journal Article", "references": null, "title": "Tacrolimus is effective for neuromyelitis optica spectrum disorders with or without anti-AQP4 antibody.", "title_normalized": "tacrolimus is effective for neuromyelitis optica spectrum disorders with or without anti aqp4 antibody" }

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TACROLIMUS IS EFFECTIVE FOR NEUROMYELITIS OPTICA SPECTRUM DISORDERS WITH OR WITHOUT ANTI-AQP4 ANTIBODY. 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TACROLIMUS IS EFFECTIVE FOR NEUROMYELITIS OPTICA SPECTRUM DISORDERS WITH OR WITHOUT ANTI-AQP4 ANTIBODY. MULTIPLE SCLEROSIS AND RELATED DISORDERS. 2020?39:1-8", "literaturereference_normalized": "tacrolimus is effective for neuromyelitis optica spectrum disorders with or without anti aqp4 antibody", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200207", "receivedate": "20200207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17391721, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200409" } ]

{ "abstract": "A retrospective chart review was conducted on 85 renal transplant patients aged 19-88 years, treated with denosumab or bisphosphonate therapy. Bone densitometry measures were compared between treatment groups at baseline; at years 1, 2, and 3; and at final follow-up (average of 3.4 years). Both bisphosphonate and denosumab treatments increased lumbar spine bone density; however, the effect of denosumab was greater compared with that of bisphosphonate treatment. Denosumab treatment increased femoral neck BMD, whereas bisphosphonate treatment had a mean decrease in femoral neck BMD at final follow-up. Thus, our study provides evidence for the efficacy of denosumab treatment in renal transplant patients. Caution around hypocalcemia is warranted. We recommend more prospective studies to analyze the effects of long-term antiresorptive therapy in patients with a renal transplant.\n\n\nBACKGROUND\nTo compare the clinical effectiveness and safety between the use of denosumab and bisphosphonates on bone density and incidence of adverse events in renal transplant patients.\n\n\nMETHODS\nA retrospective chart review was conducted on 85 renal transplant patients aged 19-88 years, treated with denosumab or bisphosphonate therapy. Bone densitometry measures were compared between treatment groups at baseline; years 1, 2, and 3; and at final follow-up (average of 3.4 years).\n\n\nRESULTS\nAbsolute change in lumbar spine and femoral neck BMD over the treatment period was 0.029 ± 0.075 g/cm2 and - 0.003 ± 0.064 g/cm2, respectively, in the bisphosphonate group. Absolute change in lumbar spine and femoral neck BMD at final follow-up was 0.072 ± 0.094 g/cm2 and 0.025 ± 0.063 g/cm2, respectively, in the denosumab group. Denosumab resulted in significantly greater increases in lumbar spine BMD (0.045 g/cm2 greater in the denosumab group). Similarly, the absolute change in BMD at the femoral neck was 0.022 g/cm2 greater in the denosumab group as compared with the bisphosphonate group. The denosumab group had one event of severe hypocalcemia following first injection and one report of hospitalized pneumonia. No serious adverse events were reported in the bisphosphonate group.\n\n\nCONCLUSIONS\nBoth treatments increased lumbar spine BMD; however, the effect of denosumab was greater compared with that of bisphosphonate treatment. Our study provides evidence for the efficacy of denosumab treatment in renal transplant patients. Caution around hypocalcemia is warranted. We recommend more prospective studies to analyze the effects of long-term antiresorptive therapy in patients with a renal transplant.", "affiliations": "McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada. mckeeh@mcmaster.ca.;McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada.;McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada.;McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada.;McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada.;McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada.;McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada.;McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada.;McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada.", "authors": "McKee|H|H|http://orcid.org/0000-0001-7141-1331;Ioannidis|G|G|;Lau|A|A|;Treleaven|D|D|;Gangji|A|A|;Ribic|C|C|;Wong-Pack|M|M|;Papaioannou|A|A|;Adachi|J D|JD|", "chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D000069448:Denosumab", "country": "England", "delete": false, "doi": "10.1007/s00198-019-05267-1", "fulltext": null, "fulltext_license": null, "issn_linking": "0937-941X", "issue": "31(5)", "journal": "Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA", "keywords": "Bisphosphonates; CKD; Denosumab; Osteoporosis; Renal transplant", "medline_ta": "Osteoporos Int", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015519:Bone Density; D050071:Bone Density Conservation Agents; D000069448:Denosumab; D004164:Diphosphonates; D006801:Humans; D016030:Kidney Transplantation; D008875:Middle Aged; D011446:Prospective Studies; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult", "nlm_unique_id": "9100105", "other_id": null, "pages": "973-980", "pmc": null, "pmid": "31900542", "pubdate": "2020-05", "publication_types": "D016428:Journal Article", "references": "21145999;18767928;10527181;29021477;19671655;26746396;28474258;15239623;27862983;20222106;1637568;21411557;18087050;27270237;16294264;30775498;16495394;28425085;28432640;29713798;27120345;21232648;23544820;10820173;22350608;24524045;29487093;23177553;24712332;8793925;28250248;17243862;22461041;12202465;18563052;12374248;19543063;24733321;19918255;15384027;23456850;22854051;17708711", "title": "Comparison of the clinical effectiveness and safety between the use of denosumab vs bisphosphonates in renal transplant patients.", "title_normalized": "comparison of the clinical effectiveness and safety between the use of denosumab vs bisphosphonates in renal transplant patients" }

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{ "abstract": "The authors report the case of an 80-year-old man who had heavily pretreated castration refractory carcinoma of the prostate and heart failure. Following the introduction of spironolactone to manage his heart failure, the patient experienced clinical and biochemical progression of his prostate cancer. Within 2 weeks of withdrawing spironolactone the patient's prostate-specific antigen returned its previous level. This is the first reported case of clinical and biochemical progression of prostate cancer following the introduction of spironolactone. The authors propose that spironolactone is a selective androgen receptor modulator. Spironolactone should be used in caution with men with prostate cancer, and should not be used to treat oedema, hypokalaemia and hypertension associated with the newly licensed hormonal therapy abiraterone acetate.", "affiliations": "Oncology Department, Nottingham University Hospitals NHS Trust, Nottingham, UK. santhanam.sundar@nuh.nhs.uk", "authors": "Sundar|Santhanam|S|;Dickinson|Peter D|PD|", "chemical_list": "D011944:Receptors, Androgen; D013148:Spironolactone; D017430:Prostate-Specific Antigen", "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2012()", "journal": "BMJ case reports", "keywords": null, "medline_ta": "BMJ Case Rep", "mesh_terms": "D000230:Adenocarcinoma; D000369:Aged, 80 and over; D000075202:Contraindications; D006333:Heart Failure; D006801:Humans; D008297:Male; D017430:Prostate-Specific Antigen; D011471:Prostatic Neoplasms; D011944:Receptors, Androgen; D013148:Spironolactone", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "22665559", "pubdate": "2012-02-25", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "20805462;7199587;6725525;762169;10973303;2462135;18819053;20142058;2943311;10963646;125803", "title": "Spironolactone, a possible selective androgen receptor modulator, should be used with caution in patients with metastatic carcinoma of the prostate.", "title_normalized": "spironolactone a possible selective androgen receptor modulator should be used with caution in patients with metastatic carcinoma of the prostate" }

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{ "abstract": "A toddler undergoing treatment for refractory Langerhans cell histiocytosis (LCH) developed concurrent hemophagocytic lymphohistiocytosis (HLH). These are thought to be distinct histiocytic disorders, with different pathophysiologies, diagnostic criteria, and treatments. HLH in a patient with LCH is thought to be quite rare. In this report, we review the presentation of our patient, as well as review the existing literature of other pediatric patients who have been diagnosed with both LCH and HLH.", "affiliations": "Division of Pediatric Cancer and Blood Disorders.;Division of Immunology and Infectious Diseases.;Division of Pediatric Cancer and Blood Disorders.", "authors": "Hinson|Ashley R P|ARP|;Patel|Niraj|N|;Kaplan|Joel|J|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1097/MPH.0000000000001652", "fulltext": "\n==== Front\nJ Pediatr Hematol Oncol\nJ Pediatr Hematol Oncol\nMPH\nJournal of Pediatric Hematology/Oncology\n1077-4114 1536-3678 Lippincott Williams & Wilkins \n\n31725543\n10.1097/MPH.0000000000001652\n00004\nClinical and Laboratory Observations\nHemophagocytic Lymphohistiocytosis in Langerhans Cell Histiocytosis: A Case Report and Review of the Literature\nHinson Ashley R.P. MD*† Patel Niraj MD†‡ Kaplan Joel DO*† * Division of Pediatric Cancer and Blood Disorders\n‡ Division of Immunology and Infectious Diseases\n† Atrium Health, Levine Children’s Hospital, Charlotte, NC\nReprints: Ashley R.P. Hinson, MD, 1001 Blythe Boulevard, MCP Suite 601, Charlotte, NC 28203 (e-mail: ashley.hinson@atriumhealth.org).\n1 2021 \n12 11 2019 \n43 1 24 27\n13 5 2019 13 10 2019 Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc.2021This 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. http://creativecommons.org/licenses/by-nc-nd/4.0/A toddler undergoing treatment for refractory Langerhans cell histiocytosis (LCH) developed concurrent hemophagocytic lymphohistiocytosis (HLH). These are thought to be distinct histiocytic disorders, with different pathophysiologies, diagnostic criteria, and treatments. HLH in a patient with LCH is thought to be quite rare. In this report, we review the presentation of our patient, as well as review the existing literature of other pediatric patients who have been diagnosed with both LCH and HLH.\n\nKey Words:\nHLHLCHpediatricOPEN-ACCESSTRUE\n==== Body\nThere are 3 distinct classes of histiocyte disorders: Langerhans cell histiocytosis (LCH), hemophagocytic lymphohistiocytosis (HLH) (and other rarer class II disorders), and malignant histiocytoses.1 LCH is characterized by the proliferation of infiltrative Langerhans cells into skin or bone; multisystem disease can also involve the lungs, liver, spleen, bone marrow, and central nervous system. Although historically thought of as a benign, reactive process, BRAF-V600E mutations have been found in 25% to 70% of LCH patients, with MAP2K1 positivity in 46% of BRAF-negative cases, raising the possibility that LCH is a malignancy.2–4 Many believe LCH may represent a myeloid-lineage neoplasm driven by ERK signaling.5,6 The treatment for LCH depends on the extent of disease and ranges from local and/or topical therapies to systemic chemotherapy.5,7\n\nHLH is a disease of systemic, dysregulated immune activation and inflammation.8 HLH can be familial or secondary to infections, autoimmune processes, or malignancies.1 Treatment is with systemic dexamethasone and etoposide per the HLH94 protocol, with some patients, especially those with familial and/or reactivated HLH, ultimately requiring hematopoietic stem cell transplant for a cure.9 Recent studies suggest that targeted therapies such as emapalumab may also play a role, especially in refractory cases.10\n\nTable 1 reviews LCH and HLH in respect to presentation, diagnostic criteria, and treatments. Though they are regarded as separate disease states, they can occur together within the same patient. Favara et al11 reviewed 30 pathology files of patients with coexisting LCH and macrophage activation; 7 of these met full diagnostic criteria for HLH. We report the case of a 20-month-old patient with multisystem LCH who developed HLH during treatment and summarize the literature for other case reports of HLH in LCH.\n\nTABLE 1 Comparison of LCH and HLH8,12\n\n\tLCH\tHLH\t\nPathophysiology\tDerived from clonal CD1a+ dendritic cells Lesions contain inflammatory infiltrates including high levels of T-cell regulatory molecules\tDefects in target cell killing by cytotoxic T cells Immune dysregulation with excessive proinflammatory cytokine production and macrophage response Uncontrolled systemic inflammation Can be primary or secondary to an infection, malignancy, autoimmune condition\t\nMolecular findings\t38%-57% possess BRAF-V600E mutation\tPerforin MUNC 13-4, MUNC 18-2\nSyntaxin 11\nLYST, CHS1, Rab27A, AP3B1\nSH2D1A, XIAP, BIRC4, SAP\t\nPresenting signs/symptoms\tBone pain, swelling, fractures Chest pain, cough, dyspnea Rash, seborrhea, otitis externa Polyuria, polydipsia Fatigue, weight loss, fevers, lymphadenopathy\tSepsis-like presentation Fever Cytopenias Hepatitis Splenomegaly Ataxia, seizures, abnormal MRI in 50%\t\nDiagnostic criteria\tTissue biopsy containing CD207+, CD1a+ dendritic cells Characteristic morphology of Langerhans cells\tRequires 5/8 diagnostic criteria:  Fever  Splenomegaly  Cytopenias in ≥2 cell lines  Hyperferritinemia >500 mg/mL  sIL2 >2400 U/mL  Hypertriglyceridemia/hypofibrinogenemia  Hemophagocytosis in tissue biopsy  Low or absent NK cell activity\t\nTreatment\tLocal therapy for unifocal bony disease Prednisone, vinblastine Cladribine, cytarabine, clofarabine for refractory/recurrent disease BMT for marrow/refractory disease\tDecadron, etoposide±cyclosporine Alemtuzumab for refractory cases Anti-INF-gamma antibodies for refractory cases\t\nBMT indicates bone marrow transplant; HLH, hemophagocytic lymphohistiocytosis; IL2, soluble interleukin-2; INF, interferon; LCH, Langerhans cell histiocytosis; MRI, magnetic resonance imaging; NK, natural killer.\n\nRESULTS: CASE DESCRIPTION\nA 20-month-old male individual presented to his pediatrician with 6 months of progressive limp and unilateral leg pain, leading to a refusal to bear weight. He also had chronic drainage from bilateral ears. A radiograph showed a lucent, expansile lesion of the child’s femur and biopsy was performed, showing s100+, CD1a+ LCH. Further evaluation using skeletal survey and positron emission tomography-computed tomography (PET/CT) revealed multiple bony lytic lesions of the skull, axial skeleton and extremities, a scaling diffuse rash of the scalp, and hypermetabolic cervical lymphadenopathy. He had no involvement of the lungs, liver, spleen, or bone marrow, and had normal magnetic resonance imaging appearance of his pituitary after passing a water deprivation test. His blood counts at diagnosis were normal other than a mild microcytic iron deficiency anemia. Liver function tests and ferritin were within normal limits. He began therapy with daily prednisone and weekly vinblastine as per the LCH-III protocol. After his initial 6 weeks of induction therapy, PET/CT showed improved but continued hypermetabolic bony lesions. He went on to the second phase of induction therapy with further improvement in lesions and then began continuation with pulses of prednisone and vinblastine every 3 weeks. Within 3 months, a follow-up PET/CT showed worsening hypermetabolic bony lesions. He was treated with cladribine for 5 days every 28 days. Interval imaging after 2 cycles again showed worsening hypermetabolic bony lesions, worsening skin rash on scalp, continued bilateral ear drainage, leg pain, and intermittent fevers with cough and rhinorrhea. He was found to be respiratory syncytial virus (RSV) positive at that time. The child began monotherapy with clofarabine 25 mg/m2 daily for 5 days. Daily fevers continued for 2 weeks and he developed transaminitis with hypoalbuminemia and fluid overload. Blood cultures were negative, and he was empirically treated with broad-spectrum antibiotics secondary to neutropenia. CT scans done as part of fever evaluation revealed multiple new lytic skull lesions. Epstein-Barr virus (EBV) polymerase chain reaction was positive at 863 copies, which resolved without intervention over the next month. He met criteria for HLH with fevers, pancytopenia, ferritin >7500 ng/mL, triglycerides 526 mg/dL, soluble interleukin (IL)2 of 8191 U/mL, and hemophagocytosis in his bone marrow. Mutational analysis for PRF1, MUNC 13-4, XIAP and other common HLH-causing genes was normal. He thus began therapy via HLH94 with dexamethasone 10 mg/m2/d and etoposide. At the end of the standard 8-week treatment period, his HLH was felt to be well controlled with resolution of fevers and cytopenias, as well as normalization of liver function tests, triglycerides, soluble IL2, and improvement in ferritin. He went on to complete an additional 5 cycles of clofarabine 25 mg/m2 (6 total cycles), with end of therapy PET/CT showing no evidence of disease. He is now 3 years off therapy and doing very well.\n\nDISCUSSION\nHistiocytes or mononuclear phagocytes, the immune cells implicated in the pathogenesis of both LCH and HLH, serve many functions in the normal immune response. These include antigen presentation, activation of immune function through cytokine signaling, and phagocytosis.12 In both LCH and HLH, affected tissues express high levels of T-cell stimulatory molecules and secrete inflammatory cytokines such as IL-6, interferon, and tumor necrosis factor.8 Studies of LCH lesions suggest that chemokine receptors, including CCR6, maybe abnormally upregulated which contributes to tissue infiltration.13,14 Furthermore, the T cells found abundantly in LCH lesions show increased expression for genes involved in leukocyte chemotaxis, such as SPP1, IL8 and plasminogen activator, among others.15 A lesion with increased accumulation of histiocytes and T cells may thus be at increased risk of uncontrolled activation of these cells, resulting in hypercytokinemia and progressive organ dysfunction like that seen in HLH.12 HLH has a known association with malignancy, especially leukemias and lymphomas. If LCH indeed represents a malignant clonal process of early myeloid-lineage cells, this may also explain the potential association between the 2 entities. Alternatively, it could be that children with LCH who require multiagent or prolonged chemotherapy courses develop HLH secondary to immune dysregulation from the treatments rather than the underlying disease.\n\nHLH in LCH is thought to be a rare phenomenon and we aimed to summarize the available reports (Table 2). In our patient (patient 8), and in those reported throughout the literature, common findings included young age, multisystem LCH, history of systemic chemotherapy, and often concurrent infection. Our patient with multisystem LCH had received a prolonged course of multiagent chemotherapy secondary to his refractory disease and then developed RSV. He was also positive for EBV. Although we did not find any other reports of RSV-associated HLH, EBV is a well-known trigger of HLH, as are other viruses including influenza, parvovirus, etc. One evaluation of 182 pediatric patients with EBV who also met criteria for HLH, showed significant immune dysregulation. These patients had abnormal natural killer cell activity, as well as decreased CD4+ T cells, and a decreased ratio of CD4+/CD8+ T cells, resulting in increased T-cell activation and decreased inhibition. HLA-DR expression was elevated, indicating high levels of T-cell activation, and further downstream cytokines such as IL2 and interferon-gamma were also significantly elevated.16 Thus, viral infections including EBV can result in uncontrolled proliferation and activation of T cells, which may be further increased in patients with preexisting immune dysregulation from chemotherapy and/or the underlying disease state. We believe the combination of immunosuppression and infection may have led to HLH in our patients. Interestingly, like our patient, another reported patient with LCH also developed HLH while receiving clofarabine, a deoxyadenosine analog. Although this may be coincidence, clofarabine after multiple other immunosuppressive agents may have contributed to significant immune dysregulation and HLH in these patients. A recently published multicenter article reviewed 29 patients who met criteria for HLH and LCH. As in the patients reviewed in Table 2, about half of the patients met criteria for HLH at or around the diagnosis of LCH. Most had active LCH at diagnosis of HLH and were receiving treatments similar to those listed in Table 2. Overall, 31% had some kind of infection when HLH developed, including EBV. HLH was increased most in those with risk organ involvement, but also seen in young females without bony involvement. The combination of HLH and LCH was associated with a poor prognosis.17 Taken together, it appears HLH in LCH is not as unusual as originally thought. Since these diagnoses share common histologic and diagnostic findings but require different treatment strategies, knowledge of their potential relationship, and which patients are at highest risk, is critical to timely diagnosis and treatment.\n\nTABLE 2 Reported Patients With LCH and HLH\n\n\tPatient 111\tPatient 211\tPatient 318\tPatient 419\tPatient 520\tPatient 621\tPatient 722\tPatient 8\t\nAge at HLH\t10 mo\t17 mo\t3 y\t2 y\t10 mo\t3 y\t1 y\t2 y\t\nAreas of LCH\tColon, skin, ln, bone marrow\tLeft mastoid\tSkin, bone, ln, bone marrow\tSkin, bone\tSkin, bone, ln, lungs\tSkin, bone, ln\tSkin, bone, ln, hepatomegaly\tSkin, bone\t\nPrior therapies\tNone\tNone\t2CDA, ARAC×6 mo\tPrednisone, VBL, 6-MP, MTX×6 mo\tNone\tPrednisone, VBL, 6-MP, MTX\tPrednisone, VCR, ARAC\tPrednisone, VBL, 2CDA\t\nClinical course\tPresented with fever, diarrhea, HSM, LAD, and pulmonary disease\tPresented with fever, HSM, LAD, and bone lesion\t2 cycles of clofarabine. Lesions improved but developed HLH\tPresented with HLH on 3 different occasions 2 to 6 mo apart in the setting of influenza, HSV, and adenovirus\tPresented with HLH and CMV. Diagnosed with HLH and LCH of skin\t9 mo after therapy completed, the patient presented with HLH\t3 wk into therapy for LCH, the patient developed HLH\t7 d after beginning clofarabine therapy, developed HLH. EBV PCR+\t\nHLH treatment\tChemotherapy\tPrednisone, VBL, VCR\tDexamethasone, etoposide\tCessation of chemotherapy, antibiotics, antivirals, IVIG\tPrednisone, etoposide\tDexamethasone, cyclo A\tDexamethasone, etoposide, cyclo A, followed by flu, mel, ATG cytox, and UCBT\tDexamethasone, etoposide\t\nOutcome\tDied 10 mo after diagnosis\tCR\tContinued disease progression, followed by death within 2 mo\tCR\tCR\tCR\tCR and engrafted\tDisease-free now 3 y off therapy\t\nARAC indicates cytarabine; ATG, anti-thymocyte globulin; 2CDA, cladribine; CMV, cytomegalovirus; CR, complete remission; cytox, cyclophosphamide; EBV, Epstein-Barr virus; flu, fludarabine; HLH, hemophagocytic lymphohistiocytosis; HSM, hepatosplenomegaly; IN, lymph node; IVIG, intravenous immunoglobulin; LAD, lymphadenopathy; LCH, Langerhans cell histiocytosis; mel, melphalan; MP, mercaptopurine; MTX, methotrexate; PCR, polymerase chain reaction; UCBT, unrelated cord blood transplant; VBL, vinblastine; VCR, vincristine.\n\nThe authors declare no conflict of interest.\n==== Refs\nREFERENCES\n1 Webb DKH \nHistiocyte disorders\n. Br Med Bull . 1996 ;52 :818 –825\n.9039734 \n2 Alayed K Medeiros LJ Patel KP \nBRAF and MAP2K1 mutations in Langerhans cell histiocytosis: a study of 50 cases\n. Hum Pathol . 2016 ;52 :61 –67\n.26980021 \n3 Harmon CM Brown N \nLangerhans cell histiocytosis\n. Arch Pathol Lab Med . 2015 ;139 :1211 –1214\n.26414464 \n4 Zeng K Ohshima K Liu Y \nBRAFV600E and MAP2K1 mutations in Langerhans cell histiocytosis occur predominantly in children\n. Hematol Oncol . 2017 ;35 :845 –851\n.27597420 \n5 Allen CE Ladisch S Kenneth LM \nHow I treat Langerhans cell histiocytosis\n. Blood . 2015 ;126 :26 –35\n.25827831 \n6 Zinn DJ Chakraborty R Allen CE \nLangerhans cell histiocytosis: emerging insights and clinical implications\n. Oncology . 2016 ;30 :122 –132\n.26888790 \n7 Rigaud C Barkaoui MA Thomas C \nLangerhans cell histiocytosis: therapeutic strategy and outcome in a 30-year nationwide cohort of 1478 patients under 18 years of age\n. Br J Hematol . 2016 ;174 :887 –898\n.\n8 Vaiselbuh SR Bryceson YT Allen CE \nUpdates on histiocytic disoders\n. Pediatr Blood Cancer . 2014 ;61 :1329 –1335\n.24610771 \n9 Henter JI Arico M Egeler RM \nHLH-94: a treatment protocol for hemophagocytic lymphohistiocytosis. HLH Study Group fo the Histiocyte Society\n. Med Pediatr Oncol . 1997 ;28 :342 –347\n.9121398 \n10 Locatelli F Jordan MB Allen CE \nSafety and efficacy of emapalumab in pediatric patients with primary hemophagocytic lymphohistiocytosis\n. Blood . 2018 ;132 :LBA6 .\n11 Favara BE Jaffe R Egeler RM \nMacrophage activation and hemophagocytic syndrome in Langerhans cell histiocytosis: report of 30 cases\n. Pediatr Dev Pathol . 2002 ;5 :130 –140\n.11910507 \n12 Filipovich A Mcclain K Grom A \nHistiocytic disorders: recent insights into pathophysiology and practical guidelines\n. 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Cancer . 2019 ;125 :963 –971\n.30521100 \n18 Simko SJ Tran HD Jones J \nClofarabine salvage therapy in refractory multifocal histiocytic disorders, including Langerhans cell histiocytosis, juvenile xanthogranuloma and Rosai-Dorfman disease\n. Pediatr Blood Cancer . 2014 ;61 :479 –487\n.24106153 \n19 Klein A Corazza F Demulder A \nRecurrent viral associated hemophagocytic syndrome in a child with Langerhans cell histiocytosis\n. J Pediatr Hematol Oncol . 1999 ;21 :554 –556\n.10598673 \n20 Hesseling PB Wessels G Egeler RM \nSimultaneous occurrence of viral-associated hemophagocytic syndrome and Langerhans cell histiocytosis\n. Pediatr Hematol Oncol . 1995 ;12 :135 –141\n.7626381 \n21 Dokmanovic L Krstovski N Jankovic S \nHemophagocytic lymphohistiocytosis arising in a child with Langerhans cell histiocytosis\n. Turk J Pediatr . 2014 ;56 :452 –457\n.25818970 \n22 Washio K Muraoka M Kanamitsu K \nA case of refractory Langerhans cell histiocytosis complicated with hemophagocytic lymphohistiocytosis rescued by cord blood transplantation with reduced-intensity conditioning\n. Acta Med Okayama . 2017 ;71 :249 –254\n.28655945\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1077-4114", "issue": "43(1)", "journal": "Journal of pediatric hematology/oncology", "keywords": null, "medline_ta": "J Pediatr Hematol Oncol", "mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D006646:Histiocytosis, Langerhans-Cell; D006801:Humans; D007223:Infant; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D011379:Prognosis", "nlm_unique_id": "9505928", "other_id": null, "pages": "24-27", "pmc": null, "pmid": "31725543", "pubdate": "2021-01", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Hemophagocytic Lymphohistiocytosis in Langerhans Cell Histiocytosis: A Case Report and Review of the Literature.", "title_normalized": "hemophagocytic lymphohistiocytosis in langerhans cell histiocytosis a case report and review of the literature" }

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{ "abstract": "Tuberculous meningitis is rare but one of the most severe forms of tuberculosis infection.\nA 78-year-old woman was diagnosed with advanced gastric cancer with multiple lymph node metastases. Four months after the beginning of second-line chemotherapy with weekly paclitaxel, she was admitted to our hospital because of fever and mild drowsiness. She had no other symptoms and no abnormalities in physical examinations. Her blood tests, urinalysis, and blood culture revealed no remarkable abnormal findings. Although her symptoms relieved, her disturbance of consciousness gradually progressed during 2 weeks thereafter. Finally, we diagnosed tuberculous meningitis on the 22nd day of hospitalization by a positive acid-fast bacilli test of the cerebrospinal fluid and tuberculosis-polymerase chain reaction. Although anti-tuberculosis therapy was started, she died on the 37th day of hospitalization because of tumor bleeding.\nTo the best of our knowledge, this is the first report of tuberculous meningitis during chemotherapy for advanced gastric cancer, suggesting that subacute onset of fever followed by disturbance of consciousness may indicate the possibility of tuberculous meningitis even without typical signs of meningitis including headache or meningeal irritation.", "affiliations": "Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.;Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.;Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.;Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.;Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.;Department of General Medicine and Infectious Diseases, National Cancer Center Hospital East, Kashiwa, Japan.;Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.", "authors": "Matsumoto|Hiroshi|H|;Sasaki|Akinori|A|;Nakamura|Yoshiaki|Y|;Kawazoe|Akihito|A|;Kuboki|Yasutoshi|Y|;Okinaka|Keiji|K|;Shitara|Kohei|K|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.1159/000488313", "fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. 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.ch 10.1159/000488313cro-0011-0228Case ReportTuberculous Meningitis during Chemotherapy for Advanced Gastric Cancer Matsumoto Hiroshi aSasaki Akinori aNakamura Yoshiaki aKawazoe Akihito aKuboki Yasutoshi aOkinaka Keiji bShitara Kohei a*aDepartment of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, JapanbDepartment of General Medicine and Infectious Diseases, National Cancer Center Hospital East, Kashiwa, Japan*Dr. Kohei Shitara, Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577 (Japan), E-Mail kshitara@east.ncc.go.jpJan-Apr 2018 5 4 2018 5 4 2018 11 1 228 233 12 3 2018 12 3 2018 Copyright © 2018 by S. Karger AG, Basel2018This 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.Introduction\nTuberculous meningitis is rare but one of the most severe forms of tuberculosis infection.\n\nCase Report\nA 78-year-old woman was diagnosed with advanced gastric cancer with multiple lymph node metastases. Four months after the beginning of second-line chemotherapy with weekly paclitaxel, she was admitted to our hospital because of fever and mild drowsiness. She had no other symptoms and no abnormalities in physical examinations. Her blood tests, urinalysis, and blood culture revealed no remarkable abnormal findings. Although her symptoms relieved, her disturbance of consciousness gradually progressed during 2 weeks thereafter. Finally, we diagnosed tuberculous meningitis on the 22nd day of hospitalization by a positive acid-fast bacilli test of the cerebrospinal fluid and tuberculosis-polymerase chain reaction. Although anti-tuberculosis therapy was started, she died on the 37th day of hospitalization because of tumor bleeding.\n\nConclusion\nTo the best of our knowledge, this is the first report of tuberculous meningitis during chemotherapy for advanced gastric cancer, suggesting that subacute onset of fever followed by disturbance of consciousness may indicate the possibility of tuberculous meningitis even without typical signs of meningitis including headache or meningeal irritation.\n\nKeywords\nGastric cancerTuberculous meningitisChemotherapyPaclitaxel\n==== Body\nIntroduction\nTuberculous meningitis is a rare disease that has an extremely poor prognosis [1, 2]. It is one of the most severe forms of tuberculosis infections, for which early intervention is important to improve treatment outcomes [3]; however, subacute and nonspecific clinical features as well as insensitive laboratory tests complicate early diagnosis [4]. Here, we report a case of tuberculous meningitis, which developed during chemotherapy for gastric cancer.\n\nCase Presentation\nA 78-year-old woman was diagnosed with advanced gastric cancer with multiple lymph node metastases in January 2017. She received second-line chemotherapy with ramucirumab plus paclitaxel starting in August 2017 after failure of first-line chemotherapy. Because of complications with gastrointestinal hemorrhage due to primary gastric tumor, weekly paclitaxel monotherapy was continued from October 2017, which achieved stable disease. Four months after the beginning of second-line chemotherapy and 1 week before hospitalization, she was febrile with a temperature of 38.0°C and consulted the outpatient department. She presented with no accompanying symptoms other than fever and showed no abnormalities in physical examinations. Moreover, her complete blood count tests, serum chemistry, urinalysis, and blood culture revealed no significant findings; therefore, she was discharged home with oral antipyretics. However, 4 days later, she was febrile again with a temperature of 39.8°C along with drowsiness and was admitted to our hospital. After admission, she almost returned to full consciousness without headache and meningeal irritation signs. A computed tomography (CT) scan did not identify a significant abnormality in the brain but revealed an emerging small infiltration in the right upper lung lobe as a possible cause of the fever. She was empirically treated with piperacillin/tazobactam for possible bacterial pneumonia. Her fever gradually improved up to the 7th day of hospitalization; however, thereafter, her mild disturbance of consciousness in the form of delirium was worsening and a fever of 38–39°C was once again observed around the 10th day of hospitalization. Her disturbance of consciousness finally progressed to drowsiness by the 14th day of hospitalization. A brain CT scan on the 14th day revealed apparent ventricular enlargement and periventricular edematous changes compared with that on admission (Fig. 1). Cerebrospinal fluid was collected through a lumbar puncture, which showed a significant increase in the number of mononuclear cells (Table 1). Due to her accompanying advanced gastric cancer, meningitis carcinomatosis was first suspected, for which dexamethasone (6.6 mg/day) treatment was initiated while waiting for cytology results. However, her disturbance of consciousness persisted and deteriorated further, and another cerebrospinal fluid test was performed on the 19th day of hospitalization because of negative cytology results in the first investigation. A significant increase in polynuclear cell numbers and overall cell counts as well as a decrease in the glucose content of the cerebrospinal fluid was noted (Table 1). The cerebrospinal fluid samples were submitted for bacterial, mycobacterial, and fungal cultures. An acid-fast bacilli test of the cerebrospinal fluid was negative, but we initiated empirical anti-tuberculosis treatment since tuberculous meningitis could not be excluded with subacute onset of symptoms. On the 22nd day of hospitalization, positive tuberculosis-polymerase chain reaction (TB-PCR) of the cerebrospinal fluid confirmed the diagnosis of tuberculous meningitis. Her sputum tested was also positive on TB-PCR. Because oral medication was not possible, a triple-drug combination therapy consisting of isoniazid, levofloxacin, and streptomycin was initiated. She continued to receive anti-tuberculosis treatment, and her state of consciousness temporarily improved. Unfortunately, she died on the 37th day of hospitalization due to gastrointestinal bleeding from the gastric cancer.\n\nDiscussion\nTuberculosis remains the 9th leading cause of death globally, with 1.3 million HIV-negative patients dying from tuberculosis in 2016. This disease is mainly prevalent in developing countries [5]. Meanwhile, in developed countries, advances of anti-tuberculosis medication and infection control measures have resulted in a decline in its incidence, but the prevalence rate of tuberculosis in Japan is still higher than in Western countries: the official estimate of incidence of tuberculous in Japan was about 13.9 per 100,000 population in 2016 [6]. Tuberculous meningitis is a particularly rare disease, with an incidence rate of 100–150 cases annually in the United States, which accounts for approximately 3% of all cases of infective meningitis and about 162 cases annually in Japan [1, 7]. The primary cause of tuberculous meningitis is reactivation due to impaired immune function, which can be attributed to aging, alcoholism, diabetes, recent steroid use, HIV infection, and other factors. Cases of concomitant malignant tumors have also been reported in a previous study [8], although, to the best of our knowledge, there was no previously reported case during chemotherapy for advanced gastric cancer.\n\nCompared with aseptic meningitis or typical bacterial meningitis, tuberculous meningitis has subacute progression and in many cases, it does not initially present with headaches or typical signs of meningeal irritation, such as neck stiffness [4]. At the early stage of onset, patients often present only with nonspecific symptoms, such as fever, loss of appetite, and fatigue, which makes early diagnosis difficult, as shown in our patient. As the disease progresses to the subacute stage, behavioral changes, drowsiness, and irritability appear and the patient gradually presents with the classic symptoms of meningitis, such as headaches, vomiting, reduced level of consciousness, meningeal irritation, and cranial nerve palsy [9]. The exact timing of disease onset was unclear in our patient, but her symptoms were limited to fever and drowsiness before admission, which are nonspecific symptoms especially in advanced cancer patients. A previous report suggested several clues to diagnose tuberculous meningitis [10]. Regarding the definitive diagnosis of Mycobacterium tuberculosis infection, a smear or culture of the cerebrospinal fluid with acid-fast bacillus staining has been found to show high specificity but a low detection sensitivity of 10–37% with smear and 43–52% with culture [11, 12, 13]. The long 4- to 8-week wait in the culturing method is also a disadvantage. The detection of M. tuberculosis gene by PCR is comparatively much faster, with a sensitivity of 60–90% and a specificity of 89–100% [14]. The timing of treatment initiation has a major impact on a patient's prognosis [3]. Therefore, not only definitive diagnosis by these tests but also probable tuberculous meningitis based on scoring clinical criteria or cerebral imaging criteria were proposed [10] to initiate empirical treatment, which might have potentially accelerated treatment in our patient.\n\nTo the best of our knowledge, this is the first report of tuberculous meningitis during chemotherapy for advanced gastric cancer. It should be noted that subacute onset of fever followed by nonspecific neurological findings, such as disturbance of consciousness, indicate the possibility of tuberculous meningitis even without typical signs including headache or meningeal irritation. Empirical therapy should be discussed based on clinical diagnosis.\n\nStatement of Ethics\nThe authors have no ethical conflicts to disclose.\n\nDisclosure Statement\nAll authors declare that there is no conflict of interest regarding the publication of this paper.\n\nFig. 1. Findings on head CT scans. a–c Head CT scans at the time of admission are within normal range considering the patient's age. d–f Head CT scans on the 14th day of hospitalization. Clear ventricular enlargement and periventricular edematous changes are seen compared with those at the time of admission.\n\nTable 1 Blood tests and cerebrospinal fluid tests during admission\n\n\tDay 1\tDay 14\tDay 19\t\nBlood tests\t\nWhite blood cell count,/µL\t8,600\t12,200\t19,800\t\nRed blood cell count, ×l04/µL\t357\t390\t303\t\nHemoglobin, g/dL\t10.6\t11.6\t9.1\t\nPlatelet count, × 104/µL\t60.8\t29.4\t21.1\t\nC-reactive protein, mg/dL\t1.34\t0.14\t8.08\t\nSodium, mEq/L\t130\t136\t155\t\nPotassium, mEq/L\t3.8\t3.3\t3.7\t\nChloride, mEq/L\t90\t94\t115\t\nCreatinine, mg/dL\t0.53\t0.37\t0.34\t\nUrea nitrogen, mg/dL\t6.3\t23.9\t38.6\t\nGlucose, mg/dL\t110\t129\t173\t\n\t\nCerebrospinal fluid tests\t\nCell count,/µL\t\t283\t1,140\t\nMononuclear cells,/µL\t\t37\t775\t\nPolymorphonuclear cells,/µL\t\t246\t366\t\nProtein, mg/dL\t\t260\t459\t\nGlucose, mg/dL\t\t54\t30\n==== Refs\nReferences\n1 Marx GE Chan ED Tuberculous meningitis: diagnosis and treatment overview. Tuberc Res Treat. 2011 2011 798764 22567269 \n2 Kamei S Takasu T Nationwide survey of the annual prevalence of viral and other neurological infections in Japanese inpatients. Intern Med. 2000 11 39 (11) 894 900 11065239 \n3 Rodrigues MG Lin J Masruha MR Vilanova LC Minett TS Prognostic factors predicting a fatal outcome in HIV-negative children with neurotuberculosis. Arq Neuropsiquiatr. 2010 10 68 (5) 755 760 21049188 \n4 Thwaites GE van Toorn R Schoeman J Tuberculous meningitis: more questions, still too few answers. Lancet Neurol. 2013 10 12 (10) 999 1010 23972913 \n5 WHO Global Tuberculosis Report 2017. \n6 Infectious Agents Surveillance Report (IASR). 2017 38 231 232 Available from: https://www.niid.go.jp/niid/ja/tuberculosis-m/tuberculosis-iasrtpc/7725-454t.html \n7 Tuberculosis Surveillance Center RIT JATA Tuberculosis annual report 2009. Series 1. Summary of TB notification statistics in 2009. Kekkaku. 2011 2 86 2 127 130 Japanese. 21404656 \n8 Berenguer J Moreno S Laguna F Vicente T Adrados M Ortega A Tuberculous meningitis in patients infected with the human immunodeficiency virus. N Engl J Med. 1992 3 326 (10) 668 672 1346547 \n9 Rodrigues MG da Rocha AJ Masruha MR Minett TS Neurotuberculosis: an overview. Cent Nerv Syst Agents Med Chem. 2011 12 11 (4) 246 260 22300226 \n10 Marais S Thwaites G Schoeman JF Török ME Misra UK Prasad K Tuberculous meningitis: a uniform case definition for use in clinical research. Lancet Infect Dis. 2010 11 10 (11) 803 812 20822958 \n11 Verdon R Chevret S Laissy JP Wolff M Tuberculous meningitis in adults: review of 48 cases. Clin Infect Dis. 1996 6 22 (6) 982 988 8783697 \n12 Thwaites G Chau TT Mai NT Drobniewski F McAdam K Farrar J Tuberculous meningitis. J Neurol Neurosurg Psychiatry. 2000 3 68 (3) 289 299 10675209 \n13 Kennedy DH Fallon RJ Tuberculous meningitis. JAMA. 1979 1 241 (3) 264 268 102806 \n14 Takahashi T Tamura M Takasu T The PCR-Based Diagnosis of Central Nervous System Tuberculosis: up to Date. Tuberc Res Treat. 2012 2012 831292 22666577\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1662-6575", "issue": "11(1)", "journal": "Case reports in oncology", "keywords": "Chemotherapy; Gastric cancer; Paclitaxel; Tuberculous meningitis", "medline_ta": "Case Rep Oncol", "mesh_terms": null, "nlm_unique_id": "101517601", "other_id": null, "pages": "228-233", "pmc": null, "pmid": "29805373", "pubdate": "2018", "publication_types": "D002363:Case Reports", "references": "20822958;22567269;21049188;11065239;10675209;22666577;8783697;1346547;22300226;21404656;23972913;102806", "title": "Tuberculous Meningitis during Chemotherapy for Advanced Gastric Cancer.", "title_normalized": "tuberculous meningitis during chemotherapy for advanced gastric cancer" }

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{ "abstract": "We present a case of a 69 year old man with phimosis associated with immunotherapy with durvalumab for metastatic non-small-cell lung cancer. The patient developed vitiligo like dermatosis after the induction dose of durvalumab, subsequent administration of the immunotherapy the patient developed a fibrous ring of the foreskin. Immune-mediated adverse reactions have been described after the use of durvalumab, but, to our knowledge, there are no reports of phimosis and vitiligo like reactions.", "affiliations": "Urology, Fundación Clínica Médica Sur, Mexico.;Immunology and Rheumatology Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico.;Health Pharma Professional Research, Mexico.;Urology, Fundación Clínica Médica Sur, Mexico.", "authors": "Vázquez-Lavista|Luis Gabriel|LG|;Llorente|Luis|L|;Alatorre-Alexander|Jorge|J|;Ramírez-Muciño|José Arturo|JA|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.eucr.2020.101350", "fulltext": "\n==== Front\nUrol Case Rep\nUrol Case Rep\nUrology Case Reports\n2214-4420 Elsevier \n\nS2214-4420(20)30239-4\n10.1016/j.eucr.2020.101350\n101350\nOncology\nPhimosis: A rare complication of immunotherapy with durvalumab\nVázquez-Lavista Luis Gabriel lugavala@gmail.coma∗ Llorente Luis b Alatorre-Alexander Jorge c Ramírez-Muciño José Arturo ad a Urology, Fundación Clínica Médica Sur, Mexico\nb Immunology and Rheumatology Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico\nc Health Pharma Professional Research, Mexico\nd Universidad Panamericana, Mexico\n∗ Corresponding author. Puente de piedra 150 (Médica Sur), Consultorio 322 Torre 1, C.P, 14050, Mexico lugavala@gmail.com\n16 7 2020 \n11 2020 \n16 7 2020 \n33 1013508 7 2020 12 7 2020 16 7 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).We present a case of a 69 year old man with phimosis associated with immunotherapy with durvalumab for metastatic non-small-cell lung cancer. The patient developed vitiligo like dermatosis after the induction dose of durvalumab, subsequent administration of the immunotherapy the patient developed a fibrous ring of the foreskin. Immune-mediated adverse reactions have been described after the use of durvalumab, but, to our knowledge, there are no reports of phimosis and vitiligo like reactions.\n\nKeywords\nDurvalumabImmunotherapyPhimosisVitiligo\n==== Body\nIntroduction\nWe present the case of an immunology related urologic complication in a patient who underwent chemotherapy and immunotherapy with durvalumab.\n\nCase presentation\nA 69 year-old man was diagnosed with metastatic non-small cell lung cancer in January 2019. He entered a protocol with pemetrexed 900 mg/100 ml, carboplatin 620 mg/AUC/500 ml and immunotherapy with Durvalumab 1500 mg/250 ml. He had partial response, with the metastatic lesions remaining stable. After several follow-up visits, on August 2019 he noticed that, after the administration of Durvalumab, the foreskin turned narrower and became hypo-pigmented with the subsequent dose. He came as an outpatient to the urologic clinic. He had had the previous Durvalumab dose 15 days before. The foreskin could only be retracted with difficulty and he had little fibrous ring. Immediately after the administration of Durvalumab, the fibrous ring became narrower and it became impossible to retract the foreskin. The phimosis was more evident two days after the administration of the immunotherapy. Fig. 1, Fig. 2.Fig. 1 Phimosis previous to the surgery, it is noteworthy the foreskin is thick and with new onset of hypo-pigmented patches.\n\nFig. 1Fig. 2 Phimosis, note the thick foreskin impossible to retract, durvalumab dosis 15 days previous to the surgery.\n\nFig. 2\n\nHe underwent circumcision with no complications. The pathology report was acanthosis with hyperkeratosis, hypergranulosis and chronic inflammatory cells that involved the dermo-epidermal junction. Fig. 3.Fig. 3 Acanthosis with hyperkeratosis, hypergranulosis and chronic inflammatory cells that involved the dermo-epidermal junction.\n\nFig. 3\n\nDiscussion\nDurvalumab is indicated in patients with unresectable stage III non-small cell lung cancer following chemo-radiotherapy.1,2 Several of the immune-mediated adverse reactions described are immune-mediated pneumonitis, hepatitis, colitis, endocrinopathies and immune-mediated dermatologic reactions. Our patient developed a vitiligo-like reaction in the foreskin, with the subsequent phimosis making circumcision necessary.\n\nVitiligo is an acquired disorder in which white patches of skin and overlying hair result from autoimmune loss of melanocytes from involved areas. A humoral immune reaction has been implicated through the detection of circulating antibodies. However, recent research focuses on a melanocyte-specific cytotoxic-T-cell immune reaction in the melanocyte destruction. Several candidate genes have been proposed for vitiligo susceptibility.3\n\nConclusion\nDurvalumab activates immune system and can enhance inflammatory reactions. Our patient developed a fibrous ring in the foreskin that was narrower where vitiligo was found. Phimosis is very common in patients with hypo-pigmented lesions of the foreskin, to our knowledge there are no reports of phimosis on patients under immunotherapy with durvalumab. We recommend that patients with known vitiligo who are candidates for this treatment must seek urologic advice to avoid complications like phimosis or the organ threatening paraphimosis.\n==== Refs\nReferences\n1 Antonia Sj Villegas A. Daniel D. Durvalumab after chemotherapy in stage III non-small-cell lung cancer N Engl J Med 377 20 2017, Nov 16 1919 1929 28885881 \n2 Mehmet C. Grauchan D. Durvalumab in stage III non-small – cell lung cancer N Engl J Med 378 9 2018 Mar 1 868 29504720 \n3 Passeron T. Ortonne J. Physiopathology and genetics of vitiligo J Autoimmun 25 Suppl 2005 63 68 Epub 2005 Nov 18\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2214-4420", "issue": "33()", "journal": "Urology case reports", "keywords": "Durvalumab; Immunotherapy; Phimosis; Vitiligo", "medline_ta": "Urol Case Rep", "mesh_terms": null, "nlm_unique_id": "101626357", "other_id": null, "pages": "101350", "pmc": null, "pmid": "33102050", "pubdate": "2020-11", "publication_types": "D002363:Case Reports", "references": "16298511;28885881;29504720", "title": "Phimosis: A rare complication of immunotherapy with durvalumab.", "title_normalized": "phimosis a rare complication of immunotherapy with durvalumab" }

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{ "abstract": "Thorough study is required to decide the appropriate management of hepatic tumors in children. We present a case report of a hepatic embryonal undifferentiated sarcoma with unfavorable prognosis in a nine-year-old girl. After undergoing a detailed cancer characteristics and extension study, a two-stage surgery approach was decided. The hepatic tumor resection was the first procedure to be performed. One week later, under cardiopulmonary bypass, deep hypothermia, and circulatory arrest, thrombectomy of the inferior vena cava and right atrium was accomplished, plus thromboendarterectomy of the right pulmonary artery. During a four-year follow-up, the patient continues to be disease-free.", "affiliations": "Department of Cardiovascular Surgery, Hospital Universitario y Politécnico La Fe, Valencia, Spain.;Department of Cardiovascular Surgery, Hospital Universitario y Politécnico La Fe, Valencia, Spain.;Department of Cardiovascular Surgery, Hospital Universitario y Politécnico La Fe, Valencia, Spain.;Department of Cardiovascular Surgery, Hospital Universitario y Politécnico La Fe, Valencia, Spain.;Department of Cardiovascular Surgery, Hospital Universitario y Politécnico La Fe, Valencia, Spain.;Department of Cardiovascular Surgery, Hospital Universitario y Politécnico La Fe, Valencia, Spain.", "authors": "Domínguez-Massa|Carlos|C|;Serrano-Martínez|Félix|F|;Blanco-Herrera|Óscar R|ÓR|;Berbel-Bonillo|Alberto|A|;Hornero-Sos|Fernando|F|;Montero-Argudo|José A|JA|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1177/2150135118775411", "fulltext": null, "fulltext_license": null, "issn_linking": "2150-1351", "issue": "11(4)", "journal": "World journal for pediatric & congenital heart surgery", "keywords": "cardiac tumors; cardiopulmonary bypass; endarterectomy; liver tumor", "medline_ta": "World J Pediatr Congenit Heart Surg", "mesh_terms": "D006348:Cardiac Surgical Procedures; D002315:Cardiopulmonary Bypass; D002648:Child; D004452:Echocardiography; D005260:Female; D006325:Heart Atria; D006338:Heart Neoplasms; D006801:Humans; D008113:Liver Neoplasms; D008279:Magnetic Resonance Imaging; D012509:Sarcoma; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "101518415", "other_id": null, "pages": "NP199-NP202", "pmc": null, "pmid": "30319025", "pubdate": "2020-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Treatment of Hepatic Embryonal Undifferentiated Sarcoma With Cardiothoracic Involvement.", "title_normalized": "treatment of hepatic embryonal undifferentiated sarcoma with cardiothoracic involvement" }

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TREATMENT OF HEPATIC EMBRYONAL UNDIFFERENTIATED SARCOMA WITH CARDIOTHORACIC INVOLVEMENT. WORLD?J?PEDIATR?CONGENIT?HEART?SURG 2020?11(4):NP199?NP202.", "literaturereference_normalized": "treatment of hepatic embryonal undifferentiated sarcoma with cardiothoracic involvement", "qualification": "1", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20200818", "receivedate": "20200818", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18160892, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "ES-BAXTER-2020BAX016223", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DACTINOMYCIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 CYCLES OF VAC REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "UNDIFFERENTIATED SARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACTINOMYCIN D" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IFOSFAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "019763", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR SOLUTION FOR INJECTION", "drugdosagetext": "4 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "UNDIFFERENTIATED SARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRONOXAL 1G INYECTABLE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 CYCLES OF VAC REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "UNDIFFERENTIATED SARCOMA", "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": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "012142", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR SOLUTION FOR INJECTION", "drugdosagetext": "5 CYCLES OF VAC REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "UNDIFFERENTIATED SARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GENOXAL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXORUBICIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "050718", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "UNDIFFERENTIATED SARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXIL" } ], "patientagegroup": null, "patientonsetage": "9", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Gastrointestinal toxicity", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anal abscess", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DOMINGUEZ?MASSA C, SERRANO?MARTINEZ F, BLANCO?HERRERA O, BERBEL?BONILLO A, HORNERO?SOS F, MONTERO?ARGUDO J. TREATMENT OF HEPATIC EMBRYONAL UNDIFFERENTIATED SARCOMA WITH CARDIOTHORACIC INVOLVEMENT. WORLD JOURNAL FOR PEDIATRIC AND CONGENITAL HEART SURGERY. 2020 JUL?11(4):NP199?NP202.", "literaturereference_normalized": "treatment of hepatic embryonal undifferentiated sarcoma with cardiothoracic involvement", "qualification": "1", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20200822", "receivedate": "20200809", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18126781, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]

{ "abstract": "Intravitreal triamcinolone and bevacizumab are emerging treatment modalities for the patients of macular oedema; however, they are known to raise intraocular pressure. A 61 year old diabetic male patient developed glaucoma after administration of triamcinolone acetonide and bevacizumab intravitreally for treatment of macular oedema. His intraocular pressure was raised up to about 42 mm Hg. Such high and sustained rise in intraocular pressure may lead to vision loss by damaging the optic nerve. The patient was managed by local as well as systematic therapy and was recovered after 1 month from the occurrence of an event. Intraocular pressure should be monitored in patients receiving intravitreal triamcinolone and bevacizumab. Risk benefit analysis must be done before using IVTA and IVB in patients with diabetic macular oedema.", "affiliations": "Department of Pharmacology, Government Medical College, Bhavnagar 364001 (Gujarat), India.", "authors": "Golakiya|Hiral N|HN|;Hirapara|Hiren N|HN|;Parmar|Sugnesh J|SJ|;Naik|Viren N|VN|;Tripathi|Chandrabhanu B|CB|", "chemical_list": "D020533:Angiogenesis Inhibitors; D005938:Glucocorticoids; D000068258:Bevacizumab; D014222:Triamcinolone Acetonide", "country": "United Arab Emirates", "delete": false, "doi": "10.2174/1574886311666160405110246", "fulltext": null, "fulltext_license": null, "issn_linking": "1574-8863", "issue": "11(3)", "journal": "Current drug safety", "keywords": null, "medline_ta": "Curr Drug Saf", "mesh_terms": "D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab; D003920:Diabetes Mellitus; D005901:Glaucoma; D005938:Glucocorticoids; D006801:Humans; D007429:Intraocular Pressure; D058449:Intravitreal Injections; D008297:Male; D008875:Middle Aged; D014222:Triamcinolone Acetonide", "nlm_unique_id": "101270895", "other_id": null, "pages": "270-1", "pmc": null, "pmid": "27048193", "pubdate": "2016", "publication_types": "D002363:Case Reports", "references": null, "title": "Triamcinolone Acetonide and Bevacizumab Induced Raised Intraocular Pressure in An Elderly Male Diabetic Patient - A Case Report.", "title_normalized": "triamcinolone acetonide and bevacizumab induced raised intraocular pressure in an elderly male diabetic patient a case report" }

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TRIAMCINOLONE ACETONIDE AND BEVACIZUMAB INDUCED RAISED INTRAOCULAR PRESSURE IN AN ELDERLY MALE DIABETIC PATIENT - A CASE REPORT.. 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TRIAMCINOLONE ACETONIDE AND BEVACIZUMAB INDUCED RAISED INTRAOCULAR PRESSURE IN AN ELDERLY MALE DIABETIC PATIENT - A CASE REPORT.. CURRENT DRUG SAFETY. 2016;11(3):270-271", "literaturereference_normalized": "triamcinolone acetonide and bevacizumab induced raised intraocular pressure in an elderly male diabetic patient a case report", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20161025", "receivedate": "20161025", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12882491, "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" } ]

{ "abstract": "To consider the potential risk of an unprovoked infectious disease, such as necrotising fasciitis, being present in patients whereby monoclonal gammopathy of undetermined significance is an active co-morbidity.", "affiliations": "University Hospital of North Tees, Stockton-on-Tees TS19 8PE, UK.;University Hospital of North Tees, Stockton-on-Tees TS19 8PE, UK.", "authors": "Vella|John X|JX|https://orcid.org/0000-0001-8443-7872;Jeavons|Richard P|RP|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1177/2054270419849352", "fulltext": "\n==== Front\nJRSM OpenJRSM OpenSHRspshrJRSM Open2054-2704SAGE Publications Sage UK: London, England 10.1177/205427041984935210.1177_2054270419849352Case ReportNecrotising fasciitis in a patient with monoclonal gammopathy of undetermined significance https://orcid.org/0000-0001-8443-7872Vella John X. Jeavons Richard P. University Hospital of North Tees, Stockton-on-Tees TS19 8PE, UKJohn X. Vella. Email: John.vella@nth.nhs.uk01 8 2019 8 2019 10 8 2054270419849352© The Author(s) 20192019The Royal Society of MedicineCreative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.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).To consider the potential risk of an unprovoked infectious disease, such as necrotising fasciitis, being present in patients whereby monoclonal gammopathy of undetermined significance is an active co-morbidity.\n\nclinicalinfectious diseasestrauma and orthopaedic surgeryedited-statecorrected-proof\n==== Body\nAbbreviations\nIgG: Immunoglobulin G, IgA: Immunoglobulin A, IgM: Immunoglobulin M, IgE: Immunoglobulin E, NaCl: Sodium Chloride, Na+: Sodium, K+: Potassium, O2: Oxygen, pO2: Partial pressure of oxygen, pCO2: Partial pressure of carbon dioxide, HCO3: Bicarbonate.\n\nCase report\nA 52-year-old man was admitted to accident and emergency following a three-day history of a painful, oedematous right hand associated with an erythematous rash which had previously been treated by his doctor with flucloxacillin for three days. On admission, the rash had worsened and covered his entire face and the proximal third of his torso but there was no evidence of regional skin hypoaesthesia, crepitus, development of haemorrhagic blisters or any gangrenous changes. The patient had a history of asthma, for which he was receiving daily steroids, bronchiectasis, chronic kidney disease (stage III), hypertension, alcoholic liver disease and monoclonal gammopathy of undetermined significance.\n\nPre-admission serum immunoglobulin levels were all elevated as follows: IgG: 16.9 g/L; IgA: 4.64 g/L; IgM: 1.09 g/L; IgE: > 5000 g/L. His baseline serum immunoglobulin levels taken in March 2016 show chronic elevation, with levels higher than that of this admission: IgG: 18.6 g/L; IgA: 4.72 g/L; IgM: 0.97 g/L; IgE: > 5000 g/L.\n\nUpon admission, the precise nature of the rash was still unclear and an allergy to flucloxacillin was not fully excluded as a contributing factor.\n\nHis observations on admission were as follows: O2 saturations: 98% on air; respiratory rate: 19; blood pressure: 101/49; heart rate: 108; capillary refill time: 4 seconds; temperature: 35.4℃; the patient’s Glasgow coma scale was 15/15, he was alert and orientated.\n\nSubsequently, the flucloxacillin was halted in case this was an anaphylactic reaction and the sepsis 6 protocol was initiated with intravenous teicoplanin, ertepenem, clindamycin, warmed 0.9% NaCL along with intramuscular adrenaline, intravenous hydrocortisone and intramuscular chlorphenamine.\n\nLaboratory studies showed:\n\nWhite blood cells: 10.9 × 109/L; haemoglobin: 136 g/L; platelets: 98 × 109/L; neutrophils: 9.6 × 109/L; C-reactive protein: 415 mg/L; urea: 15.3 mmol/L; creatinine: 284 µmol/L; Na + : 128 mmol/L; K + : 5.9 mmol/L; estimated glomerular filtration rate: 20 ml/mm/1.73 m2; bilirubin: 33 µmol/L; alanine transaminase: 25 U/L; alkaline phosphatase: 60 U/L; albumin: 28 U/L; gamma gutamyltransferase: 139 U/L; albumin: 28 g/L; prothrombin time: 13.4 seconds.\n\nWithin hours of admission, the skin rash had alarmingly spread down the patient’s back and now involved his buttocks. The patient was still alert but his O2 saturations had dropped to 90% on 15 L of oxygen and so an arterial blood gas was obtained:\n\npH: 7.15; pO2: 7.85 kPa; pCO2: 6.54 kPa; HCO3: 16.7 mEg/L; Na+: 127.4 mmol/L; K+: 5.13 mmol/L; lactate: 6.4 mmol/L; base excess: 12.1 mmol/L; glucose: 11.4 mmol/L.\n\nA laboratory risk indicator for necrotising fasciitis (LRINEC) score was calculated as 9 for this patient’s condition meaning that there was an elevated probability that the team were dealing with a case of necrotising fasciitis. A score of 9 suggests a higher mortality rate and a significantly increased amputation risk.1,2\n\nSubsequently a computed tomography scan was performed which confirmed appearances consistent with necrotising fasciitis involving the whole of the superficial fascia of the upper arm. He was taken to theatre for debridement of all the necrotic/infected tissue. Tissue culture from theatre yielded Group A beta haemolytic streptococcus. Following three more debridements and a prolonged stay in intensive treatment unit with inotropic support he recovered sufficiently to allow the plastic surgery team to begin skin grafting of the debrided areas.\nFigure 1. Coronal view of computed tomography neck/ chest/ abdomen/ pelvis showing widespread subcutaneous right arm oedema extending into the axilla.\n\n\nFigure 2. Right upper limb following initial surgical debridement.\n\n\n\nDiscussion\nThe incidence of necrotising fasciitis has increased in recent decades in several different countries. Arguably, the most concerning aspect of this is the high mortality rate that is associated with necrotising fasciitis, and this underlines the importance of identifying high-risk patients and considering the diagnosis of necrotising fasciitis early.\n\nNecrotising fasciitis may result from any major or minor injury to the skin such as needle puncture, insect bites, burns, lacerations, surgical wounds or blunt trauma that can act as an entry point for the causative organism. However, an entry point for bacteria cannot always be determined and this is also the case for our patient.\n\nCommon co-morbidities predisposing to necrotising fasciitis are diabetes mellitus, malignancies and connective tissue disorders such as rheumatoid arthritis/systemic lupus erythematosus. These conditions are treated with rheumatological immunosuppressive medications and glucocorticosteroids. The patient in this case report was taking 10 mg of prednisolone daily for asthma for several years. The association of steroid treatment with necrotising fasciitis has been reported previously.3 Angoules et al. analysed the literature on necrotising fasciitis between 1992 and 2007 and they concluded that 3% of the documented necrotising fasciitis cases were associated with corticosteroid therapy. On the contrary, there is no direct mention of an association between asthma and necrotising fasciitis.4\n\nAfter analysing 131 papers, Angoules et al. found examples in the literature indicating that chronic kidney disease was related with 3% of necrotising fasciitis cases,4 mirroring the risk caused by corticosteroids. There are other examples of case reports that indicate that there is a link between chronic kidney disease and necrotising fasciitis; however, they are usually associated with either renal transplants or haemodialysis.5,6 Despite the patient having no history of renal transplant or haemodialysis for his stage III chronic kidney disease, immunosuppression should not be overlooked as a possible predisposing factor as there are plenty of examples in the literature suggesting that chronic kidney disease itself is associated with immunosuppression.6\n\nAngoules et al. further speculated that alcoholic liver disease was a significant predisposing factor present in 17% of the cases in his review.4\n\nThe final co-morbidity that should be considered is monoclonal gammopathy of undetermined significance, a premalignant disorder involving abnormal proliferation of monoclonal plasma cells in the bone marrow. Patients with monoclonal gammopathy of undetermined significance have a lifelong risk of multiple myeloma which is associated with a median survival of 4–5 years. In 2012, Kristinsson et al. reported on a monoclonal gammopathy of undetermined significance cohort from a national hospital network in Sweden between 1965 and 2005 that compared 5326 monoclonal gammopathy of undetermined significance patients and 20,161 population matched controls. Patients with monoclonal gammopathy of undetermined significance in his study had a 2.1-fold (95% confidence interval: 2.0–2.3) increased risk of developing bacterial infections (osteomyelitis, septicaemia, pyelonephritis, cellulitis, endocarditis and meningitis) and viral infections (influenza and herpes zoster) (p < 0.05). At 5 - to 10-year follow-up, 377 monoclonal gammopathy of undetermined significance patients (7.1%) were found to have more than one infection compared to 550 control patients (2.3%) during the same period of time.7 An earlier and smaller study was conducted in Denmark by Gregersen et al. which similarly found that patients with monoclonal gammopathy of undetermined significance have a two-fold increased risk of suffering with bacterial infections.8\n\nThe predisposition to infection in monoclonal gammopathy of undetermined significance patients may be associated with a defective polyclonal immunoglobulin antibody response. Similar defects are observed in patients with multiple myeloma and Waldenström macroglobulinemia.9,10 There are numerous reports of patients with multiple myeloma developing infections including necrotising fasciitis11 but a direct connection with monoclonal gammopathy of undetermined significance has not been reported despite there being examples of patients in case reports suffering with monoclonal gammopathy of undetermined significance and contracting necrotising fasciitis.12\n\nConclusions\nOur case raises the possibility that monoclonal gammopathy of undetermined significance, which is considered a precursor of multiple myeloma, can also lead to necrotising fasciitis, although because of the simultaneous presence of additional predisposing factors, a definitive connection cannot be made based on our case alone.\n\nAcknowledgements\nThe authors thank Roisin Bevan for her ongoing support and advice.\n\nDeclarations\nCompeting Interests\nNone declared.\n\nFunding\nNone declared.\n\nEthics approval\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nGuarantor\nJXV\n\nContributorship\nJXV: Conception, research and design of the case report; obtaining informed consent from patient; first draft of case report; revision and subsequent final approval of the version to be submitted. RPJ: Guidance throughout and subsequent final approval of the version to be submitted.\n\nProvenance\nNot commissioned; peer-reviewed by Daniel Marks.\n==== Refs\nReferences\n1 Wong CH, Khin LW, Heng KS, Tan KC and Low CO. The LRINEC (Laboratory Risk Indicator for Necrotizing Fasciitis) score: a tool for distinguishing necrotizing fasciitis from other soft tissue infections. Crit Care Med 2004; 32: 1535–1541 .\n2 Liao CI Lee YK Su YC Chuang CH Wong CH \nValidation of the laboratory risk indicator for necrotizing fasciitis (LRINEC) score for early diagnosis of necrotizing fasciitis . Tzu Chi Med J \n2012 ; 24 : 73 –76 .\n3 Coutinho AE Chapman KE \nThe anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights . Mol Cell Endocrinol \n2011 ; 335 : 2 –13 .20398732 \n4 Angoules AG Kontakis G Drakoulakis E Vrentzos G Granick MS Giannoudis PV \nNecrotising fasciitis of upper and lower limb: a systematic review . Injury \n2007 ; 38 : S19 –S26 .\n5 Imhof A Maggiorini M Zbinden R Walter RB \nFatal necrotizing fasciitis due to Streptococcus pneumoniae after renal transplantation . Nephrol Dial Transplant \n2003 ; 18 : 195 –197 .12480983 \n6 Naqvi SB Collins AJ \nInfectious complications in chronic kidney disease . Adv Chronic Kidney Dis \n2006 ; 13 : 199 –204 .16815225 \n7 Kristinsson SY Tang M Pfeiffer RM Bjorkholm M Goldin LR Blimark C \nMonoclonal gammopathy of undetermined significance and risk of infections: a population-based study . Haematologica \n2012 ; 97 : 854 –858 .22180421 \n8 Gregersen H Madsen KM Sorensen HT Schonheyder HC Ibsen JS Dahlerup JF \nThe risk of bacteremia in patients with monoclonal gammopathy of undetermined significance . Eur J Haematol \n1998 ; 61 : 140 –144 .9714528 \n9 Broder S Humphrey R Durm M Blackman M Meade B Goldman C , et al.\nImpaired synthesis of polyclonal (non-paraprotein) immunoglobulins by circulating lymphocytes from patients with multiple myeloma. Role of suppressor cells . N Engl J Med \n1975 ; 293 : 887 –892 .1080834 \n10 Hunter ZR Manning RJ Hanzis C Ciccarelli BT Ioakimidis L Patterson CJ , et al.\nIgA and IgG hypogammaglobulinemia in Waldenstrom's macroglobulinemia . Haematologica \n2010 ; 95 : 470 –475 .19903677 \n11 Mondello P Pitini V Arrigo C Mondello S Mian M Altavilla G \nNecrotizing fasciitis as a rare complication of osteonecrosis of the jaw in a patient with multiple myeloma treated with lenalidomide: case report and review of the literature . Springerplus \n2014 ; 3 : 123 –123 .24711984 \n12 Dapunt U Klingmann A Schmidmaier G Moghaddam A \nNecrotising fasciitis . BMJ Case Rep \n2013 \npii: bcr2013201906 .\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2054-2704", "issue": "10(8)", "journal": "JRSM open", "keywords": "clinical; infectious diseases; trauma and orthopaedic surgery", "medline_ta": "JRSM Open", "mesh_terms": null, "nlm_unique_id": "101625786", "other_id": null, "pages": "2054270419849352", "pmc": null, "pmid": "31413855", "pubdate": "2019-08", "publication_types": "D002363:Case Reports", "references": "1080834;12480983;15241098;16815225;18048033;19903677;20398732;22180421;24326439;24711984;9714528", "title": "Necrotising fasciitis in a patient with monoclonal gammopathy of undetermined significance.", "title_normalized": "necrotising fasciitis in a patient with monoclonal gammopathy of undetermined significance" }

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{ "abstract": "A 26-year-old male vitiliginous patient presented with decreased visual acuity because of a central scotoma in the left eye with no significant retinal changes on fundus examination. In this case report, a diagnosis of possible drug-induced premaculopathy was made, and the drugs were withdrawn. On the follow-up, after 3 months, the visual acuity in the left eye gradually improved. Early suspicion of drug-induced maculopathy and withdrawal of the drug may prevent the progression of maculopathy.", "affiliations": "Department of Ophthalmology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India.;Department of Ophthalmology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India.", "authors": "Kasturi|Nirupama|N|;Srinivasan|Renuka|R|", "chemical_list": null, "country": "India", "delete": false, "doi": "10.4103/0976-500X.189685", "fulltext": "\n==== Front\nJ Pharmacol PharmacotherJ Pharmacol PharmacotherJPPJournal of Pharmacology & Pharmacotherapeutics0976-500X0976-5018Medknow Publications & Media Pvt Ltd India JPP-7-14910.4103/0976-500X.189685Case ReportClofazimine-induced premaculopathy in a vitiliginous patient Kasturi Nirupama Srinivasan Renuka Department of Ophthalmology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, IndiaAddress for correspondence: Nirupama Kasturi, Department of Ophthalmology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry - 605 006, India. E-mail: kasturiniru@gmail.comJul-Sep 2016 7 3 149 151 28 4 2016 09 7 2016 15 7 2016 Copyright: © Journal of Pharmacology and Pharmacotherapeutics2016This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.A 26-year-old male vitiliginous patient presented with decreased visual acuity because of a central scotoma in the left eye with no significant retinal changes on fundus examination. In this case report, a diagnosis of possible drug-induced premaculopathy was made, and the drugs were withdrawn. On the follow-up, after 3 months, the visual acuity in the left eye gradually improved. Early suspicion of drug-induced maculopathy and withdrawal of the drug may prevent the progression of maculopathy.\n\nKey words\nCentral scotomaclofazimine drug toxicitymaculopathy\n==== Body\nINTRODUCTION\nClofazimine is a drug used to treat leprosy and mycobacterium avium infections. It is well tolerated when the dose does not exceed 100mg/day. Clofazimine is known to cause conjunctival and corneal pigmentation but drug induced retinopathy is rare. It is to be used with caution in immunocompromised individuals and patients taking other drugs due to its toxic effects on the eye.\n\nCASE REPORT\nA 26-year-old nonimmunocompromised male presented with a history of blurring of vision in the left eye for 8 months. He was diagnosed with vitiligo and under oral therapy with clofazimine 100 mg/week and methoxsalen 10 mg/day along with some herbal products for 1 year. Ocular examination revealed a drop in the best-corrected Snellen visual acuity by 5 lines in the left eye with prolonged photostress recovery time indicating a maculopathy. Visual examination was normal in the right eye. Fundus examination in the left eye was within normal limits [Figure 1a and b]. Fluorescein angiography did not reveal any abnormalities in the retina. [Figure 1c and d]. Color vision discrimination was low in both eyes. Visual field analysis of the macula was normal in the right eye and showed a central scotoma in the left eye [Figure 2]. A diagnosis of possible drug-induced premaculopathy was made using the WHO causality assessment and scoring of 3 using the Naranjo's scale. The patient was referred to his treating dermatologist for withdrawal of the drugs. Other causes of central scotoma such as multiple sclerosis, optic nerve glioma, toxic, nutritional, and hereditary optic neuropathies were ruled out with detailed history and investigations. On follow-up after 3 months with discontinuation of clofazimine, methoxsalen, and the herbal products, the visual acuity in the left eye improved. Photostress recovery time decreased with improvement in the color vision discrimination scores. Visual field analysis was normal in the right eye and showed reduction in the size and density of the central scotoma in the left eye [Figure 3].\n\nFigure 1 (a and b) Fundus photograph of the right and left eyes showing normal macula (c and d) Fundus fluorescein angiography in both eyes\n\nFigure 2 Visual field macula analysis showing central scotoma in the left eye\n\nFigure 3 Visual field macula analysis showing reduction in the size and density of central scotoma in the left eye\n\nDISCUSSION\nClofazimine is an iminophenazine drug with antimycobacterial and anti-inflammatory activities and it is used for the treatment of lepromatous leprosy, dapsone-resistant leprosy, and Mycobacterium avium complex infections in patients with acquired immunodeficiency syndrome (AIDS).[1]\n\nIt causes an increase in both the number of strata of pigment-bearing cells and the density of the pigment in stratum germinativum of the skin. Later, melanocytes rupture, with the release of their melanin content into the papillary layer of the dermis.[2] This property of clofazimine to stimulate melanogenesis prompted the use of this drug in patients with established vitiligo, pyoderma gangrenosum, and discoid lupus in an attempt to restore pigment to the affected skin.\n\nAfter several months of treatment, clofazimine crystals may accumulate in the ocular tissues and cause side effects such as cornea verticillata, brownish discoloration of the conjunctiva and tears, crystals in the iris and sclera, and toxic retinopathy.[3] Clofazimine-induced retinopathy have been reported in two patients with AIDS following a higher dose of 200 mg/day.[45] Unlike the two previously mentioned cases, in the present case study, the patient received a lower dose, was not immunocompromised, and had a unilateral presentation. Methoxsalen is a psoralen drug used to treat psoriasis, eczema, vitiligo, and some cutaneous lymphomas in conjunction with exposing the skin to ultraviolet A light from lamps or sunlight. Photosensitization in ducklings has shown vacuolization of retinal ganglion cells, pigmentary retinopathy, and congestion of choroidal vessels.[6] It is plausible that in our patient, methoxsalen being a photosensitizing drug may interact with clofazimine, making the macula more sensitive to light-induced damage as the drug is reported to be very safe in the usual doses in nonimmunocompromised adults.[7] The appearance of central scotoma before visible changes in the fundus suggests that the initial site of damage is in the outer segment of the photoreceptors, which is then followed by degeneration of the retinal pigment epithelium (RPE) and choriocapillaris. Fundus autofluorescence imaging and multifocal electroretinogram although not available in our setup have been used to detect early retinal changes in drug-induced retinopathy.[8]\n\nCONCLUSION\nAccumulation of clofazimine in RPE in the outer retina with phototoxic damage and reduction of photoreceptors leads to maculopathy. Ophthalmologists should be aware of this entity in spite of its unilateral presentation. Early suspicion and withdrawal of the drug may result in reversibility of the retinal side effects and prevents the progression of maculopathy.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Woolons A Black MM Wakelin SH Howard IM Clofazimine Handbook of Systemic Drug Treatment in Dermatology 2004 1st ed USA Manson Publishing Ltd. 101 4 \n2 Bor S Clofazimine (lamprene) in the treatment of vitiligo S Afr Med J 1973 47 1451 4 4725625 \n3 Agarwal A Clofazimine retinopathy. Toxic diseases affecting the pigment epithelium and retina Gass’ Atlas of Macular Diseases 2011 Vol. 1 5th ed US Elsevier Health Sciences 764 Ch. 9 \n4 Cunningham CA Friedberg DN Carr RE Clofazimine-induced generalized retinal degeneration Retina 1990 10 131 4 2402554 \n5 Craythorn JM Swartz M Creel DJ Clofazimine-induced bull's-eye retinopathy Retina 1986 6 50 2 3704351 \n6 Barishak YR Beemer AM Egyed MN Shlosberg A Eilat A Histology of the iris in geese and ducks photosensitized by ingestion of Ammi majus seeds Acta Ophthalmol (Copenh) 1975 53 585 90 1242280 \n7 Kumar B Kaur S Kaur I Gangowar DN More about clofazimine – 3 years experience and review of literature Indian J Lepr 1987 59 63 74 3611862 \n8 Kellner U Renner AB Tillack H Fundus autofluorescence and mfERG for early detection of retinal alterations in patients using chloroquine/hydroxychloroquine Invest Ophthalmol Vis Sci 2006 47 3531 8 16877425\n\n", "fulltext_license": "CC BY-NC-SA", "issn_linking": "0976-500X", "issue": "7(3)", "journal": "Journal of pharmacology & pharmacotherapeutics", "keywords": "Central scotoma; clofazimine drug toxicity; maculopathy", "medline_ta": "J Pharmacol Pharmacother", "mesh_terms": null, "nlm_unique_id": "101552113", "other_id": null, "pages": "149-51", "pmc": null, "pmid": "27651714", "pubdate": "2016", "publication_types": "D002363:Case Reports", "references": "16877425;3611862;1242280;4725625;3704351;2402554", "title": "Clofazimine-induced premaculopathy in a vitiliginous patient.", "title_normalized": "clofazimine induced premaculopathy in a vitiliginous patient" }

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CLOFAZIMINE-INDUCED PREMACULOPATHY IN A VITILIGINOUS PATIENT. JOURNAL OF PHARMACOLOGY AND PHARMACOTHERAPEUTICS. 2016;7(3):149-51", "literaturereference_normalized": "clofazimine induced premaculopathy in a vitiliginous patient", "qualification": "3", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20160928", "receivedate": "20160928", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12789759, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" }, { "companynumb": "IN-BAUSCH-BL-2016-024062", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLOFAZIMINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "VITILIGO", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2014", "drugstartdateformat": "602", "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOFAZIMINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOXSALEN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "009048", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "VITILIGO", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2014", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOXSALEN." } ], "patientagegroup": null, "patientonsetage": "26", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Maculopathy", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "KASTURI N, SRINIVASAN R. CLOFAZIMINE-INDUCED PREMACULOPATHY IN A VITILIGINOUS PATIENT. JOURNAL OF PHARMACOLOGY AND PHARMACOTHERAPEUTICS. 2016;7:149-151.", "literaturereference_normalized": "clofazimine induced premaculopathy in a vitiliginous patient", "qualification": "3", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20161028", "receivedate": "20161005", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12809402, "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": "Vanishing bile duct syndrome (VBDS) refers to a group of disorders characterized by prolonged cholestasis as a result of destruction and disappearance of intrahepatic bile ducts. Multiple etiologies have been indentified including infections, neoplastic disorders, autoimmune conditions and drugs. The natural history of this condition is variable and may involve resolution of cholestasis or progression with irreversible damage. VBDS is extremely rare in human immunodeficiency virus (HIV)-infected patients and anti-retroviral therapy has never been implicated as a cause. We encountered a young pregnant female with HIV and VBDS secondary to anti-retroviral therapy. Here, we report her clinical course and outcome.", "affiliations": "Division of Gastroenterology, Hepatology and Nutrition, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA. rajankochar@gmail.com", "authors": "Kochar|Rajan|R|;Nevah|Moises I|MI|;Lukens|Frank J|FJ|;Fallon|Michael B|MB|;Machicao|Victor I|VI|", "chemical_list": "D019380:Anti-HIV Agents; D019829:Nevirapine", "country": "United States", "delete": false, "doi": "10.3748/wjg.v16.i26.3335", "fulltext": null, "fulltext_license": null, "issn_linking": "1007-9327", "issue": "16(26)", "journal": "World journal of gastroenterology", "keywords": null, "medline_ta": "World J Gastroenterol", "mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D001649:Bile Duct Diseases; D001653:Bile Ducts, Intrahepatic; D002780:Cholestasis, Intrahepatic; D005260:Female; D015658:HIV Infections; D006801:Humans; D019829:Nevirapine; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D013577:Syndrome", "nlm_unique_id": "100883448", "other_id": null, "pages": "3335-8", "pmc": null, "pmid": "20614492", "pubdate": "2010-07-14", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "11669021;11994412;17906981;10824944;18615121;3057064;2047885;2229999;17944694;7982642;15062202;6609104;19418576;18242505;11374701;17305935", "title": "Vanishing bile duct syndrome in human immunodeficiency virus: nevirapine hepatotoxicity revisited.", "title_normalized": "vanishing bile duct syndrome in human immunodeficiency virus nevirapine hepatotoxicity revisited" }

[ { "companynumb": "US-CIPLA LTD.-2021US02334", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ZIDOVUDINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078349", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST HIV INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZIDOVUDINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "NEVIRAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST HIV INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NEVIRAPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VITAMINS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "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": "MULTIVITAMINS [VITAMINS NOS]" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST HIV INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMIVUDINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FOLIC ACID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "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": "FOLIC ACID." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vanishing bile duct syndrome", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2009" } }, "primarysource": { "literaturereference": "KOCHAR R, NEVAH MI, LUKENS FJ, FALLON MB, MACHICAO VI.. VANISHING BILE DUCT SYNDROME IN HUMAN IMMUNODEFICIENCY VIRUS: NEVIRAPINE HEPATOTOXICITY REVISITED. WORLD JOURNAL OF GASTROENTEROLOGY. 2010?16 (26):3335 TO 3338", "literaturereference_normalized": "vanishing bile duct syndrome in human immunodeficiency virus nevirapine hepatotoxicity revisited", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210331", "receivedate": "20210331", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19078381, "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": "Tumor lysis syndrome (TLS) is a rare but life-threatening phenomenon that occurs mainly in patients with aggressive hematologic or highly chemotherapy sensitive solid tumors such as high-grade neuroendocrine carcinoma or testicular cancer. Tumor lysis syndrome is exceedingly rare in hormone receptor-positive, HER2-negative breast cancer. Furthermore, TLS following treatment with alpelisib, a novel phosphatidylinositol 3-kinase (PI3K) inhibitor used to treat PIK3CA-mutated (gene encoding p110α subunit of PI3K), hormone receptor positive advanced breast cancer, has never been described in patients with nonhematologic malignancies.\nIn the following case, we present a patient with hormone receptor-positive, HER2-negative, PIK3CA-mutated metastatic breast cancer who developed TLS 12 days after starting fulvestrant and alpelisib.\nPatient was promptly treated with improvement in her renal function to baseline without requiring renal replacement therapy. Alpelisib was resumed at a reduced dose with no further complications.\nThrough this case, we discuss the potential complications of TLS and the importance of prompt recognition and treatment.", "affiliations": "Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA.;Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.;Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA.;Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA.;Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.;Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.;Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.;Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.;Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.", "authors": "Handy|Caitlin|C|;Wesolowski|Robert|R|;Gillespie|Michelle|M|https://orcid.org/0000-0002-1813-5443;Lause|Michael|M|https://orcid.org/0000-0001-6373-7956;Sardesai|Sagar|S|;Williams|Nicole|N|;Grimm|Michael|M|;Kassem|Mahmoud|M|;Ramaswamy|Bhuvaneswari|B|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1177/11782234211037421", "fulltext": "\n==== Front\nBreast Cancer (Auckl)\nBreast Cancer (Auckl)\nBCB\nspbcb\nBreast Cancer : Basic and Clinical Research\n1178-2234\nSAGE Publications Sage UK: London, England\n\n10.1177/11782234211037421\n10.1177_11782234211037421\nCase Report\nTumor lysis Syndrome in a Patient with Metastatic Breast Cancer Treated with Alpelisib\nHandy Caitlin 1*\nWesolowski Robert 2*\nhttps://orcid.org/0000-0002-1813-5443\nGillespie Michelle 1\nhttps://orcid.org/0000-0001-6373-7956\nLause Michael 1\nSardesai Sagar 2\nWilliams Nicole 2\nGrimm Michael 2\nKassem Mahmoud 2\nRamaswamy Bhuvaneswari 2\n1 Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA\n2 Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA\nBhuvaneswari Ramaswamy, Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, 43212, USA. Email: bhuvaneswari.ramaswamy@osumc.edu\n* Both authors contributed to this work equally.\n\n29 8 2021\n2021\n15 1178223421103742123 12 2020\n7 7 2021\n© The Author(s) 2021\n2021\nSAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons Licenses\nhttps://creativecommons.org/licenses/by-nc/4.0/ This 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 page (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nPurpose:\n\nTumor lysis syndrome (TLS) is a rare but life-threatening phenomenon that occurs mainly in patients with aggressive hematologic or highly chemotherapy sensitive solid tumors such as high-grade neuroendocrine carcinoma or testicular cancer. Tumor lysis syndrome is exceedingly rare in hormone receptor-positive, HER2-negative breast cancer. Furthermore, TLS following treatment with alpelisib, a novel phosphatidylinositol 3-kinase (PI3K) inhibitor used to treat PIK3CA-mutated (gene encoding p110α subunit of PI3K), hormone receptor positive advanced breast cancer, has never been described in patients with nonhematologic malignancies.\n\nMethods:\n\nIn the following case, we present a patient with hormone receptor-positive, HER2-negative, PIK3CA-mutated metastatic breast cancer who developed TLS 12 days after starting fulvestrant and alpelisib.\n\nResults:\n\nPatient was promptly treated with improvement in her renal function to baseline without requiring renal replacement therapy. Alpelisib was resumed at a reduced dose with no further complications.\n\nConclusion:\n\nThrough this case, we discuss the potential complications of TLS and the importance of prompt recognition and treatment.\n\nAlpelisib\ntumor lysis syndrome (TLS)\nmetastatic breast cancer (MBC)\noncology\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\npmcIntroduction\n\nTumor lysis syndrome (TLS) is the constellation of metabolic derangements associated with extensive tumor lysis and represents an oncologic emergency. Characterized by hyperuricemia, hyperphosphatemia, hyperkalemia, and hypocalcemia, TLS can cause acute renal injury due to the precipitation of uric acid crystals in the renal tubules. In addition, severe electrolyte derangements predispose to cardiac dysrhythmias, seizures, and sudden cardiac death. Tumor lysis syndrome is more commonly a complication of treatment of hematologic malignancies, but there are rare cases reported in adult solid tumors, in particular in patients with poorly differentiated neuroendocrine carcinoma and testicular cancer.1,2 Aggressive intravenous (IV) fluid resuscitation and correction of electrolyte abnormalities such as hyperkalemia are essential to management in the acute setting.2 Urate lowering therapy with rasburicase (recombinant urate oxidase) and xanthine oxidase inhibitors, such as allopurinol, can reduce the risk of further renal damage through uric acid crystal deposition. Occasionally, hemodialysis may be required in patients who are refractory to the above strategies.\n\nAlpelisib is a novel orally bioavailable inhibitor of p110α subunit of phosphoinositol-3-kinase (PIK3CA) used in the treatment of patients with PIK3CA-mutated, hormone receptor positive (HR+), HER2-negative advanced breast cancer.3 Recent phase-III SOLAR-1 trial demonstrated a progression-free survival of 11.0 months (95% confidence interval [CI], 7.5-14.5) in previously treated patients with metastatic hormone receptor-positive, PIK3CA-mutated breast cancer who received fulvestrant and alpelisib as their subsequent therapy, as compared with 5.7 months (95% CI, 3.7-7.4) in the placebo-fulvestrant group.3 Frequent adverse effects were hyperglycemia (36.6% in the alpelisib-fulvestrant group vs 0.7% in the placebo-fulvestrant group) and diarrhea (6.7% vs 0.7%), but grade 3 or greater nephrotoxicity was less frequently reported (2.8% vs 0.7%). Moreover, there were no reported cases of hyperuricemia or TLS.3\n\nWhile prompt recognition and treatment are essential to successful patient outcomes, TLS is an exceedingly rare and underrecognized phenomenon in HR+, HER2-negative breast cancer. We report here for the first time a case of TLS in the setting of metastatic breast cancer treated with alpelisib.\n\nCase Description\n\nThe patient is a 66-year-old woman with HR+, PIK3CA mutation-positive (E542K), breast cancer metastatic to bone, brain, peritoneum, pleura, and liver and a baseline Eastern Cooperative Oncology Group performance status of 1. Her oncologic course was complicated by the development of new brain metastases while receiving letrozole and palbociclib. Twenty-one days after completing brain radiation, patient’s systemic therapy was changed to fulvestrant and alpelisib. Twelve days following the start of this therapy, she presented to the hospital with altered mental status. Her mental status had worsened over the preceding days and on admission, she endorsed hallucinations. The patient also had asterixis on a physical examination. The results of patient’s blood work were notable for creatinine of 15.15 (baseline < 1.0), blood urea nitrogen (BUN) of 129 (baseline 14), uric acid 16.2 (baseline unknown), lactate dehydrogenase (LDH) 226, phosphate of 8.2 (baseline 2.1), potassium of 8.2 (baseline 3.9), and glucose of 124 (baseline 111, Table 1). Electrocardiogram showed widening of the QRS complex with acute T-wave changes (Figure 1) that resolved after electrolyte normalization (Figures 2 and 3). Renal ultrasound did not demonstrate obstructive uropathy. Urinalysis revealed amorphous and calcium oxalate crystals. She received aggressive fluid hydration and was started on allopurinol and rasburicase within the first 12 hr of her hospital course. She developed worsening hypotension and decreased urine output requiring transfer to the intensive care unit (ICU). Rheumatologic testing including C3, C4, antinuclear antibody (ANA), rheumatoid factor (RF) levels, hepatitis serologies, and serum/urine protein electrophoresis (SPEP/UPEP) were within normal limits. Her hypotension, mental status, and urine output slowly improved without requiring renal replacement therapy. Creatinine continued to downtrend and normalized to 1.00 on hospital day 6 (Table 1 and Figure 4). All other clinically significant laboratory abnormalities also resolved (Figure 4). After discharge, alpelisib was resumed at a reduced dose of 250 mg daily which was well tolerated. Repeat staging scans after 2 cycles of fulvestrant and alpelisib showed a mixed response with stable diffuse osseous and peritoneal metastatic disease, progression of pleural metastases, and resolution of liver metastasis.\n\nTable 1. Blood work during hospitalization showing elevated uric acid, elevated lactate dehydrogenase, acute renal failure, and electrolyte abnormalities consistent with tumor lysis syndrome.\n\n\tReference range\tBaseline prior to alpelisib (12 days prior to admission)\tAdmission (hospital day 0)\tICU transfer (hospital day 1)\tDischarge (hospital day 6)\t\nSodium\t133-143 mmol/L\t133\t125\t129\t140\t\nPotassium\t3.5-5.0 mmol/L\t3.9\t8.2\t6.0\t3.2\t\nBUN\t7-22 mg/dL\t14\t129\t114\t47\t\nCreatinine\t0.5-1.2 mg/dL\t0.69\t15.15\t13.83\t1.00\t\nGlucose\t70-99 mg/dL\t111\t124\t152\t85\t\nAlbumin\t3.5-5.0 g/dL\t3.8\t3.8\t3.8\t3.4\t\nCalcium\t8.6-10.5 mg/dL\t9.6\t9.0\t8.5\t8.8\t\nPhosphate\t2.2-4.6 mg/dL\t2.1\t8.2\t6.2\t2.9\t\nUric acid\t2.8-6.0 mg/dL\tUnknown\t16.2\t3.8\t<1.5\t\nLactate dehydrogenase\t100-190 U/L\tUnknown\t226\t190\t177\t\nAbbreviations: BUN, blood urea nitrogen; ICU, intensive care unit.\n\nFigure 1. Twelve-lead electrocardiogram (ECG) of the patient. ECG showed wide QRS complexes and peaked T waves consistent with hyperkalemia at the time of patient’s admission to the hospital.\n\nFigure 2. Peaked T waves resolved after the patient’s potassium normalized following treatment.\n\nFigure 3. Electrocardiogram (ECG) after resumption of alpelisib. Remains at baseline without return of acute T wave abnormalities.\n\nFigure 4. Graphic representation of trends in potassium (A), phosphate (B), creatinine (C), uric acid (D), and lactate dehydrogenase (E) during patient’s hospitalization.\n\nDiscussion\n\nWhile TLS remains a rare complication in the treatment of solid tumor malignancies, there have been no reported cases in the setting of PI3K inhibitors in patients with nonhematologic malignancies.1,2 Rare cases of TLS in metastatic breast cancer are predominantly those treated with cytotoxic chemotherapy. Alpelisib has never before been implicated as a causative agent TLS. This case of TLS cannot be correlated to central nervous system (CNS) penetration as this patient received radiation therapy 20 days prior to initiating alpelisib, it would be difficult to quantify degree of CNS response to alpelisib. Breast cancer is a very radiosensitive malignancy and hence the previous radiation was likely a big contributor to response in the CNS. Although there was likely a component of volume depletion contributing to renal decline in this patient, the combination of laboratory abnormalities at the time of presentation and rapid improvement with uric acid lowering therapy and volume expansion are consistent with TLS. In addition, the patient met the Cairo-Bishop definition of laboratory TLS and grade-IV clinical TLS.4 She did not have any arrhythmias during her stay but did have acute T wave changes as demonstrated in Figure 1. Given that these resolved with the resolution of metabolic derangements, this was unlikely to be due to alpelisib alone. While the patient did receive radiation for new brain metastases, treatment was completed about 4 to 5 weeks prior to presentation making this an unlikely precipitating factor. The patient in this case had additional risk factors for TLS including large disease burden and low volume state given her poor oral intake in the days leading up to hospitalization.5 This case illustrates the need to include TLS on the list of differential diagnosis for a patient with metastatic, HR+ breast cancer treated with alpelisib and presenting with acute renal insufficiency associated with electrolyte derangement.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nAuthor Contributions: All authors contributed to the study conception and design. Material preparation,and analysis were performed by Caitlin Handy, Robert Wesolowski, Michelle Gillespie, Michael Lause, Sagar Sardesai, Nicole Williams, Michael Grimm, Mahmoud Kassem and Bhuvaneswari Ramaswamy. The first draft of the manuscript was written by Caitlin Handy and Robert Wesolowski, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\n\nORCID iDs: Michelle Gillespie https://orcid.org/0000-0002-1813-5443\n\nMichael Lause https://orcid.org/0000-0001-6373-7956\n==== Refs\nReferences\n\n1 Taira F Horimoto Y Saito M. Tumor lysis syndrome following trastuzumab for breast cancer: a case report and review of the literature. Breast Cancer. 2015;22 :664-668.23420376\n2 Mirrakhimov AE Ali AM Khan M Barbaryan A. Tumor lysis syndrome in solid tumors: an up to date review of the literature. Rare Tumors. 2014;6 :68-76.\n3 Rugo HS Andre F Rubovszky G , et al . A phase 3 study of alpelisib (ALP) plus fulvestrant (FUL) in men and postmenopausal women with hormone receptor-positive (HR plus), human epidermal growth factor receptor 2-negative (HER2-) ABC progressing on or after aromatase inhibitor (AI) therapy: SOLAR-1. J Clin Oncol. 2017;35 :5.\n4 Cairo MS Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol. 2004;127 :3-11.15384972\n5 Cairo MS Coiffier B Reiter A Younes A , TLS Expert Panel. Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus. Br J Haematol. 2010;149 :578-586.20331465\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1178-2234", "issue": "15()", "journal": "Breast cancer : basic and clinical research", "keywords": "Alpelisib; metastatic breast cancer (MBC); oncology; tumor lysis syndrome (TLS)", "medline_ta": "Breast Cancer (Auckl)", "mesh_terms": null, "nlm_unique_id": "101474356", "other_id": null, "pages": "11782234211037421", "pmc": null, "pmid": "34483661", "pubdate": "2021", "publication_types": "D002363:Case Reports", "references": "15384972;20331465;23420376;25002953", "title": "Tumor lysis Syndrome in a Patient with Metastatic Breast Cancer Treated with Alpelisib.", "title_normalized": "tumor lysis syndrome in a patient with metastatic breast cancer treated with alpelisib" }

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{ "abstract": "A 10-year-old female with Williams Syndrome (WS) presented with a two-month history of fatigue, weight loss, and bilateral ovarian masses. Histologic, immunophenotypic, and cytogenetic studies confirmed the diagnosis of Burkitt lymphoma (BL). While there is no established association between the two disorders, this is the third case in the literature of Burkitt lymphoma in a patient with Williams Syndrome.", "affiliations": "Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.", "authors": "Onimoe|Grace Ifeyinwa|GI|;Kahwash|Samir|S|;Termuhlen|Amanda|A|;Gross|Thomas G|TG|;Varga|Elizabeth|E|;Rose|Melissa J|MJ|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1155/2011/327263", "fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 2168753710.1155/2011/327263Case ReportBilateral Burkitt Lymphoma of the Ovaries: A Report of a Case in a Child with Williams Syndrome Onimoe Grace Ifeyinwa \n1, 2\n\nKahwash Samir \n1, 3\n\nTermuhlen Amanda \n1, 2\n\nGross Thomas G. \n1, 2\n\nVarga Elizabeth \n1, 2\n\nRose Melissa J. \n1, 2\n\n*1Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA2Department of Pediatric Hematology-Oncology, Nationwide Children' Hospital, Columbus, OH 43205, USA3Department of Pathology, College of Medicine, The Ohio State University, Columbus, OH 43210, USA*Melissa J. Rose: melissa.rose@nationwidechildrens.orgAcademic Editor: Cherie H. Dunphy\n\n2011 26 5 2011 2011 32726331 1 2011 29 3 2011 4 4 2011 Copyright © 2011 Grace Ifeyinwa Onimoe et al.2011This 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.A 10-year-old female with Williams Syndrome (WS) presented with a two-month history of fatigue, weight loss, and bilateral ovarian masses. Histologic, immunophenotypic, and cytogenetic studies confirmed the diagnosis of Burkitt lymphoma (BL). While there is no established association between the two disorders, this is the third case in the literature of Burkitt lymphoma in a patient with Williams Syndrome.\n==== Body\n1. Introduction\nAlthough relatively rare in adults, Burkitt lymphoma constitutes more than 40% of pediatric non-Hodgkin lymphomas (NHL). The World Health Organization (WHO) classification (2008) recognizes three clinical subtypes: endemic, sporadic, and immunodeficiency associated. In the Western Hemisphere, most cases present in the gastrointestinal tract. Cases involving the jaw, kidneys, breasts, and other sites are common, including bilateral involvement [1].\n\nWilliams Syndrome (also known as Williams-Beuren Syndrome) is a rare genetic disorder with an incidence of one per 7,500–20,000 births; most cases occurring sporadically. Clinical characteristics of Williams Syndrome are growth and mental retardation with a friendly, outgoing personality, dysmorphic facial features, hypercalcemia in early infancy, and congenital cardiovascular malformations, in particular supravalvular aortic stenosis [2]. Williams Syndrome is the consequence of an interstitial microdeletion at 7q11.23, which includes the elastin gene producing hemizygosity at the elastin gene locus.\n\nWe describe the third case of Burkitt lymphoma in a child with Williams Syndrome [3, 4].\n\n2. Case Presentation\nA 10-year-old female diagnosed with Williams Syndrome at age 9 years, confirmed by fluorescent in situ hybridization (FISH), presented with a two-month history of fatigue, decreased activity, weight loss, regression in bladder control, and a recently palpated pelvic mass. Her medical history was also significant for congenital hypothyroidism and aortic valvular stenosis. \n\nPhysical examination showed WS facial dysmorphia, murmur consistent with aortic valvular stenosis, mild hypertension, and a 2.5 cm by 2.5 cm protruding mass just medial to the left anterior superior iliac spine, without defined edges. \n\nAbdominal CT study revealed four discrete masses: two large masses within the pelvis causing bilateral hydronephrosis, a third involving the hilum of the left kidney interfering with arterial and venous blood flow of the kidney, and a fourth involving the head of the pancreas. Metastasis to the left femoral diaphyses and proximal left humerus was also noted. Laboratory evaluation demonstrated a progressively elevated LDH, normal uric acid, BUN, and creatinine. Serological workup for Epstein Barr Virus and cytomegalovirus was negative. The patient underwent exploratory laparotomy, salpingo-oophorectomy, partial omentectomy, and a wedge biopsy of right lobe of liver. The cut surface of the ovaries is shown in Figure 1. Microscopic examination of the ovaries showed diffuse infiltrates consisting of medium-sized hyperchromatic cells with irregular nuclei, and small multiple nucleoli (Figure 2). Mitotic activity was high, and there were areas of increased debris-laden macrophages, giving the appearance of a “starry-sky”. Cell marker study by flow cytometry revealed a monotypic lymphoid cell population, positive for CD10, CD19, CD20, and HLA: DR with kappa light chain restriction. Cytogenetics and molecular genetics showed 46, XX, t(8; 14) (q24; q32).\n\nThere was no evidence of tumor in the liver or omentum. The bone marrow and CSF were negative for malignant cells. The results of pathology and staging indicated Stage III Burkitt lymphoma (by Murphy staging) [5]. \n\nIntention was to treat the patient as per FAB/LMB96 regimen B4, but therapy reductions were made due to complications [6]. Her regimen included COP (cyclophosphamide 300 mg/m2, vincristine 1 mg/m2 once, prednisolone 60 mg/m2/day for 7 days, and intrathecal chemotherapy with methotrexate/hydrocortisone (once)), COPADM1 (cyclophosphamide 250 mg/m2 BID for 6 doses, vincristine 2 mg/m2 once, prednisolone 60 mg/m2/day for 5 days, then taper over 3 days, doxorubicin 60 mg/m2 once, methotrexate 3000 mg/m2 once, and methotrexate/hydrocortisone given intrathecally twice), dose-reduced COPADM2 (cyclophosphamide 250 mg/m2 BID for 6 doses, vincristine 1 mg/m2 once, prednisolone 60 mg/m2/day for 5 days, then taper over 3 days, doxorubicin 30 mg/m2 once, methotrexate 1500 mg/m2 once, and methotrexate/hydrocortisone given intrathecally twice), and dose-reduced CYM1 (cytarabine 100 mg/m2 continuous infusion daily for 5 days, methotrexate 1500 mg/m2 once, and intrathecal methotrexate/hydrocortisone once and cytarabine/hydrocortisone once). The last cycle of chemotherapy, CYM2, was omitted. Rituximab was given every 2–4 weeks for 5 total doses, starting between COPADM1 and COPADM2, with a cumulative dose of 1875 mg/m2. \n\nOur patient developed several complications during and after therapy. These included hypertension and renal insufficiency requiring intensive care. She presented with a small bowel obstruction after induction therapy, followed by abdominal compartment Syndrome; both required surgical intervention and prolonged administration of parental nutrition. She experienced a two-month delay in chemotherapy to allow for healing. The patient had multiple episodes of febrile neutropenia with concomitant sepsis producing delays and dose reduction of chemotherapy. Chemotherapy was discontinued early due to poor tolerance. Cytopenias persisted for several months off chemotherapy, but did not require intervention with transfusions or growth factors and spontaneously resolved at approximately 6 months after rituximab completion. At the time of this report, she has been off therapy for 22 months and remains in complete remission.\n\n3. Discussion\nFeatures of WS include congenital heart disease, hypertension, premature aging of skin, dysmorphic facial features, infantile hypercalcemia, gregarious personality, and mental retardation with Intelligence Quotients ranging from 20 to 106 [7]. A submicroscopic deletion of contiguous genes on the long arm of chromosome 7 is seen in Williams Syndrome. Chromosome 7 is the second most frequently involved chromosome among the cytogenetic abnormalities observed in human malignancies after chromosome 8 [8]. The cytogenetic abnormalities in human cells are considered acquired; however, cancer has been reported in persons with constitutional cytogenetic abnormalities involving chromosome 7 [9–15], and it has been speculated that these abnormalities may predispose to malignancies. The literature contains reports of malignancy occurring in Williams Syndrome including five cases in the pediatric age group and four cases in the adult age group [16]. The pediatric cases include two cases of Burkitt lymphoma (ages 1 and 5 years), a Cutaneous fibrous harmartoma (age 5 years), acute lymphoblastic lymphoma (age 14 years), and astrocytoma in a 5-year-old child [16]. \n\nThe two prior reported patients with WS and BL tolerated chemotherapy well, without unexpected complications; one patient received standard-dosing chemotherapy per the same protocol as our patient, but followed the B1 arm which included the second CYM cycle as well as COPADM3, while the other patient received 4 courses of CHOP (cyclophosphamide, doxorubicin, vincristine and, prednisolone). Due to the inability to deliver full intensity chemotherapy, treatment was modified in our patient, by adding rituximab, reducing doses of cyclophosphamide, methotrexate, doxorubicin, and vincristine, and deleting the second cycle of consolidation therapy. Though the efficacy of rituximab in BL has yet to be proven, there is data showing that rituximab has activity in pediatric Burkitt lymphoma [17]. The efficacy of rituximab is difficult to determine for this patient. Our patient's medical complications were likely multifactorial in etiology and may or may not be related to her underlying WS. It is important to note that so far, there is no established association between the genetic consequences of the chromosomal abnormalities observed in WS and BL. \n\nMost patients with WS have a de novo submicroscopic deletion of 7q11.23 detectable by FISH [2, 4, 7]. WS is a contiguous gene Syndrome caused by 1.5 megabase microdeletion, which is most often due to unbalanced recombination during meiosis. The critical region encodes the elastin gene (ELN), which contributes to supravalvular aortic stenosis, hoarse voice, and some of the characteristic facial features of WS, and there are at least 25 other genes adjacent to the ELN gene that may also contribute to the phenotype [2, 18–20]. A number of these genes have been described as being involved in mediating processes that can lead to the development of malignancy. A review of the literature shows that one gene (BAZ1B) also known as Williams-Beuren Syndrome transcription factor (WSTF) is associated with response/repair to DNA damage [21]. Xiao et al. demonstrated that WSTF has intrinsic tyrosine kinase activity which allows it to phosphorylate H2A.X, a specialized histone variant. This prompts chromatin remodeling necessary for DNA repair. Inability to repair DNA leads to genomic instability, carcinogenesis, and cell death. This pathway is of possible interest since H2A.X deficiency has been shown to accelerate B and T cell lymphoma development in p53 deficient mice [22, 23]. Further, H2A.X-deficient mouse embryonic fibroblasts and B and T cells display pronounced levels of genomic instability [24]. Another gene, LIMK1, deleted in the WS critical region has been associated with prostate cancer metastasis [25]. A third gene named GTF2IRD1 interacts with the retinoblastoma (RB1) gene in vitro and in vivo [26]. RB1 is a known regulator of cell cycle and development, as well as an important tumor suppressor. \n\nFinally, the BCL7 gene family is of greatest interest in association with BL. The BCL7A gene maps to chromosome 12 and occurs in translocation with a Burkitt lymphoma cell line [27]. The BCL7B gene maps within the commonly deleted Williams Syndrome region [28], and 90 percent identify with the N-terminal 51 amino acids of BCL7A but investigators have not implicated it in cancer so far. Whether the hemizygosity of BCL-7B disrupts important developmental processes or is implicated in the pathogenesis of a lymphomatous proliferation remains to be answered [3]. \n\n We, like others, speculate that the Williams Syndrome deletion could predispose to a malignant development through the loss of heterozygosity in a tumor suppressor gene, but more studies are necessary to establish a true association [3]. \n\nIn conclusion, while there is no established link between WS and an increased incidence of malignancy or complications with chemotherapy, more case reports with detailed molecular findings are needed to facilitate exploring the possibility of a linkage.\n\nFigure 1 Sectioned right and left ovaries, with near-total obliteration of the usual follicular cut surface, replaced by the typical tan white appearance of lymphoma.\n\nFigure 2 Low power photomicrograph showing sheets of lymphoma cell replacing the usual histology of ovary (arrow) and infiltrating fallopian tube (arrow heads).\n==== Refs\n1 Ferry JA Burkitt’s lymphoma: clinicopathologic features and differential diagnosis Oncologist 2006 11 4 375 383 16614233 \n2 Dutly F Schinzel A Unequal interchromosomal rearrangements may result in elastin gene deletions causing the Williams-Beuren syndrome Human Molecular Genetics 1996 5 12 1893 1898 8968740 \n3 Amenta S Moschovi M Sofocleous C Kostaridou S Mavrou A Fryssira H Non-Hodgkin lymphoma in a child with Williams syndrome Cancer Genetics and Cytogenetics 2004 154 1 86 88 15381380 \n4 Thornburg CD Roulston D Castle VP Burkitt lymphoma and Williams syndrome: a model for children with a multisystem disorder and malignancy Journal of Pediatric Hematology/Oncology 2005 27 2 109 111 15701989 \n5 Murphy SB Fairclough DL Hutchison RE Berard CW Non-Hodgkin’s lymphomas of childhood: an analysis of the histology, staging, and response to treatment of 338 cases at a single institution Journal of Clinical Oncology 1989 7 2 186 193 2915234 \n6 Patte C Auperin A Gerrard M Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin lymphoma in children and adolescents: it is possible to reduce treatment for the early responding patients Blood 2007 109 7 2773 2780 17132719 \n7 Ewart AK Morris CA Atkinson D Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome Nature Genetics 1993 5 1 11 16 7693128 \n8 Hasle H Olsen JH Hansen J Friedrich U Tommerup N Occurrence of cancer in a cohort of 183 persons with constitutional chromosome 7 abnormalities Cancer Genetics and Cytogenetics 1998 105 1 39 42 9689928 \n9 Marles SL Goldberg NA Chudley AE Mucinous cystadenoma of ovary in a patient with Williams syndrome American Journal of Medical Genetics 1993 46 3 p. 349 \n10 Wilmore HP White GFJ Howell RT Brown KW Germline and somatic abnormalities of chromosome 7 in Wilms’ tumor Cancer Genetics and Cytogenetics 1994 77 2 93 98 7954327 \n11 Stanley WS Burkett SS Segel B Constitutional inversion of chromosome 7 and hematologic cancers Cancer Genetics and Cytogenetics 1997 96 1 46 49 9209470 \n12 Johnson EJ Scherer SW Osborne L Molecular definition of a narrow interval at 7q22.1 associated with myelodysplasia Blood 1996 87 9 3579 3586 8611680 \n13 Riccardi VM Humbert JR Peakman D Acute leukemia associated with trisomy 8 mosaicism and a familial translocation 46,XY,t(7;20)(p13;p12) American Journal of Medical Genetics 1978 2 1 15 21 299456 \n14 Passmore SJ Hann IM Stiller CA Pediatric myelodysplasia: A study of 68 children and a new prognostic scoring system Blood 1995 85 7 1742 1750 7703482 \n15 Semmekrot BA Rotteveel JJ Bakker-Niezen SH vd Logt F Occurrence of an astrocytoma in a patient with Williams syndrome Pediatric Neuroscience 1985 12 3 188 191 3843262 \n16 Montano N De Bonis P Lauriola L Late onset cerebellar metastasis from oesophageal adenocarcinoma in Williams Syndrome Journal of Neuro-Oncology 2008 88 3 349 351 18392775 \n17 Meinhardt A Burkhardt B Zimmermann M Phase II window study on rituximab in newly diagnosed pediatric mature B-cell non-Hodgkin's lymphoma and Burkitt leukemia Journal of Clinical Oncology 2010 28 19 3115 3121 20516455 \n18 Flanders TY Foulkes WD Pancreatic adenocarcinoma: Epidemiology and genetics Journal of Medical Genetics 1996 33 11 889 898 8950667 \n19 Bayes M Magano LF Rivera N Flores R Perez Jurado LA Mutational mechanisms of williams-beuren syndrome deletions American Journal of Human Genetics 2003 73 1 131 151 12796854 \n20 Lowery MC Morris CA Ewart A Strong correlation of elastin deletions, detected by FISH, with Williams syndrome: evaluation of 235 patients American Journal of Human Genetics 1995 57 1 49 53 7611295 \n21 Xiao A Li H Shechter D WSTF regulates the H2A.X DNA damage response via a novel tyrosine kinase activity Nature 2009 457 7225 57 62 19092802 \n22 Celeste A Difilippantonio S Difilippantonio MJ H2AX haploinsufficiency modifies genomic stability and tumor susceptibility Cell 2003 114 3 371 383 12914701 \n23 Bassing CH Suh H Ferguson DO Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors Cell 2003 114 3 359 370 12914700 \n24 Celeste A Petersen S Romanienko PJ Genomic instability in mice lacking histone H2AX Science 2002 296 5569 922 927 11934988 \n25 Davila M Frost AR Grizzle WE Chakrabarti R LIM kinase 1 is essential for the invasive growth of prostate epithelial cells: implications in prostate cancer Journal of Biological Chemistry 2003 278 38 36868 36875 12821664 \n26 Yan X Zhao X Qian M Guo N Gong X Zhu X Characterization and gene structure of a novel retinoblastoma-protein-associated protein similar to the transcription regulator TFII-I Biochemical Journal 2000 345 3 749 757 10642537 \n27 Zani VJ Asou N Jadayel D Molecular cloning of complex chromosomal translocation t(8;14;12)(q24.1;q32.3;q24.1) in a Burkitt lymphoma cell line defines a new gene (BCL7A) with homology to caldesmon Blood 1996 87 8 3124 3134 8605326 \n28 Jadayel DM Osborne LR Coignet LJA The BCL7 gene family: deletion of BCL7B in Williams syndrome Gene 1998 224 1-2 35 44 9931421\n\n", "fulltext_license": "CC BY", "issn_linking": null, "issue": "2011()", "journal": "Case reports in medicine", "keywords": null, "medline_ta": "Case Rep Med", "mesh_terms": null, "nlm_unique_id": "101512910", "other_id": null, "pages": "327263", "pmc": null, "pmid": "21687537", "pubdate": "2011", "publication_types": "D002363:Case Reports", "references": "12914701;7693128;10642537;7954327;7611295;2915234;18392775;16614233;3843262;8488885;15381380;8950667;299456;19092802;17132719;8611680;15701989;12821664;9209470;11934988;12914700;9689928;20516455;8605326;7703482;12796854;9931421;8968740", "title": "Bilateral burkitt lymphoma of the ovaries: a report of a case in a child with williams syndrome.", "title_normalized": "bilateral burkitt lymphoma of the ovaries a report of a case in a child with williams syndrome" }

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"reactionoutcome": "1" }, { "reactionmeddrapt": "Small intestinal obstruction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abdominal compartment syndrome", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Renal failure", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug intolerance", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypertension", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ONIMOE G, KAHWASH S, TERMUHLEN A, GROSS T, VARGA E, ROSE M. BILATERAL BURKITT LYMPHOMA OF THE OVARIES: A REPORT OF A CASE IN A CHILD WITH WILLIAMS SYNDROME. CASE REPORTS IN MEDICINE. 2011;2011:1-4.", "literaturereference_normalized": "bilateral burkitt lymphoma of the ovaries a report of a case in a child with williams syndrome", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20171128", "receivedate": "20171128", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14233890, "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": "BACKGROUND\nInflammatory bowel disease (IBD) is chronic inflammation of the gastrointestinal tract, although its etiology has largely been unclear. Tumor necrosis factor inhibitors (TNF-I) are effective for the treatment. Recently, biosimilars of TNF-I, such as CT-P13, have been developed and are thought to possess equal efficacy and safety to the original TNF-I. Sarcoidosis is also a systemic granulomatous disease of unknown etiology. In steroid-resistant cases of sarcoidosis, TNF-I have been reported effective for achieving resolution. However, the progression of sarcoidosis due to the TNF-I also has been reported. We herein report a case of pulmonary sarcoidosis with a Crohn's disease (CD) patient developed after a long period administration (15 years) of TNF-I.\n\n\nMETHODS\nA 37-year-old woman with CD who had been diagnosed at 22 years old had been treated with the TNF-I (original infliximab; O-IFX and infliximab biosimilar; IFX-BS). Fifteen years after starting the TNF-I, she developed a fever and right chest pain. Chest computed tomography (CT) revealed clustered small nodules in both lungs and multiple enlarged hilar lymph nodes. Infectious diseases including tuberculosis were negative. Bronchoscopic examination was performed and the biopsy specimens were obtained. A pathological examination demonstrated noncaseating granulomatous lesions and no malignant findings. TNF-I were discontinued because of the possibility of TNF-I-related sarcoidosis. After having discontinued for four months, her symptoms and the lesions had disappeared completely. Fortunately, despite the discontinuation of TNF-I, she has maintained remission.\n\n\nCONCLUSIONS\nTo our knowledge, this is the first case in which sarcoidosis developed after switching from O-IFX to IFX-BS. To clarify the characteristics of the cases with development of sarcoidosis during administration of TNF-I, we searched PubMed and identified 106 cases. When developing an unexplained fever, asthenia, uveitis and skin lesions in patients with TNF-I treatment, sarcoidosis should be suspected. Once the diagnosis of sarcoidosis due to TNF-I was made, the discontinuation of TNF-I and administration of steroid therapy should be executed promptly. When re-starting TNF-I, another TNF-I should be used for disease control. Clinicians should be aware of the possibility of sarcoidosis in patients under anti-TNF therapy.", "affiliations": "Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido, 078-8510, Japan. shin1014@asahikawa-med.ac.jp.;Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido, 078-8510, Japan.;Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido, 078-8510, Japan.;Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido, 078-8510, Japan.;Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido, 078-8510, Japan.;Department of Diagnostic Pathology, Asahikawa Medical University Hospital, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido, 078-8510, Japan.;Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido, 078-8510, Japan.", "authors": "Kashima|Shin|S|http://orcid.org/0000-0001-8309-4281;Moriichi|Kentaro|K|;Ando|Katsuyoshi|K|;Ueno|Nobuhiro|N|;Tanabe|Hiroki|H|;Yuzawa|Sayaka|S|;Fujiya|Mikihiro|M|", "chemical_list": "D000911:Antibodies, Monoclonal; D059451:Biosimilar Pharmaceuticals; D000079424:Tumor Necrosis Factor Inhibitors; D000069285:Infliximab", "country": "England", "delete": false, "doi": "10.1186/s12876-021-01948-6", "fulltext": "\n==== Front\nBMC Gastroenterol\nBMC Gastroenterol\nBMC Gastroenterology\n1471-230X\nBioMed Central London\n\n1948\n10.1186/s12876-021-01948-6\nCase Report\nDevelopment of pulmonary sarcoidosis in Crohn’s disease patient under infliximab biosimilar treatment after long-term original infliximab treatment: a case report and literature review\nhttp://orcid.org/0000-0001-8309-4281\nKashima Shin shin1014@asahikawa-med.ac.jp\n\n1\nMoriichi Kentaro morimori@asahikawa-med.ac.jp\n\n1\nAndo Katsuyoshi k-ando@asahikawa-med.ac.jp\n\n1\nUeno Nobuhiro u-eno@asahikawa-med.ac.jp\n\n1\nTanabe Hiroki tant@asahikawa-med.ac.jp\n\n1\nYuzawa Sayaka ysayaka528@asahikawa-med.ac.jp\n\n2\nFujiya Mikihiro fjym@asahikawa-med.ac.jp\n\n1\n1 grid.252427.4 0000 0000 8638 2724 Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido 078-8510 Japan\n2 grid.413955.f 0000 0004 0489 1533 Department of Diagnostic Pathology, Asahikawa Medical University Hospital, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido 078-8510 Japan\n12 10 2021\n12 10 2021\n2021\n21 3736 7 2021\n30 9 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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 in a credit line to the data.\nBackground\n\nInflammatory bowel disease (IBD) is chronic inflammation of the gastrointestinal tract, although its etiology has largely been unclear. Tumor necrosis factor inhibitors (TNF-I) are effective for the treatment. Recently, biosimilars of TNF-I, such as CT-P13, have been developed and are thought to possess equal efficacy and safety to the original TNF-I. Sarcoidosis is also a systemic granulomatous disease of unknown etiology. In steroid-resistant cases of sarcoidosis, TNF-I have been reported effective for achieving resolution. However, the progression of sarcoidosis due to the TNF-I also has been reported. We herein report a case of pulmonary sarcoidosis with a Crohn’s disease (CD) patient developed after a long period administration (15 years) of TNF-I.\n\nCase presentations\n\nA 37-year-old woman with CD who had been diagnosed at 22 years old had been treated with the TNF-I (original infliximab; O-IFX and infliximab biosimilar; IFX-BS). Fifteen years after starting the TNF-I, she developed a fever and right chest pain. Chest computed tomography (CT) revealed clustered small nodules in both lungs and multiple enlarged hilar lymph nodes. Infectious diseases including tuberculosis were negative. Bronchoscopic examination was performed and the biopsy specimens were obtained. A pathological examination demonstrated noncaseating granulomatous lesions and no malignant findings. TNF-I were discontinued because of the possibility of TNF-I-related sarcoidosis. After having discontinued for four months, her symptoms and the lesions had disappeared completely. Fortunately, despite the discontinuation of TNF-I, she has maintained remission.\n\nConclusions\n\nTo our knowledge, this is the first case in which sarcoidosis developed after switching from O-IFX to IFX-BS. To clarify the characteristics of the cases with development of sarcoidosis during administration of TNF-I, we searched PubMed and identified 106 cases. When developing an unexplained fever, asthenia, uveitis and skin lesions in patients with TNF-I treatment, sarcoidosis should be suspected. Once the diagnosis of sarcoidosis due to TNF-I was made, the discontinuation of TNF-I and administration of steroid therapy should be executed promptly. When re-starting TNF-I, another TNF-I should be used for disease control. Clinicians should be aware of the possibility of sarcoidosis in patients under anti-TNF therapy.\n\nSupplementary Information\n\nThe online version contains supplementary material available at 10.1186/s12876-021-01948-6.\n\nKeywords\n\nCrohn’s disease\nSarcoidosis\nTNF-inhibitors\nOriginal infliximab\nInfliximab biosimilar\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nInflammatory bowel disease (IBD) is chronic inflammation of the entire gastrointestinal tract, although its etiology has largely been unclear. Tumor necrosis factor (TNF) inhibitors are known to be effective treatment for treating IBD patients with moderate to severe activity. The cost-effectiveness and efficacy of TNF inhibitors (TNF-I) has been demonstrated through their reduction in the rates of hospitalization and surgery [1]. Recently, biosimilars of TNF-I, such as CT-P13, have been developed and are thought to possess equal efficacy and safety to the original with dramatic cost benefits. Switching from the original to a biosimilar is thus considered an acceptable treatment [2, 3].\n\nSimilar to IBD, sarcoidosis is a systemic granulomatous disease of unknown etiology, affecting various organs, including the lung, heart, lymphatic system and skin. In many cases of sarcoidosis, steroids are effective for treatment, and in case of steroid resistance, TNF-I are reported to be effective. While some studies have reported that the administration of TNF-I caused the progression of sarcoidosis, no reports regarding the relationship between sarcoidosis and infliximab biosimilar (IFX-BS) have been published.\n\nWe herein report a case of pulmonary sarcoidosis in a Crohn’s disease (CD) patient during fifteen years administration of IFX-BS after switching from original infliximab (O-IFX). To our knowledge, this is the first case of sarcoidosis developing after switching from O-IFX to IFX-BS in a CD patient.\n\nCase presentation\n\nA 37-year-old Japanese woman was diagnosed with CD at 22 years of age. She had no relevant family history. At the onset of CD, she had symptoms of fever, abdominal pain, and frequent diarrhea. On total colonoscopy, she was found to have multiple longitudinal ulcers in the terminal ileum with stricture. Her symptoms were severe; thus, we administered O-IFX first, without steroid therapy. Clinical remission was obtained after 3 months of O-IFX treatment. She had maintained clinical remission without any adverse events for twelve years after the administration of O-IFX, and then O-IFX was switched to IFX-BS (CT-P13) after obtaining informed consent, because IFX-BS demonstrated equivalent efficacy and safety in the treatment of CD and the drug price was approximately half that of O-IFX in Japan. After switching to IFX-BS, clinical remission was still maintained for three years.\n\nFifteen years after starting the TNF-I (O-IFX and CT-P13), she developed a fever and right chest pain but had no respiratory symptoms, such as cough or sputum. Laboratory findings showed total bilirubin, 1.5 mg/dL; alanine aminotransferase, 248 U/L; aspartate aminotransferase, 105 U/L; gamma glutamyl aminotransferase, 192 U/L; alkaline phosphatase, 489 U/L; C-reactive protein (CRP), 0.44 mg/dL; anti-nuclear antibody, 1:160. Hepatitis B and C were negative. Chest X-ray and computed tomography (CT) revealed clustered small nodules in both lungs and multiple enlarged hilar lymph nodes (Fig. 1). The interferon gamma release assay and an acid-fast bacilli antibody were negative. A tuberculosis polymerase chain reaction (PCR) assay and bacterium culture of her sputum were both negative. Subsequently, a bronchoscopic examination was performed, and biopsy specimens were obtained from the middle and lower lobes of the right lung. A pathological examination demonstrated noncaseating granulomatous lesions and no malignant findings (Fig. 2). The serum angiotensin-converting enzyme and lysozyme levels were within normal limits, and soluble interleukin-2 receptor (sIL-2R) was increased to 627 U/mL (reference range 122–496 U/mL). Thus, the diagnosis of sarcoidosis was made. Her symptoms (low-grade fever and slight chest pain) could be sufficiently managed by the administration of an analgesic antipyretic. Therefore, we did not use steroids and, considering the possibility of TNF-I related sarcoidosis, TNF-I was discontinued. Subsequently, her symptoms improved gradually. In addition, the abnormal laboratory findings, including hepatobiliary enzymes, improved naturally without any treatment after one month. After having discontinued TNF-I for four months, her symptoms of sarcoidosis and the lesions detected by chest CT had disappeared completely (Fig. 3). Fortunately, despite the discontinuation of TNF-I, she has maintained clinical and endoscopic remission for 18 months after the discontinuation of TNF-I.Fig. 1 CT scan showing multiple nodular lung lesions and mediastinal and hilar lymphadenopathies\n\nFig. 2 Histological findings of the lung. Histology demonstrated noncaseating granulomatous lesions and no malignant findings (X100)\n\nFig. 3 The nodular lung lesions disappeared after discontinuation of IFX-BS in CT scan\n\nDiscussions and conclusions\n\nWe herein report the pulmonary sarcoidosis after the long-term use of TNF-inhibitors in a CD patient.\n\nTwo possible causes were considered responsible for the development of sarcoidosis in our case: the long-term IFX administration and the switching from the original agent to its biosimilar. To confirm the involvement of these causes and clarify the characteristics of patients likely to develop sarcoidosis under TNF-I therapy, we searched for case reports in PubMed concerning sarcoidosis due to TNF-I using the combination of the heading terms ‘infliximab’, ‘adalimumab’, ‘etanercept’, ‘certolizumab’, ‘golimumab’, ‘infliximab biosimilar’, with or without ‘Crohn’s disease’, combined with ‘sarcoidosis’. We identified 6 articles concerning 7 cases using the word combination with CD [4–9] and 65 articles concerning 99 cases using the word combination without CD (details in Additional file 1: Table 1) [10–74]. Regarding the impact of long-term TNF-I administration, in 103 cases, the median duration of developing sarcoidosis was 21 (range 1–90) months, and the maximum period was 90 months, according to previous reports. However, since those reports contained various diseases, we reviewed the seven cases with CD (excluding our own case). The median duration to the development of sarcoidosis was 24 (range 7–90) months, and the maximum period was 90 months. Our case was administered O-IFX for 144 months and then IFX-BS for 36 months. Based on the previous reports, the duration of 180 months until the development of sarcoidosis in our case was the longest, exceeding the longest period in previous reports by more than 7 years. Long-term IFX administration may affect the development of sarcoidosis, as the administration of TNF-I presumably induces cytokine imbalance (TNF-α suppression and excessive Interferon-α production) [75]. It took a very long time to for the patient to develop sarcoidosis; however, it may have been a possible complication as the time to the induction of cytokine imbalance seems to show individual differences. In addition, infection is suggested to be a cause of sarcoidosis, and the treatment with TNF-I increases the risk of various infections [10–12], which can lead to the onset of sarcoidosis. Prudent follow-up should thus be performed, including observation of CD patients under long-term IFX administration. Regarding the impact of switching from O-IFX to IFX-BS, we thought that the possibility of sarcoidosis caused by changing O-IFX to IFX-BS would be quite low because of the very slight differences in the sugar chain sequences of O-IFX and IFX-BS and their almost equivalent immunogenicity [76].\n\nRegarding other characteristics of CD patients, the median age was 30 (range 21–44) years, and the male:female ratio was 5:3 when including our case. The causative TNF inhibitors were adalimumab (ADA) (n = 4, 50.0%, including a case switching from IFX to ADA) and IFX (n = 4, 50%, including our case). The symptoms depended on the organs involved. Our case showed an unexplained fever and chest pain because of pleuritis. Asthenia, uveitis, and skin lesions were also reported. There were no specific symptoms.\n\nIn this case, the serum ACE level was normal. It was reported that serum ACE shows low sensitivity and specificity in the diagnosis of sarcoidosis [77]. In addition, it is known that the serum ACE level is affected by genetic polymorphism [78, 79]. Clinicians should recognize that the serum ACE levels alone are not enough to diagnose sarcoidosis.\n\nWe also investigated the difference in the duration until the development of sarcoidosis under IFX and ADA therapy in the six CD cases without switching cases. The median duration to the development of sarcoidosis in CD patients under IFX (n = 3) and ADA (n = 3) therapy was 12 and 24 months, respectively. Patients receiving ADA therapy showed a longer duration until development than those receiving IFX, which might have influenced the difference in antibody type, such as chimeric human-mouse IgG monoclonal antibody and fully human monoclonal antibody. However, the number of such cases has been limited so far, so the accumulation of more cases will be required to verify whether or not differences in antibodies affects the development of sarcoidosis.\n\nRegarding the therapy delivered after the development of sarcoidosis, six of eight cases discontinued TNF-I, two without steroid and four with additional steroid, and two cases continued TNF-I therapy while adding steroid therapy or topical therapy. All six cases who discontinued TNF-I with/without steroids showed the resolution of sarcoidosis. In one case, in which the patient continued TNF-I with steroid treatment, improvement of the lung lesion was observed. In one case in which the patient continued TNF-I with topical steroid treatment, improvement of the lung lesion, but not the skin lesion, was observed. In CD patients who develop sarcoidosis, discontinuation of TNF-I seems to be a feasible treatment. Among 107 cases with various diseases, 47 discontinued TNF-I without the addition of steroid therapy, and sarcoidosis was improved or resolved in 43 (91.5%), while 49 cases discontinued TNF-I with the addition of steroid therapy, and 46 (93.9%) showed improvement or resolution of sarcoidosis. These data support the notion that discontinuing TNF-I is effective for treating patients with chronic inflammatory disease, but the efficacy of additional steroid therapy is unclear.\n\nOur case has maintained remission despite having discontinued TNF-I; however, TNF-I may be key drugs for CD patients. Thus, whether or not TNF-I can be re-initiated for these patients is important to clarify. Only one CD patient re-initiated the same TNF inhibitor (O-IFX) with no recurrence of sarcoidosis observed [8]. When expanding target diseases to include rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, spondyloarthropathy, psoriasis, CD, juvenile idiopathic arthritis, SAPHO (synovitis, pustulosis, acne, hyperostosis, osteitis), ulcerative colitis, 25 patients re-initiated TNF-I. Of 25 patients, 7 were administered the same TNF-I, and sarcoidosis consequently recurred in 4 cases (57.1%) [8, 11, 23, 27, 39, 63]. Eighteen cases started another TNF-I, and sarcoidosis recurred in 3 cases (16.7%) [13, 27, 64–74]. These data suggested that another TNF-I should be administered when re-initiating TNF-I in such patients.\n\nIn conclusion, should be aware that TNF-I can cause several drug related complications, including sarcoidosis. Sarcoidosis due to TNF-I can be caused by IFX-BS and develop even after long-term administration. Clinicians should be aware of the possibility of sarcoidosis in patients under anti-TNF therapy. The efficacy of additional steroid therapy remains unclear; however, TNF-I should be discontinued as soon as possible, even in CD patients who maintain long-term remission with TNF-I. When re-starting TNF-I, another TNF-I should be used for disease control, as relapse of sarcoidosis is frequent when patients are treated with the same TNF-I (Table 1).Table 1 The characteristics of sarcoidosis in CD patients receiving TNF inhibitor therapy\n\nReferences\tSex\tTNF inhibitor/delay until onset of causative TNF inhibitor (months)\tOrgans involved\tTreatment/outcome\tRe-initiation TNF inhibitor\tRelapse after re-initiation\t\n[4]\tF\tIFX/60\tSpinal cord\tIFX discontinuation and PSL/resolution\t–\t\t\n[5]\tM\tADA/24\tHilar and mediastinal nodes, erythema nodosum\tADA discontinuation and PSL/resolution\t–\t\t\n[6]\tF\tADA/18\tMediastinal nodes, nodules on the spleen\tADA continue and PSL/resolution\t–\t\t\n[7]\tM\tIFX/7\tErythematous skin plaques, bilateral nodular pulmonary infiltrates\tIFX continue and topical therapy /resolution of lung, but skin not resolved\t–\t\t\n[8]\tM\tIFX/12\thilar adenopathies, pulmonary infiltrate\tIFX discontinuation/resolution\tIFX re-start\t\t\n[9]\tM\tADA/60\tUveitis, mediastinal nodes, mesenterial nodes\tADA discontinuation and PSL/resolution\t–\t\t\n\tM\tIFX/72, ADA/18\tErythema nodosum, mediastinal nodes\tADA discontinuation and PSL/resolution\t–\t\t\nPresent case\tF\tO-IFX 144, IFX-BS 36\tBilateral pulmonary infiltrates, hilar and mediastinal lymphadenopathy\tIFX-BS discontinuation/resolution\t–\t\t\nM, male; F, female; ETN, etanercept; ADA, adalimumab; IFN, infliximab; IFX-BS, infliximab biosimilar\n\nSupplementary Information\n\nAdditional file 1. To confirm the involvement of these causes and clarify the characteristics of patients likely to develop sarcoidosis under TNF inhibitor therapy, we searched for case reports in PubMed concerning sarcoidosis due to TNF inhibitor using the combination of the heading terms ‘infliximab’, ‘adalimumab’, ‘etanercept’, ‘certolizumab’, ‘golimumab’, ‘infliximab biosimilar’, without ‘Crohn’s disease’, combined with ‘sarcoidosis’.\n\nAbbreviations\n\nIBD Inflammatory bowel disease\n\nTNF Tumor necrosis factor\n\nTNF-I TNF inhibitor\n\nCD Crohn’s disease\n\nO-IFX Original infliximab\n\nIFX-BS Infliximab biosimilar\n\nCT Computed tomography\n\nADA Adalimumab\n\nAcknowledgements\n\nAll authors have read the journal's policy on conflicts of interest and the journal's authorship agreement.\n\nAuthors' contributions\n\nSK and KM drafted the initial and final version of the manuscript and were involved in the care of this patient as gastroenterologists. KA and NU provided an intellectual review of the manuscript and were involved in the medical management of this patient as physicians in charge. HT were involved in the medical management of this patient as gastroenterologists and contributed to the intellectual review of the manuscript. SY were involved in the pathological evaluation and contributed to the intellectual review of the manuscript. MF contributed to the critical revision for important intellectual content. All authors read and approved the final manuscript.\n\nFunding\n\nNone.\n\nAvailability of data and materials\n\nThe datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.\n\nDeclarations\n\nEthics approval and consent to participate\n\nThis is a case report, and we did not receive any approval from the ethics review board. We obtained the patient's written informed consent to publish the material.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient for the publication of this case report and accompanying images.\n\nCompeting interests\n\nDr. Fujiya reports grants and personal fees from Nippon Kayaku Co., Ltd., and Mitsubishi Tanabe Pharma Corporation as well as grants from AYUMI Pharmaceutical Corporation.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. van der Valk ME Mangen MJJ Leenders M Health care costs of inflammatory bowel disease have shifted from hospitalisation and surgery towards anti-TNFα therapy: results from the COIN study Gut 2014 63 72 79 10.1136/gutjnl-2012-303376 23135759\n2. 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Biller H Zissel G Ruprecht B Genotype-corrected reference values for serum angiotensin-converting enzyme Eur Respir J 2006 28 1085 1090 10.1183/09031936.00050106 17138677\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-230X", "issue": "21(1)", "journal": "BMC gastroenterology", "keywords": "Crohn’s disease; Infliximab biosimilar; Original infliximab; Sarcoidosis; TNF-inhibitors", "medline_ta": "BMC Gastroenterol", "mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D059451:Biosimilar Pharmaceuticals; D003424:Crohn Disease; D005260:Female; D006801:Humans; D000069285:Infliximab; D017565:Sarcoidosis, Pulmonary; D000079424:Tumor Necrosis Factor Inhibitors; D055815:Young Adult", "nlm_unique_id": "100968547", "other_id": null, "pages": "373", "pmc": null, "pmid": "34641810", "pubdate": "2021-10-12", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": "1976655;20040649;31017685;14611117;25534463;18412298;19797509;23357593;18474661;21899592;19763766;17139647;20638761;17373994;25517302;23306600;12847707;31316856;27591675;24841734;24460777;20185892;20808167;21834808;24680117;25612132;19147181;26150616;18260163;19966199;18520114;17343313;17138677;18578973;12426295;30839343;20536653;20062997;20972592;23157794;22017197;26632413;24978390;17417999;22398084;19464223;22751454;28124746;25818847;28272203;23135759;28503520;19703000;23826822;19004058;21592629;20456350;18539237;21380931;22389903;24373564;20886249;24005973;23849401;22017171;21525138;17896899;24631310;24346918;19423648;21482342;29274117;30411382;17340045;30929895;17013853;22885144;16082636", "title": "Development of pulmonary sarcoidosis in Crohn's disease patient under infliximab biosimilar treatment after long-term original infliximab treatment: a case report and literature review.", "title_normalized": "development of pulmonary sarcoidosis in crohn s disease patient under infliximab biosimilar treatment after long term original infliximab treatment a case report and literature review" }

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{ "abstract": "Jacobsen syndrome (JS) is a rare genetic condition characterized by intellectual disability, hematologic abnormalities, and congenital heart defects. A male infant presented at birth with phenotypic findings of JS and echocardiographic findings of hypoplastic left heart syndrome (HLHS). Array comparative genomic hybridization was performed at age three days and revealed an 8.1 Mb terminal deletion on the long arm of chromosome 11, consistent with JS. At five days of age, a hybrid stage 1 procedure was performed. At age 46 days, he underwent a Norwood operation followed by bidirectional Glenn at age six months. He is presently 23 months old and doing well. With careful consideration of the individual patient and comorbidities associated with JS, we propose that at least a subset of patients with JS and HLHS can do well with staged surgical palliation.", "affiliations": "Department of Pediatrics, Rady Children's Hospital San Diego, San Diego, CA, USA.;Department of Cardiothoracic Surgery, Rady Children's Hospital San Diego, San Diego, CA, USA.;Department of Cardiology, Rady Children's Hospital San Diego, San Diego, CA, USA.;Department of Cardiothoracic Surgery, Rady Children's Hospital San Diego, San Diego, CA, USA.", "authors": "Herrick|Nicole L|NL|0000-0001-5255-8848;Lamberti|John|J|;Grossfeld|Paul|P|;Murthy|Raghav|R|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1177/2150135118822678", "fulltext": null, "fulltext_license": null, "issn_linking": "2150-1351", "issue": "12(3)", "journal": "World journal for pediatric & congenital heart surgery", "keywords": null, "medline_ta": "World J Pediatr Congenit Heart Surg", "mesh_terms": "D002675:Child, Preschool; D055028:Comparative Genomic Hybridization; D006801:Humans; D018636:Hypoplastic Left Heart Syndrome; D007223:Infant; D054868:Jacobsen Distal 11q Deletion Syndrome; D008297:Male; D008875:Middle Aged; D058327:Norwood Procedures; D010166:Palliative Care; D012189:Retrospective Studies; D012307:Risk Factors; D016896:Treatment Outcome", "nlm_unique_id": "101518415", "other_id": null, "pages": "421-424", "pmc": null, "pmid": "31117916", "pubdate": "2021-05", "publication_types": "D016428:Journal Article", "references": null, "title": "Successful Management of a Patient With Jacobsen Syndrome and Hypoplastic Left Heart Syndrome.", "title_normalized": "successful management of a patient with jacobsen syndrome and hypoplastic left heart syndrome" }

[ { "companynumb": "US-BAYER-2021-167430", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "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": "ASPIRIN (CARDIO)" } ], "patientagegroup": "2", "patientonsetage": "23", "patientonsetageunit": "802", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haematuria", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "24.0", "reactionoutcome": null }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "HERRICK NL, LAMBERTI J, GROSSFELD P, MURTHY R. SUCCESSFUL MANAGEMENT OF A PATIENT WITH JACOBSEN SYNDROME AND HYPOPLASTIC LEFT HEART SYNDROME. WORLD JOURNAL FOR PEDIATRIC AND CONGENITAL HEART SURGERY. 2021?12:3:(421?424)", "literaturereference_normalized": "successful management of a patient with jacobsen syndrome and hypoplastic left heart syndrome", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210701", "receivedate": "20210701", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19481781, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" } ]

{ "abstract": "OBJECTIVE\nTo investigate the relationship between the serum level of vancomycin and its clinical efficacy as well as adverse reactions in adult patient so as to provide recommendations for clinical management.\n\n\nMETHODS\nAn open observational research was performed from 1st July 2013 to 31st December 2017 in Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, which recruited the adult patients who were infected with Gram positive (G+) bacteria and treated with vancomycin. The initial dose was decided by the patient's creatinine clearance rate, and the treating dose was directed by the serum drug concentration and the patient's clinical response. By recording the associated clinical information (pathogen eradication, blood test results, adverse reactions, etc.), the clinical outcome and adverse reactions for vancomycin to treat G+ bacterial infections were analyzed.\n\n\nRESULTS\nEighty-nine cases who meet research standards were finally recruited, with 67.42% of male patients, and an average age of (50.5±17.9) years. The most common type of infection was bloodstream infection (61.80%), followed by low respiratory infection (17.98%). Infections caused by Staphylococcus aureus accounted for 39.33%. The bacterial eradication rate was 89.89% (80/89) and the total effective rate was 77.53% (69/89). The effective rate was 80.30% (53/66) with minimum inhibitory concentration (MIC) < 2 mg/L vs. 69.57% (16/23) with MIC ≥ 2 mg/L, the difference was not statistically significant (χ2 = 1.129, P = 0.288). The effective rate was 72.92% (35/48) with trough levels < 10 mg/L vs. 82.93% (34/41) with trough levels ≥ 10 mg/L, the difference was not statistically significant (χ2 = 1.272, P = 0.259). There were 4 cases of vancomycin associated nephrotoxicity, the incidence of nephrotoxicity was 4.49%, and the vancomycin serum trough levels were 17.22-28.53 mg/L. There were 33 cases of liver dysfunction, and elevated γ-glutamine transferase, alkaline phosphatase and aspartate aminotransferase were most common. There were 2 cases of neutropenia and 2 patients appeared rash during vancomycin period.\n\n\nCONCLUSIONS\nTreatment outcomes were similar regardless of vancomycin MIC and serum trough level. The incidence of vancomycin associated nephrotoxicity rises apparently when serum trough level is over 15 mg/L.\nChinese Clinical Trail Registry, ChiCTR-OPC-16007920.", "affiliations": "Department of Critical Care, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China (Zhang HF, Wang RL); Department of Clinical Laboratory, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China (Shu W, Tang R); Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai 200040, China (Liang XY, Zhang J, Wu JF). Corresponding author: Wang Ruilan, Email: wangyusun@hotmail.com.", "authors": "Zhang|Huifang|H|;Wang|Ruilan|R|;Shu|Wen|W|;Tang|Rong|R|;Liang|Xiaoyu|X|;Zhang|Jing|J|;Wu|Jufang|J|", "chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin", "country": "China", "delete": false, "doi": "10.3760/cma.j.issn.2095-4352.2018.06.007", "fulltext": null, "fulltext_license": null, "issn_linking": null, "issue": "30(6)", "journal": "Zhonghua wei zhong bing ji jiu yi xue", "keywords": null, "medline_ta": "Zhonghua Wei Zhong Bing Ji Jiu Yi Xue", "mesh_terms": "D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D002681:China; D005260:Female; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D012189:Retrospective Studies; D016896:Treatment Outcome; D014640:Vancomycin", "nlm_unique_id": "101604552", "other_id": null, "pages": "538-543", "pmc": null, "pmid": "30009727", "pubdate": "2018-06", "publication_types": "D016428:Journal Article", "references": null, "title": "Monitoring of vancomycin serum concentrations and the evaluation of its safety and treatment outcomes in adult patients.", "title_normalized": "monitoring of vancomycin serum concentrations and the evaluation of its safety and treatment outcomes in adult patients" }

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MONITORING OF VANCOMYCIN SERUM CONCENTRATIONS AND THE EVALUATION OF ITS SAFETY AND TREATMENT OUTCOMES IN ADULT PATIENTS. ZHONGHUA?WEI?ZHONG?BING?JI?JIU?YI?XUE 2018?30(6):538?543.", "literaturereference_normalized": "monitoring of vancomycin serum concentrations and the evaluation of its safety and treatment outcomes in adult patients", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20180906", "receivedate": "20180906", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15357449, "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": "CN-MYLANLABS-2018M1065455", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": "1", "drugadministrationroute": "041", "drugauthorizationnumb": "065397", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BACTERIAL INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METRONIDAZOLE" }, "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": "METRONIDAZOLE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CEFOPERAZONE SODIUM" }, "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": "CEFOPERAZONE SODIUM" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Leukopenia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HUIFANG Z, RUILAN W, WEN S, RONG T, XIAOYU L, JING Z, ET AL. MONITORING OF VANCOMYCIN SERUM CONCENTRATIONS AND THE EVALUATION OF ITS SAFETY AND TREATMENT OUTCOMES IN ADULT PATIENTS. ZHONGHUA?WEI?ZHONG?BING?JI?JIU?YI?XUE 2018?30(6):538?543.", "literaturereference_normalized": "monitoring of vancomycin serum concentrations and the evaluation of its safety and treatment outcomes in adult patients", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20180906", "receivedate": "20180906", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15357450, "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": "CN-MYLANLABS-2018M1065434", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": "065397", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ENDOCARDITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CEFTRIAXONE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ENDOCARDITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE SODIUM." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Therapeutic product cross-reactivity", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dermatitis allergic", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Type IV hypersensitivity reaction", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HUIFANG Z, RUILAN W, WEN S, RONG T, XIAOYU L, JING Z, ET AL. MONITORING OF VANCOMYCIN SERUM CONCENTRATIONS AND THE EVALUATION OF ITS SAFETY AND TREATMENT OUTCOMES IN ADULT PATIENTS. ZHONGHUA?WEI?ZHONG?BING?JI?JIU?YI?XUE 2018?30(6):538?543.", "literaturereference_normalized": "monitoring of vancomycin serum concentrations and the evaluation of its safety and treatment outcomes in adult patients", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20180914", "receivedate": "20180914", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15385605, "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": "Iatrogenic Cushing's syndrome (ICS) is usually related to prolonged and/or high-dose oral or parenteral steroid use. Psoriasis vulgaris (PV) is chronic inflammatory disease and characterized by periods of attack and remission. Topical steroid (TS) is the first choice of treatment for localized and mild PV. The development of systemic side effects of the steroids is usually not observed after TS application. But the risk of developing ICS still exists. In the literature, there are a few adult cases who developed ICS and subsequent adrenal insufficiency associated with TS. In this article, a male patient with PV developing ICS and secondary adrenal insufficiency after treatment of TS for 12 years is presented.", "affiliations": "Department of Dermatology, Mugla Sitki Kocman University, Faculty of Medicine, 48000 Mugla, Turkey.;Department of Dermatology, Mugla Sitki Kocman University, Faculty of Medicine, 48000 Mugla, Turkey.;Department of Endocrinology and Metabolic Diseases, Mugla Sitki Kocman University, Faculty of Medicine, 48000 Mugla, Turkey.", "authors": "Pektas|Suzan Demir|SD|0000-0001-5074-986X;Dogan|Gursoy|G|;Cinar|Nese|N|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1155/2017/8320254", "fulltext": "\n==== Front\nCase Rep EndocrinolCase Rep EndocrinolCRIECase Reports in Endocrinology2090-65012090-651XHindawi 10.1155/2017/8320254Case ReportIatrogenic Cushing's Syndrome with Subsequent Adrenal Insufficiency in a Patient with Psoriasis Vulgaris Using Topical Steroids http://orcid.org/0000-0001-5074-986XPektas Suzan Demir suzandpektas@gmail.com\n1\nDogan Gursoy \n1\nCinar Nese \n2\n\n1Department of Dermatology, Mugla Sitki Kocman University, Faculty of Medicine, 48000 Mugla, Turkey\n2Department of Endocrinology and Metabolic Diseases, Mugla Sitki Kocman University, Faculty of Medicine, 48000 Mugla, TurkeyAcademic Editor: J. Paul Frindik\n\n2017 13 11 2017 2017 832025419 6 2017 24 10 2017 Copyright © 2017 Suzan Demir Pektas et al.2017This 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.Iatrogenic Cushing's syndrome (ICS) is usually related to prolonged and/or high-dose oral or parenteral steroid use. Psoriasis vulgaris (PV) is chronic inflammatory disease and characterized by periods of attack and remission. Topical steroid (TS) is the first choice of treatment for localized and mild PV. The development of systemic side effects of the steroids is usually not observed after TS application. But the risk of developing ICS still exists. In the literature, there are a few adult cases who developed ICS and subsequent adrenal insufficiency associated with TS. In this article, a male patient with PV developing ICS and secondary adrenal insufficiency after treatment of TS for 12 years is presented.\n==== Body\n1. Introduction\nIatrogenic Cushing's syndrome (ICS) is usually related to prolonged and/or high-dose oral or parenteral steroid use [1]. The development of systemic side effects after topical steroid therapy is rare, but the risk of developing ICS still exists. In the literature, patients with ICS associated with topical steroids (TS) are more common in children [2, 3]. Since children have thinner dermis layer of epidermis than adults with a higher surface/volume ratio steroids are more absorbed through the skin of children leading to systemic side effects [2, 3]. In the literature, there are a few adult cases who developed ICS and secondary adrenal insufficiency associated with TS [1, 4, 5]. In this case report, a male patient with psoriasis vulgaris (PV) developing ICS after treatment of TS for 12 years is presented.\n\n2. Case Presentation\nA 32-year-old man was referred to the outpatient clinic of the Department of Endocrinology and Metabolism in Mugla Sitki Kocman University Training and Research Hospital with complains of excessive weight gain and muscle weakness. The patient gained 8 kgs in 12 months. He had a history of PV for 12 years. He used clobetasol propionate (CP) 0.05% ointment continuously at 150 mg/week for the past 12 years and stopped the steroid ointment treatment a month ago by himself. On physical examination, he had a moon face appearance with truncal obesity, buffalo hump, hirsutism, and purple striae in the axilla, periumbilical, and inguinal region (Figure 1). Numerous erythematous, scaly psoriatic plaques were located on the shoulders, all extremities, dorsum of hands, and feet and at the intertriginous areas (Figure 2).\n\nVital signs revealed an arterial blood pressure of 130/80 mmHg, pulse rate 75/min, height 172 cm, weight 85 kg, and body mass index 28.7 kg/cm2. On laboratory studies, liver and kidney function tests and fasting blood glucose were within normal limits. The following were found: morning adrenocorticotropic hormone (ACTH): 17 : 53 pg/ml (N: 7.2–63.3); morning basal cortisol: 3.83 mg/dL (N = 6.24–18.0). Other anterior hypophyseal hormones were as follows: thyroid stimulating hormone (TSH): 2.77 μ/ml (N: 0.27–4.2); fT4: 17.6 pmol/L (N: 12–22); fT3: 7.26 pmol/L (N: 3.1–6.8); prolactin: 7.34 ng/ml (N: 4.04–15.2); follicle stimulated hormone (FSH): 3.81 mIU/mL; luteinizing hormone (LH): 2.7 mIU/mL; total testosterone: 2.77 ng/mL (N: 2.9–8.36). 1 μg ACTH stimulation test was performed to evaluate hypophyseal-adrenal axis and there was insufficient response to the test (peak cortisol level 7.7 mg/dL). Clinical symptoms and laboratory findings of the patient suggested the diagnosis of ICS due to the prolonged use of a high-potent TS with subsequent ACTH deficiency. The patient had osteopenia on dual energy X-ray absorptiometry (DEXA) scan of the spine. The topical steroid was ceased, and methotrexate (10 mg/week) for psoriatic plaques and hydrocortisone acetate (20 mg/m2/d) were prescribed in order to prevent adrenal insufficiency. Calcium and vitamin D supplementation were given for osteopenia. Calcipotriene ointment and moisturizing lotion treatment were also started.\n\n3. Discussion\nLocal adverse effects of topical steroids are acne, purpura, atrophy, striae, and telangiectasia. ICS and hypothalamic-pituitary-adrenal (HPA) axis suppression are rare but unignorable complications of topical steroids [1, 4–6]. ICS patients may present with purple striae, central obesity, hypertension, buffalo hump, muscle weakness, moon face, hirsutism, and easy bruising of skin like in our patient [1, 4–6].\n\nPV is chronic inflammatory disease and characterized by periods of attack and remission [4–6]. TS is the first choice of treatment for localized and mild PV [4, 5]. In the literature, patients with ICS associated with TS are more frequent in the pediatric age group due to thinner dermis layer of skin and higher surface/volume ratio leading to more absorption rate through the skin [2, 3]. ICS rarely occurs through the topical administration in adults [1, 4, 5]. In the literature, the risk of developing steroid-induced ICS is reported to be associated with the age of the patient, size and localization of lesions, the epithelium integrity, individual metabolic variation, duration of use, powder of drug, duration of therapy, and the sensitivity of steroid receptors [1]. CP binds with high affinity to steroid receptors, with a long half-life making it an effective agent. Sahip et al. [4] presented an adult patient who developed ICS after the treatment of CP 0.005% for 10 years in psoriasis. It was reported in a review that 43 cases including children and adults developed ICS after very potent topical steroid use (majority CP) [7]. The majority of the patients in the children group (n: 22) had diaper dermatitis (86%). The rest of the children (27%) had disorders such as skin dryness, psoriasis, and burn. Mostly used steroid agents in child group were CP and betamethasone. The mean duration of use was 2.75 months (1–17 months). Almost all cases showed the specific Cushing's features. Psoriasis was the most commonly observed disorder in the adult group (71%) as it is in our case. The other diseases were xerosis, lichen planus, intertrigo, dermatitis, and skin lightening (19%). Similar to the group of children, CP 0.05% was the mostly used agent in adult group. The duration of steroid use in adults was about 18 months (0.3–84 months). In this review, it was reported that the suppression of the HPA and secondary adrenal insufficiency in children group was more prominent than in adult group because of multiple risk factors written above [7]. The use of highly effective topical corticosteroids, the amount, frequency, and duration of the application, the structure and the area of the affected skin, and the application of steroids with absorbent clothing were among the main risk factors for the development of ICS after topical steroid use. Additionally, in some countries, individuals can easily buy steroid-containing topical products without a doctor's prescription. Our patient has expressed that steroid ointments were easily purchased in our country.\n\nMoreover, most of these risk factors also play a role in the development of ICS and subsequent adrenalin sufficiency in our patient since he has been using a potent TS (CP) on a great area of the body with large lesions for a very long period of 12 years.\n\nAllenby et al. [8] studied the effects of CP on the HPA axis in 39 patients and found that when more than 50 g per week of CP was applied to the skin, adrenal suppression was to be expected. On the other hand, Sibel et al. [6] showed that four patients (three psoriasis, one atopic dermatitis), who used CP 0.005% cream over a long-term period, developed secondary adrenal deficiency almost 4 months after withdrawal of treatment though three of them used less than 50 g topical steroid per week. Even relatively small doses of CP cream may disrupt the HPA axis, occurring more commonly than has previously been recognized. Following prolonged use of CP at medium doses, adrenal insufficiency may be more common than previously described.\n\nThere is no consensus regarding withdrawal of the steroid treatment in case of development of ICS [1, 4, 6]. The three major complications that may develop upon the cessation of the steroid treatment are exacerbation of the underlying disorder, secondary ACTH failure, and steroid withdrawal syndrome [1, 4, 6, 9]. When CP 0.05% ointment has been used over 2 g per day, it reduces morning cortisol levels after a short time [3, 7]. Tempark et al. [7] reported that the estimated period of the amelioration of the HPA axis disruption was 3.49 ± 2.92 months in children and 3.84 ± 2.51 months in adults. Sibel et al. [6] reported that four patients had evidence of secondary adrenal failure following withdrawal of CP or considerable lowering of the dose, and the HPA axis activity returned normal after 1–4 months. They suggested that when topical CP is used chronically, it should be kept in mind that secondary adrenal failure is likely to occur even though small amount of steroids (7.5 g per week) is used [10]. The dose of glucocorticoids should be increased in case of intervening infections or any operation causing major stress in the patient. This procedure should be applied while using topical steroids or in the 4 months' period after cessation of the treatment. The topical steroid was ceased, and methotrexate (10 mg/week) for psoriatic plaques and hydrocortisone acetate (20 mg/m2/d) per oral were initiated in order to prevent adrenal insufficiency in our case.\n\nIt is difficult to determine the safe dose of steroids. It has been recommended not to exceed four weeks of topical use of steroids, 50 grams per week in adults and 15 grams per week in children [6]. The cut-off value of the CP leading to the HPA axis suppression and Cushing's syndrome is not yet determined. Therefore, further studies are needed to find out the extent of absorption of steroids [1]. Which patients are more prone to the development of adrenal insufficiency during topical steroid application is still not clear. A few months after steroid treatment, we recommend investigation of ACTH and cortisol levels to evaluate adrenal function in all patients. Additionally, all patients should be informed about the characteristic Cushing's syndrome sign and symptoms, for earlier referral to the doctor to diagnose the systemic side effects of glucocorticoids such as hyperglycemia and hypertension.\n\nAcknowledgments\nThe authors would like to thank their patient for the participation in this case report.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 He had a moon face appearance with truncal obesity, buffalo hump, hypertrichosis in trunk, and purple striae in the axilla, periumbilical, and inguinal region.\n\nFigure 2 He had numerous erythematous, scaly psoriatic plaques located on the shoulders, all extremities, dorsum of hands, and feet and at the intertriginous areas.\n==== Refs\n1 Decani S. Federighi V. Baruzzi E. Sardella A. Lodi G. Iatrogenic Cushing's syndrome and topical steroid therapy: Case series and review of the literature Journal of Dermatological Treatment 2014 25 6 495 500 2-s2.0-84892181454 10.3109/09546634.2012.755252 23210698 \n2 Ho C. W.-L. Loke K. Y. Lim Y. Y.-J. Lee Y. S. Exogenous Cushing syndrome: A lesson of diaper rash cream Hormone Research in Paediatrics 2014 82 6 415 418 2-s2.0-84921407781 10.1159/000363517 25300899 \n3 Tiwari A. Manjusha G. Pankaj P. Gohiya P. Exogenous Cushing syndrome: a lesson of diaper rash cream Indian Journal of Endocrinology and Metabolism 2013 17 Supplement 1 S257 S258 24251179 \n4 Sahip B. Celik M. Ayturk S. Iatrogenic Cushing's syndrome after topical steroid therapy for psoriasis Indian Journal of Dermatology 2016 61 1 p. 120 10.4103/0019-5154.174094 \n5 Aydin Y. Kudas O. Kir S. Iatrogenic cushing syndrome due to unrestrained topical steroid usage in an adult patient with psoriasis Case Reports in Endocrinology 2010 5 2 p. 81 \n6 Sibel A. Melih A. Nilgün A. Baskan B. Turkish Guideline for the Treatment of Psoriasis—Archieves of The Turkish Dermatology and Venerology, 2012 \n7 Tempark T. Phatarakijnirund V. Chatproedprai S. Watcharasindhu S. Supornsilchai V. Wananukul S. Exogenous cushing's syndrome due to topical corticosteroid application: Case report and review literature Endocrine Journal 2010 38 3 328 334 2-s2.0-79951722129 10.1007/s12020-010-9393-6 \n8 Allenby C. F. Main R. A. Marsden R. A. Sparkes C. G. Effect on adrenal function of topically applied clobetasol propionate (Dermovate) BMJ 1975 4 5997 619 621 10.1136/bmj.4.5997.619 1203701 \n9 Igaz P. Rácz K. Tóth M. Gláz E. Tulassay Z. Treatment of iatrogenic cushing's syndrome: Questions of glucocorticoid withdrawal Orvosi Hetilap 2007 148 5 195 202 2-s2.0-34249666516 10.1556/OH.2007.27964 17344139 \n10 Ohman E. M. Rogers S. Meenan F. O. McKenna T. J. Adrenal suppression following low-dose topical clobetasol propionate Journal of the Royal Society of Medicine 1987 80 7 422 424 2-s2.0-0023268146 10.1177/014107688708000709 3656312\n\n", "fulltext_license": "CC BY", "issn_linking": "2090-651X", "issue": "2017()", "journal": "Case reports in endocrinology", "keywords": null, "medline_ta": "Case Rep Endocrinol", "mesh_terms": null, "nlm_unique_id": "101576457", "other_id": null, "pages": "8320254", "pmc": null, "pmid": "29259830", "pubdate": "2017", "publication_types": "D002363:Case Reports", "references": "26955131;24251179;1203701;3656312;20972726;23210698;25300899;17344139", "title": "Iatrogenic Cushing's Syndrome with Subsequent Adrenal Insufficiency in a Patient with Psoriasis Vulgaris Using Topical Steroids.", "title_normalized": "iatrogenic cushing s syndrome with subsequent adrenal insufficiency in a patient with psoriasis vulgaris using topical steroids" }

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{ "abstract": "A 53-year-old man was found to have a giant 16 × 6-cm hemorrhagic and cystic mass centered on the pancreas and duodenum. Initially diagnosed as a pancreatic pseudocyst at the time of autopsy, the cystic mass was later determined by histologic examination to be a true diverticulum of the duodenum as microscopic examination of the wall revealed 2 layers of muscle, as well as a neutrophilic infiltrate. While the cause of death of the individual was certified as methamphetamine toxicity, cardiomegaly and probable dehydration associated with a giant duodenal diverticulum were listed as contributory conditions. While duodenal diverticula in general are relatively uncommon findings, an extramural, true, giant duodenal diverticulum that is inflamed is a rare clinical or autopsy finding, with only 2 case reports identified in the clinical medical literature and none in the forensic literature.", "affiliations": "From the University of North Dakota School of Medicine and Health Sciences.;Department of Pathology, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND.", "authors": "Sakry|Rachel C|RC|;Kemp|Walter L|WL|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1097/PAF.0000000000000571", "fulltext": null, "fulltext_license": null, "issn_linking": "0195-7910", "issue": "41(3)", "journal": "The American journal of forensic medicine and pathology", "keywords": null, "medline_ta": "Am J Forensic Med Pathol", "mesh_terms": "D006332:Cardiomegaly; D003681:Dehydration; D004240:Diverticulum; D004378:Duodenal Diseases; D006801:Humans; D008297:Male; D008875:Middle Aged", "nlm_unique_id": "8108948", "other_id": null, "pages": "e54-e55", "pmc": null, "pmid": "32568884", "pubdate": "2020-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "An Inflamed, Giant, True, Extramural Duodenal Diverticulum: A Rare Autopsy Finding.", "title_normalized": "an inflamed giant true extramural duodenal diverticulum a rare autopsy finding" }

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{ "abstract": "Parvovirus-B19 disease in immunocompromised children can cause myelosuppression and therapeutic delays. We studied the clinical profiles of children having symptoms suggestive of parvoviral disease at our institution, a large tertiary cancer center.\n\n\n\nChildren below age 15 years undergoing treatment for malignancies with clinical features suggestive of parvoviral infection, and/or unexplained drop in hemoglobin, and/or prolonged cytopenia were screened for parvovirus infection using DNA-PCR for parvovirus-B19 (PB19) in the peripheral blood. Patients testing positive from September 2014 till February 2017 were studied.\n\n\n\nOf the 59 patients (36 patients with hematolymphoid malignancies, 23 with solid tumors) screened for suspected parvoviral infections, 27 tested positive. Median age was 9.6 years (2.25-15 years), 18 (66%) had hematolymphoid malignancies, while 7 (33%) had solid tumors. Six patients (26%) were on intensive phases, 16 (60%) patients developed the symptoms during maintenance chemotherapy, and 4 (15%) after completion of therapy. Isolated anemia was the commonest feature seen in 10 patients (37%) while bicytopenia and pancytopenia were noticed in 8 (30%) and 9 (33%) patients respectively. Fifty percent of patients those who received rituximab (3/6) developed persistent parvoviremia (>4 weeks) as compared with 24% (5/21) of those who did not. Two patients (7%) developed hemophagocytic lymphohistiocytosis (HLH). Treatment delay by more than 14 days was encountered in a majority (62%), with 5 patients requiring treatment modification or even suspension.\n\n\n\nParvoviral infection in children who are on or have recently completed chemotherapy can lead to multiple cytopenias and significant treatment delays. Rituximab exposure may lead to persistent parvoviral disease (p < 0.05). HLH, though occasional, can be a serious complication.", "affiliations": "Department of Pediatric Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India.;Department of Pediatric Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India.;Department of Pediatric Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India.;Department of Pediatric Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India.;Department of Pediatric Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India.;Department of Pediatric Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India.", "authors": "Ramanathan|Subramaniam|S|0000-0001-5299-2265;Narula|Gaurav|G|0000-0002-8539-295X;Prasad|Maya|M|0000-0003-0127-7987;Vora|Tushar|T|;Chinnaswamy|Girish|G|;Banavali|Shripad|S|", "chemical_list": "D000970:Antineoplastic Agents", "country": "United States", "delete": false, "doi": "10.1002/pbc.27357", "fulltext": null, "fulltext_license": null, "issn_linking": "1545-5009", "issue": "65(11)", "journal": "Pediatric blood & cancer", "keywords": "childhood cancer; parvovirus B19; rituximab", "medline_ta": "Pediatr Blood Cancer", "mesh_terms": "D000293:Adolescent; D000970:Antineoplastic Agents; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007194:India; D008297:Male; D009369:Neoplasms; D010198:Pancytopenia; D010322:Parvoviridae Infections; D016732:Parvovirus B19, Human", "nlm_unique_id": "101186624", "other_id": null, "pages": "e27357", "pmc": null, "pmid": "30058287", "pubdate": "2018-11", "publication_types": "D016428:Journal Article", "references": null, "title": "Parvoviral disease in childhood cancer: Clinical outcomes and impact on therapy at a tertiary cancer center in India.", "title_normalized": "parvoviral disease in childhood cancer clinical outcomes and impact on therapy at a tertiary cancer center in india" }

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PARVOVIRAL DISEASE IN CHILDHOOD CANCER: CLINICAL OUTCOMES AND IMPACT ON THERAPY AT A TERTIARY CANCER CENTER IN INDIA. PEDIATRIC BLOOD AND CANCER 2018?65 (11):1-5.", "literaturereference_normalized": "parvoviral disease in childhood cancer clinical outcomes and impact on therapy at a tertiary cancer center in india", "qualification": "3", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20181013", "receivedate": "20181013", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15495467, "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": "IN-ROCHE-2195851", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DIFFUSE LARGE B-CELL LYMPHOMA", "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": "5", "activesubstance": { "activesubstancename": "IFOSFAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DIFFUSE LARGE B-CELL LYMPHOMA", "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": null, "activesubstance": { "activesubstancename": "HUMAN IMMUNOGLOBULIN G" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 GM/KG", "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": "IVIG" }, { "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": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "008", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FILGRASTIM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DIFFUSE LARGE B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DIFFUSE LARGE B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." } ], "patientagegroup": null, "patientonsetage": "9", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Bone marrow failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Parvovirus B19 infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RAMANATHAN S, NARULA G, PRASAD M, VORA T, PRASAD M, VORA T, CHINNASWAMY G AND BANAVALI S. PARVOVIRAL DISEASE IN CHILDHOOD CANCER: CLINICAL OUTCOMES AND IMPACT ON THERAPY AT A TERTIARY CANCER CENTER IN INDIA. PEDIATRIC BLOOD AND CANCER 2018?65 (11):1-5.", "literaturereference_normalized": "parvoviral disease in childhood cancer clinical outcomes and impact on therapy at a tertiary cancer center in india", "qualification": "3", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20181013", "receivedate": "20181013", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15495468, "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": "IN-MYLANLABS-2018M1079423", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "PART OF VAD CHEMOTHERAPY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRIMITIVE NEUROECTODERMAL TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "040802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "PART OF VCD CHEMOTHERAPY; EVERY THREE WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRIMITIVE NEUROECTODERMAL TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "PART OF VAD CHEMOTHERAPY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRIMITIVE NEUROECTODERMAL TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "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": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "PART OF VCD CHEMOTHERAPY; EVERY THREE WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRIMITIVE NEUROECTODERMAL TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "040802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "PART OF VAD CHEMOTHERAPY", "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": "DEXAMETHASONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BORTEZOMIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "PART OF VCD CHEMOTHERAPY; EVERY THREE WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRIMITIVE NEUROECTODERMAL TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VELCADE" } ], "patientagegroup": null, "patientonsetage": "13", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Parvovirus B19 infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Bicytopenia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20150312" } }, "primarysource": { "literaturereference": "RAMANATHAN S, NARULA G, PRASAD M, VORA T, CHINNASWAMY G, BANAVALI S. PARVOVIRAL DISEASE IN CHILDHOOD CANCER: CLINICAL OUTCOMES AND IMPACT ON THERAPY AT A TERTIARY CANCER CENTER IN INDIA. 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{ "abstract": "Aminoglycoside nephrotoxicity may manifest as nonoliguric renal failure or tubular dysfunction, such as Fanconi-like syndrome, Bartter-like syndrome (BS), or distal renal tubular acidosis. We report a case who developed severe renal tubular dysfunction on the the 7th day of gentamicin therapy, resulting in metabolic alkalosis, refractory hypokalemia, hypocalcemia, hypomagnesemia, and polyuria. The patient was diagnosed as a case of transient BS associated with gentamicin exposure. The patient recovered with conservative management.", "affiliations": "Department of Medicine, King George Medical University, Lucknow, Uttar Pradesh, India.;Department of Medicine, King George Medical University, Lucknow, Uttar Pradesh, India.;Department of Medicine, King George Medical University, Lucknow, Uttar Pradesh, India.;Department of Nephrology, King George Medical University, Lucknow, Uttar Pradesh, India.;Department of Microbiology, Institute of Medical Science, BHU, Varanasi, Uttar Pradesh, India.", "authors": "Singh|J|J|;Patel|M L|ML|;Gupta|K K|KK|;Pandey|S|S|;Dinkar|A|A|", "chemical_list": null, "country": "India", "delete": false, "doi": "10.4103/0971-4065.177206", "fulltext": "\n==== Front\nIndian J NephrolIndian J NephrolIJNIndian Journal of Nephrology0971-40651998-3662Medknow Publications & Media Pvt Ltd India IJN-26-46110.4103/0971-4065.177206Case ReportAcquired Bartter syndrome following gentamicin therapy Singh J. Patel M. L. Gupta K. K. Pandey S. 1Dinkar A. 2Department of Medicine, King George Medical University, Lucknow, Uttar Pradesh, India1 Department of Nephrology, King George Medical University, Lucknow, Uttar Pradesh, India2 Department of Microbiology, Institute of Medical Science, BHU, Varanasi, Uttar Pradesh, IndiaAddress for correspondence: Dr. J. Singh, Department of Medicine, King George's Medical University, Lucknow, Uttar Pradesh, India. E-mail: drjitengsvm@gmail.comNov-Dec 2016 26 6 461 463 Copyright: © Indian Journal of Nephrology2016This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Aminoglycoside nephrotoxicity may manifest as nonoliguric renal failure or tubular dysfunction, such as Fanconi-like syndrome, Bartter-like syndrome (BS), or distal renal tubular acidosis. We report a case who developed severe renal tubular dysfunction on the the 7th day of gentamicin therapy, resulting in metabolic alkalosis, refractory hypokalemia, hypocalcemia, hypomagnesemia, and polyuria. The patient was diagnosed as a case of transient BS associated with gentamicin exposure. The patient recovered with conservative management.\n\nAcquired Bartter-like syndromeelectrolyte imbalancegentamicin\n==== Body\nIntroduction\nBartter syndrome is a rare autosomal recessive disorder, manifested in childhood or in the perinatal period with severe hypokalemia, metabolic alkalosis, and low-normal blood pressure. It is due to primary defect in sodium chloride reabsorption in the medullary thick ascending limb of the loop of Henle. Bartter syndrome is caused by inactivating mutation of each of its major transport proteins NKCC2, ROMK, ClC-Kb, and bartin which are typed as Bartter syndrome 1, 2, 3, and 4, respectively.[1] Gentamicin-induced renal tubular dysfunction may present as a acquired Bartter-like syndrome (BS) and to the best of our knowledge, only a few cases are reported in literature.[234]\n\nCase Report\nA 26-year-old male was admitted with 6-day history of high-grade fever followed by productive cough who was diagnosed as a case of the right-sided pneumonitis. He was put on two intravenous (IV) ampicillin and gentamicin. Investigations showed increased white cells count (15,100/cmm) with normal serum electrolytes, renal profile, and liver function test. Subsequently, white cells count normalizzed on the the 5th day of treatment. The patient was relieved and became afebrile.\n\nOn the 7th day of admission, the patient complained of nausea and generalized weakness. In the evening he had one episode of generalized tonic-clonic seizure. On the initial evaluation, his Glasgow Coma Scale was 10/15 (E2V3M5). Both pupils were normal in size and reactive to light. His vital signs were blood pressure 124/70 mmHg, pulse rate 104/min, temperature 98.6°F, and respiratory rate 18/min. Signs of meningeal irritation were absent. General and systemic examinations were unremarkable. He was managed immediately with intravenous (IV) diazepam 10mg bolus dose and IV phenytoin at a loading dose of 15mg/kg followed by 100mg 8 hourly.\n\nThe blood gas analysis revealed pH 7.54, PCO2 42 mmHg, PO2 114 mmHg, SO2 98.8%, sodium 112 mmol/L, potassium 2.2 mmol/L, bicarbonate 38 mmol/L, and calcium (Ca) (ionic) 0.82 mmol/L. His ultrasonography revealed normal kidneys. Computed tomography of the head detected no abnormality, and cerebrospinal fluid cerebrospinal fluid analysis was normal. Thyroid profile and serum cortisol level were normal. We noted increase in urine output (>5 L/24 h) after an episode of seizure. Urinary osmolality was measured as 400 mOsm/kg (500-800). Spot urine found K+ 13 (3.5-5.0 mmol/L) and Na+ 129 (<20 mmol/L). Twenty-four hours urine collection revealed Ca of 475 mg (50-300).\n\nBlood chemistry showed gross electrolytes abnormalities, suggestive of metabolic encephalopathy, and the seizure episode could be due to severe hypocalcemia and/or hyponatremia. These abnormalities persisted for many days [Table 1]. These deranged parameters as a result of severe renal salt wasting were due to defective renal tubular concentrating ability. The patient was diagnosed as a case of BS associated with gentamicin exposure. Gentamicin was stopped immediately. Electrolyte replacements were started accordingly. His laboratory parameters normalized after 13 days and remained asympotomatic thereafter.\n\nTable 1 Significant investigations of patient, since the day of hospitalization* and seizure#\n\nDiscussion\nAminoglycosides are known to produce vestibular, cochlear, and renal toxicity. Approximately, 8%–26% of patients receiving an aminoglycoside for several days will develop mild renal impairment which is almost always reversible.[5] Gentamicin is excreted by glomerular filtration, and toxicity is due to the the accumulation of drug in porphyria cutanea tarda porphyria cutanea tarda cells. The drug interferes with cellular energetic, impares intracellular phospholipase, and induces oxidative stress which in turn results in cell destruction.[1] However, mitochondrial dysfunction is hypothesized for underlying abnormalities in all parts of the renal tubule.[2] Thus, aminoglycoside-induced renal tubular dysfunction may present as Fanconi-like syndrome, BS, and distal renal tubular acidosis.[23] The exact pathways culminating in aminoglycoside-induced BS is not well known and may be similar to the hereditary variant of Bartter's disease which involves a transporter defect situated in the thick ascending loop of the renal tubule. It is hypothesised that gentamicin, a polyvalent cationic molecule, directly activates the Ca sensing receptor in the thick ascending loop of Henle and the distal tubule, which results in renal wasting of sodium, potassium, chloride, Ca, and magnesium.[34] The risk of renal tubular dysfunction is related to a prolonged and inappropriately high-dose aminoglycosides use.[2] Cases of transient Bartter's syndrome associated with aminoglycoside use have been described to recover after 2–6 weeks following cessation of the antibiotics.[26] The presentation of our patient (metabolic alkalosis, refractory hypokalemia, hypocalcemia hypomagnesemia, and hypercalceuria) was suggestive of BS while other close differential diagnosis, Gitelman syndrome was ruled out by the the presence of low serum Ca level and documentation of hypercalciuria.[7] Our case represents characterization of a rare and potential danger of gentamicin therapy.\n\nConclusion\nPatients on gentamicin therapy should be monitored. Routinely for electrolyte imbalances to avoid potential morbidity and life-threatening condition.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Gross P Heduschka P Floege J Johnson RJ Feehally J Inherited disorder of sodium and water handling. Comprehensive Clinical Nephrology 2010 4th ed Saunders An Imprint of Elsevier Inc 573 84 \n2 Chrispal A Boorugu H Prabhakar AT Moses V Amikacin-induced type 5 Bartter-like syndrome with severe hypocalcemia J Postgrad Med 2009 55 208 10 19884751 \n3 Hung CC Guh JY Kuo MC Lai YH Chen HC Gentamicin-induced diffuse renal tubular dysfunction Nephrol Dial Transplant 2006 21 547 8 16204274 \n4 Chou CL Chen YH Chau T Lin SH Acquired bartter-like syndrome associated with gentamicin administration Am J Med Sci 2005 329 144 9 15767821 \n5 Smith CR Lipsky JJ Laskin OL Hellmann DB Mellits ED Longstreth J Double-blind comparison of the nephrotoxicity and auditory toxicity of gentamicin and tobramycin N Engl J Med 1980 302 1106 9 6988713 \n6 Workeneh B Sangsiraprapha W Addison D Longfield E A novel case of persistent Bartters-like syndrome associated with gentamicin exposure Saudi J Kidney Dis Transpl 2013 24 144 6 23354214 \n7 Onem Y Kucukardali Y Sahan B Atasoyu EM Ipcioglu O Terekeci H Analyses of subjects with hypokalemic metabolic alkolosis, Gitelman's and Bartter's syndrome Ren Fail 2008 30 691 4 18704817\n\n", "fulltext_license": "CC BY-NC-SA", "issn_linking": "0971-4065", "issue": "26(6)", "journal": "Indian journal of nephrology", "keywords": "Acquired Bartter-like syndrome; electrolyte imbalance; gentamicin", "medline_ta": "Indian J Nephrol", "mesh_terms": null, "nlm_unique_id": "8914356", "other_id": null, "pages": "461-463", "pmc": null, "pmid": "27942182", "pubdate": "2016", "publication_types": "D002363:Case Reports", "references": "15767821;16204274;23354214;19884751;18704817;6988713", "title": "Acquired Bartter syndrome following gentamicin therapy.", "title_normalized": "acquired bartter syndrome following gentamicin therapy" }

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{ "abstract": "Orbital decompression is a surgical procedure aimed at increasing the orbital volume and/or decreasing the volume of the orbital fat. The indications for orbital decompression are determined in the course of thorough eye examination. An important objective of examination of a patient with thyroid eye disease (TED) is determination of inflammation activity and severity. Orbital decompression is a surgical procedure that can be performed in both the active and nonactive stages of the disease. However, the indications for the surgery in these cases are different. Optic neuropathy and severe corneal disease are threatening complications that may lead to permanent visual loss and generally occur in the presence of active orbital inflammation. If treatment with high-dose corticosteroids has proven ineffective, an urgent surgical procedure consisting of orbital decompression and, in case of involvement of the cornea, eyelid and corneal surgery has to be performed. Owing to significant progress in technology, improvement of methods and accumulated experience over the past decade, the indications for bone orbital decompression have extended compared to the time when this procedure was used only in patients with extremely severe TED. The most common complication of the orbital decompression is the development or deterioration of previously existing binocular diplopia and strabismus. In addition, other parameters may change as well, including the position of the globe, the eyelids, the angle of deviation of the eye, and intraocular pressure. Thus, bone orbital decompression is a major step of a comprehensive, often multistage, system of rehabilitation of patients with severe refractory TED.", "affiliations": "Research Institute of Eye Diseases, Moscow, Russia.;Endocrinology Research Centre, Moscow, Russia, natsvir@inbox.ru.;Research Institute of Eye Diseases, Moscow, Russia.;Endocrinology Research Centre, Moscow, Russia, natsvir@inbox.ru.", "authors": "Ismailova|Dilyara S|DS|;Belovalova|Irina M|IM|;Grusha|Yaroslav O|YO|;Sviridenko|Natalya Y|NY|", "chemical_list": null, "country": "New Zealand", "delete": false, "doi": "10.2147/IMCRJ.S164372", "fulltext": "\n==== Front\nInt Med Case Rep JInt Med Case Rep JInternational Medical Case Reports JournalInternational Medical Case Reports Journal1179-142XDove Medical Press 10.2147/IMCRJ.S164372imcrj-11-243Case ReportOrbital decompression in the system of treatment for complicated thyroid eye disease: case report and literature review Ismailova Dilyara S 1Belovalova Irina M 2Grusha Yaroslav O 13Sviridenko Natalya Y 2\n1 Research Institute of Eye Diseases, Moscow, Russia\n2 Endocrinology Research Centre, Moscow, Russia, natsvir@inbox.ru\n3 I.M. Sechenov First Moscow State Medical University, Moscow, RussiaCorrespondence: Natalya Y Sviridenko, Endocrinology Research Centre, 11, Dmitriya Ulyanova Street, 117036 Moscow, Russia, Tel +74 99 124 5832, Email natsvir@inbox.ru2018 01 10 2018 11 243 249 © 2018 Ismailova et al. This work is published and licensed by Dove Medical Press Limited2018The 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.Orbital decompression is a surgical procedure aimed at increasing the orbital volume and/or decreasing the volume of the orbital fat. The indications for orbital decompression are determined in the course of thorough eye examination. An important objective of examination of a patient with thyroid eye disease (TED) is determination of inflammation activity and severity. Orbital decompression is a surgical procedure that can be performed in both the active and nonactive stages of the disease. However, the indications for the surgery in these cases are different. Optic neuropathy and severe corneal disease are threatening complications that may lead to permanent visual loss and generally occur in the presence of active orbital inflammation. If treatment with high-dose corticosteroids has proven ineffective, an urgent surgical procedure consisting of orbital decompression and, in case of involvement of the cornea, eyelid and corneal surgery has to be performed. Owing to significant progress in technology, improvement of methods and accumulated experience over the past decade, the indications for bone orbital decompression have extended compared to the time when this procedure was used only in patients with extremely severe TED. The most common complication of the orbital decompression is the development or deterioration of previously existing binocular diplopia and strabismus. In addition, other parameters may change as well, including the position of the globe, the eyelids, the angle of deviation of the eye, and intraocular pressure. Thus, bone orbital decompression is a major step of a comprehensive, often multistage, system of rehabilitation of patients with severe refractory TED.\n\nKeywords\nGraves’ diseasethyroid eye diseaseorbital decompressionophthalmopathycorneal ulcertarsoraphy\n==== Body\nIntroduction\nThyroid eye disease (TED) is the most common and quite often severe autoimmune disorder complicating the course of Graves’ disease. In most cases (60%), TED is not associated with serious eye disorders; however, even minimal cosmetic changes are sometimes poorly tolerated by patients. In approximately one-third of patients (mostly smokers), TED becomes severe and requires surgical treatment (40%–45%) with the purpose of vision correction and correction of cosmetic defects. This may be due to delayed diagnosis of Graves’ disease and TED itself, as well as untimely and inappropriate treatment.\n\nTeamwork with patients is very important since therapy for TED requires strict maintenance of euthyroidism (normal levels of thyroid hormones). In addition to maintaining euthyroidism, other important factors related to TED treatment include decrease in duration and severity of active TED, prevention of fibrosis development, decrease in the frequencies of adverse effects, and complications of immunosuppressive therapy. The major personalized treatment criteria are the severity and activity of inflammation in the orbits1 since moderate and severe TED2 may be observed in patients with non-active disease, when immunosuppressive and radiation therapy are not effective. Optic neuropathy (ON) is a threatening complication of TED that develops in about 5% of patients and includes progressive visual loss, color vision impairment, visual field defects, and optic disc edema.3 In case of marked exophthalmos, lagophthalmos, lack of Bell’s phenomenon, ophthalmoplegia, and subluxation of globe, a corneal ulceration and haze may occur.4 In these cases, treatment of active TED begins with immunosuppressive therapy with high-dose corticosteroids (CSs). High-dose methylprednisolone (pulse therapy) is recommended as a first-line therapy.5 If no improvement is observed within 2–3 weeks and the process in the orbits continues progressing, the only way to preserve vision is to perform an orbital decompression.6 The greatest difficulties are associated with treatment of patients with refractory TED complicated with ON with involvement of the cornea and marked hypotropia.\n\nIn Russia, treatment of severe TED is attended with great difficulties. There are several reasons for this. The first is connected with often inappropriate treatment of TED in non-specialized clinics, which leads to delay in orbital surgery. The second reason is the orthodox opinion that bony orbital decompression carries a high risk of complications and has low effectiveness. And finally, access to specialized treatment in TED centers in faraway regions of Russia and monitoring of these patients is often difficult.\n\nWe present a clinical case of a female patient with severe TED and discuss the difficult choice of her personalized therapy.\n\nCase report\nWritten informed consent was obtained from the patient to have the case details and images published.\n\nA female patient aged 64 years presented to the Endocrinology research centre (Moscow, Russia) with complaints of continuous diplopia, bulging of both eyes, eye pain, eye redness, vision impairment, and color vision disturbances.\n\nEye pain, sensation of eye pressure, diplopia, and lacrimation manifested in June 2012.Thyrotoxicosis was diagnosed and therapy with antithyroid agents was initiated. The patient received the medications regularly and did not smoke. In September 2012, the patient received CS therapy (dexamethasone, 12 tablets per day followed by dose tapering), with insignificant improvement namely reduction of diplopia. Multiple periocular injections of CS were performed, resulting in insignificant positive changes.\n\nIn October 2013, the first pulse therapy with methylprednisolone 500 mg IV (three injections) and oral dexamethasone was conducted, leading to short-term improvement. Starting from March 2014, methylprednisolone was administered according to the following regimens: 500 mg IV No.3; 1000 mg IV No.3; 500 mg No. 9; 250 mg No. 9; 125 mg No.9. Between methylprednisolone infusions, oral prednisone was administered. The patient reported short-term improvement and reduction in exophthalmos and diplopia. Overall cumulative dose of methylprednisolone comprised 15,170 mg (>15 g), which is not currently considered an appropriate dosage. As a result of therapy, the patient’s face became more round-shaped and she gained 7 kg of weight. Although pulse therapy with CS is better tolerated by patients compared to treatment with CS in tablets, approximately 0.8% of patients receiving high cumulative doses of CS develop acute liver disorder and fatal hepatic failure. The safe cumulative dose of methylprednisolone is <8 g.\n\nRegarding the prior treatment, we should note that from the standpoint of evidence-based medicine, neither dexamethasone (because of its narrow therapeutic window) nor periocular injections of dexamethasone can be considered an optimal treatment option. Therefore, it is very disappointing that these regimens were used for a long time despite disease progression and the observed side effects.\n\nOn December 16, 2014, a thyroidectomy was performed at a local clinic and treatment with levothyroxine sodium 125 µg was prescribed. Histological examination demonstrated sclerosing follicular microcarcinoma. Thyroid scintigraphy was performed on January 22, 2015, and showed foci of weakly functioning tissue (1.2×1 cm on the right and 0.8×0.8 cm on the left) in the bed of the removed thyroid gland. Blood tests were conducted on April 21, 2015, while the patient was receiving levothyroxine sodium 125 µg, and showed the following: thyroid-stimulating hormone =0.57 mIU/L (0.23–4.2); free thyroxine (fT4) =20 pmol/L (12–22); thyroglobulin (Tg) ≤0.20 ng/mL. No significant changes were observed in the eyes following surgical treatment. It should be noted that detection of microcarcinoma during thyroidectomy for Graves’ disease is a well-known phenomenon, which does not significantly affect further treatment strategy. However, it can be a source of additional emotional burden for the patient.\n\nIn April 2015, there was exophthalmos progression and eye pain. A corneal ulcer was discovered by a physician at a local clinic. Tarsorrhaphy was performed on the left eye.\n\nOn May 18, 2015, the patient was admitted to the Department of Therapeutic Endocrinology presenting with euthyroidism (thyroid-stimulating hormone =1.26 mIU/L; Tg =1.51 ng/mL; anti-Tg antibodies =13 IU/mL; glucose =5.0 mmol/L). At the moment of admission, the patient was receiving levothyroxine sodium 125 µg.\n\nExamination revealed bilateral marked exophthalmos, hyperpigmentation, and eyelid swelling. OD: dilated episcleral vessels, chemosis, and restriction of globe motility when looking upward and outward. Partial ankyloblepharon (result of tarsorrhaphy), lagophathalmos, hypotropia, and corneal ulcer were revealed (Figure 1). Multislice CT scan of the orbits revealed marked enlargement of extraocular muscles, apical crowding, swelling and fibrous changes in the orbital fat, and tightening optic nerves (Figure 2). Thyroid ultrasonography showed the following measurements: total volume =1.1 cm3, dimensions of the right lobe =1.0×1.0×1.4 cm, and dimensions of the left lobe =0.9×0.8×1.3 cm. The texture was heterogeneous, and echogenicity was decreased; color Doppler flow imaging showed moderately increased vascularization. Regional lymph nodes were up to 0.6 cm in diameter and of normal structure. Our conclusion after the subtotal thyroidectomy was that the echotexture of the residual thyroid tissue was typical of an autoimmune disorder.\n\nOur diagnosis was primary hypothyroidism resulting from subtotal thyroidectomy for Graves’ disease at the stage of drug-induced compensation, severe TED (active phase), optic neuropathy, binocular diplopia, and keratopathy. There was sclerosing microcarcinoma in the tissue of the removed thyroid gland.\n\nIt should be noted that although microcarcinoma is an accidental finding and no suppressive therapy with levothyroxine is required after its removal (and its detection does not affect the treatment strategy), subsequent thorough follow-up with control of the condition of lymph nodes and thyroglobulin levels may be needed because of the type of the tumor (sclerosing microcarcinoma).\n\nTaking into account the lack of response to drug therapy, the presence of optic neuropathy, and the involvement of the cornea, the patient was referred to the Research Institute of Eye Diseases (Moscow, Russia) for orbital decompression.\n\nAt the moment of admission to the Institute of Eye Diseases, the OD visual acuity with the best correction (BCVA) was 1.0 and the OS was 0.2. The OD IOP was18 mmHg and the OS IOP was 39 mmHg. There was marked bilateral eyelid swelling and bilateral exophthalmos. There was OD orthotropia; the movements were insignificantly restricted when looking upward. There was also retraction of the upper and lower eyelids but no lagophthalmos. Mild hyperemia and swelling of the conjunctiva were noted. The cornea had anterior stromal round opacities, most likely as a result of adenoviral conjunctivitis. The left palpebral fissure was partially closed in the outer half because of an interpalpebral adhesion (a result of tarsorrhaphy). The globe was deviated downward by 25°, with no movements above the level of primary gaze. Mild “red” chemosis and deep stromal opacity in the lower third of the cornea (outcome of the corneal ulcer) were seen. The lens showed initial cortical opacifications. The optic nerves on both sides were pale pink with well-defined borders.\n\nOn June 9, 2015, the bony decompression of three orbital walls of the left eye was performed. The lateral wall was resected via a transcutaneous approach; the medial and a part of the inferior wall were resected via a transconjunctival approach. However, due to lack of upward movements of the globe and poor Bell’s phenomenon, temporary partial tarsorrhaphy was performed in order to prevent a recurrence of a corneal ulcer. At the moment of discharge from the hospital, the OS visual acuity was 0.4 and exophthalmos had decreased by 5 mm, while the parameters of visual field examination and color perception improved and the intraocular pressure decreased to normal values. The findings of the multislice CT scan after the surgery are shown in Figure 3. The effect of the surgery remained stable for 1.5 months.\n\nOne-and-a-half months after OS decompression, the patient developed signs of reactivation of orbital inflammation. She received three IV injections of methylprednisolone 250 mg, which resulted in positive changes. Two-and-a-half months after the decompression, a course of radiation therapy was conducted with a focal radiation therapy dose of 15 mSv on each orbit. The treatment resulted in significant improvement.\n\nEight months after the end of radiation therapy, the patient underwent a surgical procedure for OS strabismus correction at a local clinic (Figure 4). Normalization of the eye position allowed to cut interpalpebral adhesion without a risk of a corneal ulcer recurrence (Figure 5). The patient also underwent cataract surgery (phacoemulsification) on both eyes at a local clinic, resulting in improvement of BCVA OD to 1.0, and OS to 0.9. In this patient, a posterior capsular cataract was a complication of long-term therapy with corticosteroids as well as radiation therapy. There was no diplopia in primary gaze. While on therapy with antiglaucoma agents, IOP remained normal.\n\nDuring a 2-year follow-up after the surgery, there were no new episodes of reactivation of the orbital inflammation, and no signs of exposure keratopathy or optic neuropathy. On replacement therapy with levothyroxine sodium 125 µg, the patient maintained stable euthyroidism.\n\nDiscussion\nCorneal damage and ON are the most dangerous vision threatening complications of TED. In the case of delayed treatment, they can cause permanent visual loss.7 For patients with TED demonstrating no response to immunosuppressive therapy, bony orbital decompression is a key element of treatment and subsequent rehabilitation.8 Decompression surgery has been used for TED treatment for over 100 years. At first, it was only used in cases of severe complications, such as ON and keratopathy, which were refractory to drug therapy. Over the past several years, orbital decompression has been used in non-TED, with the purpose of eliminating cosmetic and functional defects. To date, many methods of decompression have been suggested in order to improve surgical outcomes and esthetic results, to decrease the duration of recovery period, to decrease the risk of iatrogenic complications, and specifically, to decrease the development of strabismus.9–15 The studies have shown that in most cases (except for rare cases when individual approaches were applied), the selection of a technique of surgical decompres sion was based on clinical features, personal experience of a surgeon, and current treatment algorithms adopted in a particular country. Therefore, such parameters as reduction in the degree of exophthalmos, frequencies of complications and side effects, and the degree of patients’ satisfaction were generally predictable and comparable. As has been demonstrated in clinical and experimental studies, decompression of two orbital walls leads to a decrease of approximately 3–6 mm in exophthalmos, which is why this procedure is most widely used.16–18 Removal of orbital fat results in an exophthalmos reduction of approximately 3–4 mm.19–22 In some cases, the average exophthalmos reduction following the fat decompression is 5.3 mm.23 Exophthalmos regression as a result of endonasal endoscopic orbital decompression via the transethmoidal approach is 3.5–6 mm.24,25 Improvement of the visual functions is observed in 82% of patients the next morning following the orbital decompression. The most common complications of this surgery include diplopia and strabismus, occurring in 15%–74% of patients.26–37 Ptosis and globe dystopia are far less frequent. Cases of some other rare complications such as cerebrospinal fluid leak, central nervous system infection, eye or optic nerve injury, cerebral vasospasm, traumatic neurinoma, trigeminal nerve damage, and intracranial hemorrhage have been reported.38–44 The methods of bony orbital decompression are constantly evolving. The preferred methods are combined ones: medial + inferior or balanced (medial + lateral).45 Up-to-date algorithms imply the use of bony orbital decompression followed by extraocular muscle surgery, correction of eyelid retraction, and esthetic eyelid and facial surgery. Each surgical procedure should be conducted while taking into account the needs of a particular patient and should aim not only to prevent blindness and restore the visual functions, but also for esthetic rehabilitation. This clinical case is of interest because of a severe course of refractory TED, which resulted in both corneal ulcer and ON. Using this case, we would like to demonstrate the necessity of a definite sequence of different treatment modalities and surgical interventions, in particular: immunosuppressive drug therapy, bony orbital decompression with tarsorrhaphy, radiation therapy during the active phase of the disease, and strabismus correction in fibrotic stage. In this case, the involvement of cornea in the active phase was caused by several factors, with the major role played by the enlargement of the inferior rectus muscle, secondary upward restriction, and, as a consequence, lack of Bell’s phenomenon which, in the presence of lagophthalmos, led to corneal ulcer. At the same time, significantly enlarged extraocular muscles compressed the optic nerve at the apex of the orbit and caused the development of ON. Since TED was active, the pulse therapy was the first line of treatment. However, as a result of insufficient efficacy of prior therapy, bony orbital decompression was performed to “unload” the retrobulbar part of the orbit and tarsorrhaphy was performed to protect the cornea.46,47 The sequence used was quite unusual because the eyelid surgery was performed during the active phase; however, it was an urgent procedure because of corneal ulcer. In such a situation, this sequence was justifiable, as it allowed us to maintain the transparency of the optical zone of the cornea prior to the fibrotic stage when extraocular muscle surgery could be performed. Thus, bony orbital decompression is a major step of a comprehensive, often multistage system of rehabilitation of patients with severe refractory TED.\n\nAcknowledgments\nThe authors acknowledge Dr Yury I Philippov for the help in formatting the manuscript and for submitting it to the journal.\n\nAuthor contributions\n\nNY Sviridenko and IM Belovalova (endocrinologists) supervised the patient. YO Grusha and DS Ismailova (ophthalmologists and surgeons) supervised the patient. All authors equally contributed to the case report data acquisition, and its analysis and interpretation. All authors substantially contributed to drafting, editing, and revising the article. They all read and approved the final version of the manuscript to be published and agree 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\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 The patient’s appearance on admission to Endocrinology research centre (Moscow, Russia).\n\nNotes: OU (both eyes): exophthalmos; OS (left eye): interpalpebral adhesion, lagophthalmos, hypotropia, and corneal ulcer.\n\nFigure 2 Multislice CT scan (coronal plane) prior to orbital decompression.\n\nNote: There is significant enlargement of the extraocular muscles, more pronounced on the left, and apical crowding.\n\nFigure 3 Multislice scan (coronal plane) 1 week after bony decompression of the left orbit.\n\nNotes: There are defects in the lateral, medial, and inferior orbital walls. Significantly enlarged medial and inferior rectus muscles are displaced toward the defects in the corresponding walls. The lateral rectus muscle and orbital fat are observed outside the internal contour of the lateral wall.\n\nFigure 4 The patient’s appearance 3 months after the orbital decompression and 1 month after the radiation therapy.\n\nNotes: OS (left eye): hypotropia, upper eyelid retraction, lagophthalmos, and superficial keratopathy.\n\nFigure 5 The patient’s appearance 16 months after bony orbital decompression and strabismus surgery. Orthotropy in primary gaze position.\n==== Refs\nReferences\n1 Mourits MP Koornneef L Wiersinga WM Prummel MF Berghout A van der Gaag R Clinical criteria for the assessment of disease activity in Graves’ ophthalmopathy: a novel approach Br J Ophthalmol 1989 73 8 639 644 2765444 \n2 Werner SC Modification of the classification of the eye changes of Graves’ disease Am J Ophthalmol 1977 83 5 725 727 577380 \n3 Brovkina AF Aubakirova AS Zritel’nye rasstrojstva pri opticheskoj nejropatii u bol’nyh jendokrinnoj oftal’mopatiej [Visual disorders in optic neuropathy in patients with edematous exophthalmos] Proceedings of the IX Conference, Aktual’nye voprosy nejrooftal’mologii Moscow 26 Jan 2007 19 21 \n4 European Group on Graves’ Orbitopathy (EUGOGO) Wiersinga WM Perros P Clinical assessment of patients with Graves’ orbitopathy: the European Group on Graves’ Orbitopathy recommendations to generalists, specialists and clinical researchers Eur J Endocrinol 2006 155 3 387 389 16914591 \n5 Bartalena L Baldeschi L Boboridis K The 2016 European Thyroid Association/European Group on Graves’ Orbitopathy Guidelines for the Management of Graves’ Orbitopathy Eur Thyroid J 2016 5 1 9 26 27099835 \n6 Krassas GE Wiersinga WM Thyroid eye disease: current concepts and the EUGOGO perspective Thyroid International 2005 4 3 21 \n7 Sviridenko NY Belovalova IM Sheremeta MS Graves’ Ophthalmopathy Moscow MAI-PRINT 2012 \n8 Della Rocca RC Thyroid-related orbitopathy: concepts and management Facial Plast Surg 2007 23 3 168 173 17691064 \n9 Reich SS Null RC Timoney PJ Sokol JA Trends in Orbital Decompression Techniques of Surveyed American Society of Ophthalmic Plastic and Reconstructive Surgery Members Ophthal Plast Reconstr Surg 2016 32 6 434 437 \n10 European Group on Graves’ Orbitopathy (EUGOGO) Mourits MP Bijl H Outcome of orbital decompression for disfiguring proptosis in patients with Graves’ orbitopathy using various surgical procedures Br J Ophthalmol 2009 93 11 1518 1523 19028743 \n11 Mehta P Durrani OM Outcome of deep lateral wall rim-sparing orbital decompression in thyroid-associated orbitopathy: a new technique and results of a case series Orbit 2011 30 6 265 268 22132843 \n12 Sasim IV de Graaf ME Berendschot TT Kalmann R van Isterdael C Mourits MP Coronal or swinging eyelid decompression for patients with disfiguring proptosis in Graves’ orbitopathy? Comparison of results in one center Ophthalmology 2005 112 7 1310 1315 15950284 \n13 Baldeschi L Macandie K Hintschich C Wakelkamp IM Prummel MF Wiersinga WM The removal of the deep lateral wall in orbital decompression: its contribution to exophthalmos reduction and influence on consecutive diplopia Am J Ophthalmol 2005 140 4 642.e1 64642 16140250 \n14 Bailey KL Tower RN Dailey RA Customized DRA Customized, single-incision, three-wall orbital decompression Ophthalmic Plast Reconstr Surg 2005 21 1 1 9 15677945 \n15 Terwee CB Gerding MN Dekker FW Prummel MF Wiersinga WM Development of a disease specific quality of life questionnaire for patients with Graves’ ophthalmopathy: the GO-QOL Br J Ophthalmol 1998 82 7 773 779 9924370 \n16 Goldberg RA Perry JD Hortaleza V Tong JT Strabismus after balanced medial plus lateral wall versus lateral wall only orbital decompression for dysthyroid orbitopathy Ophthalmic Plast Reconstr Surg 2000 16 4 271 277 10923974 \n17 Leone CR Piest KL Newman RJ Medial and lateral wall decompression for thyroid ophthalmopathy Am J Ophthalmol 1989 108 2 160 166 2757096 \n18 Mourits MP Koornneef L Wiersinga WM Prummel MF Berghout A van der Gaag R Orbital Decompression for Graves’ Ophthalmopathy by Inferomedial, by Inferomedial Plus Lateral, and by Coronal Approach Ophthalmology 1990 97 5 636 641 2342809 \n19 Prat MC Braunstein AL Dagi Glass LR Kazim M Orbital fat decompression for thyroid eye disease: retrospective case review and criteria for optimal case selection Ophthalmic Plast Reconstr Surg 2015 31 3 215 218 25198394 \n20 Trokel S Kazim M Moore S Orbital fat removal. Decompression for Graves orbitopathy Ophthalmology 1993 100 5 674 682 8493010 \n21 Kazim M Trokel SL Acaroglu G Elliott A Reversal of dysthyroid optic neuropathy following orbital fat decompression Br J Ophthalmol 2000 84 6 600 605 10837384 \n22 Richter DF Stoff A Olivari N Transpalpebral decompression of endocrine ophthalmopathy by intraorbital fat removal (Olivari technique): experience and progression after more than 3000 operations over 20 years Plast Reconstr Surg 2007 120 1 109 123 17572552 \n23 Brovkina AF Endokrinnaja oftalmopatija [Endocrine ophthalmopathy] Moscow GEOTAR-Media 2004 \n24 Kochetkov PA Sviridenko NY Endonasal endoscopic transethmoidal orbital decompression for patients with Graves` desease and endocrine ophthalmopathy Clinical and Experimental Thyroidology 2010 6 1 26 31 \n25 Kochetov PA Lopatin AS Sergienko NIu Endonasal endoscopic orbital decompression through the transethmoidal approach Vestn Otorinolaringol 2009 4 4 23 26 \n26 European Group on Graves’ Orbitopathy (EUGOGO) Mourits MP Bijl H Outcome of orbital decompression for disfiguring proptosis in patients with Graves’ orbitopathy using various surgical procedures Br J Ophthalmol 2009 93 11 1518 1523 19028743 \n27 Metson R Samaha M Endoscopic orbital decompression Woog JJ Manual of Endoscopic Lacrimal and Orbital Surgery 1 Philadelphia, PA Butterworth-Heinemann Medical 2004 \n28 Michel O Oberländer N Neugebauer P Neugebauer A Rüssmann W Follow-up of transnasal orbital decompression in severe Graves’ ophthalmopathy Ophthalmology 2001 108 2 400 404 11158820 \n29 Metson R Samaha M Reduction of diplopia following endoscopic orbital decompression: the orbital sling technique Laryngoscope 2002 112 10 1753 1757 12368609 \n30 Leone CR Piest KL Newman RJ Medial and lateral wall decompression for thyroid ophthalmopathy Am J Ophthalmol 1989 108 2 160 166 2757096 \n31 Mourits MP Koornneef L Wiersinga WM Prummel MF Berghout A van der Gaag R Orbital decompression for Graves’ ophthalmopathy by inferomedial, by inferomedial plus lateral, and by coronal approach Ophthalmology 1990 97 5 636 641 2342809 \n32 Rocchi R Lenzi R Marinò M Rehabilitative orbital decompression for Graves’ orbitopathy: risk factors influencing the new onset of diplopia in primary gaze, outcome, and patients’ satisfaction Thyroid 2012 22 11 1170 1175 23072549 \n33 Ben Simon GJ Syed HM Syed AM Lee S Strabismus after deep lateral wall orbital decompression in thyroid-related orbitopathy patients using automated hess screen Ophthalmology 2006 113 6 1050 1055 16751042 \n34 Esser J Eckstein A Ocular muscle and eyelid surgery in thyroid-associated orbitopathy Exp Clin Endocrinol Diabetes 1999 107 Suppl 5 S214 S221 10614926 \n35 Fichter N Schittkowski M Hingst V Guthoff RF Graves’ orbitopathy – radiological aspect safer orbital decompression and correlation to clinical findings Proceedings of the 24th Meeting of the European Society of Ophthalmic Plastic and Reconstructive Surgery 2006 London \n36 Esser J Schittkowski M Eckstein A Graves’ orbitopaty: inferior rectus tendon elongation for large vertical squint angles that cannot be corrected by simple muscle recession Klin Monbl Augenheilkd 2011 228 10 880 886 21997825 \n37 Ruttum MS Effect of prior orbital decompression on outcome of strabismus surgery in patients with thyroid ophthalmopathy J Aapos 2000 4 2 102 105 10773808 \n38 Baldeschi L Lupetti A Vu P Wakelkamp IM Prummel MF Wiersinga WM Reactivation of Graves’ orbitopathy after rehabilitative orbital decompression Ophthalmology 2007 114 7 1395 1402 17320178 \n39 Anderson RL Linberg JV Transorbital approach to decompression in Graves’ disease Arch Ophthalmol 1981 99 1 120 124 6893929 \n40 Chang EL Piva AP Temporal fossa orbital decompression for treatment of disfiguring thyroid-related orbitopathy Ophthalmology 2008 115 9 1613 1619 18486219 \n41 Bonavolontà G Postoperative blindness following orbital surgery Orbit 2005 24 3 195 200 16169806 \n42 Rose GE The “devil’s touch”; visual loss and orbital surgery. A synopsis of the Mustardé Lecture, 2006 Orbit 2007 26 3 147 158 17891642 \n43 Goldberg RA Weinberg DA Shorr N Wirta D Maximal, three-wall, orbital decompression through a coronal approach Ophthalmic Surg Lasers 1997 28 10 832 843 9336777 \n44 Baldeschi L Small versus coronal incision orbital decompression in Graves’ orbitopathy Orbit 2010 29 4 177 182 20812832 \n45 Reich SS Null RC Timoney PJ Sokol JA Trends in Orbital Decompression Techniques of Surveyed American Society of Ophthalmic Plastic and Reconstructive Surgery Members Ophthalmic Plast Reconstr Surg 2016 32 6 434 437 27828915 \n46 Grusha YO Ismailova DS Gankovskaja OA Risk factors damage to the cornea of patient with Graves’ orbitopathy Vestnik Oftalmologii 2010 127 6 35 38 \n47 Grusha YO Ismailova DS Sherstneva LV Main principles of treatment the damage to the cornea of patient with Graves’ orbitopathy Vestnik Oftalmologii 2015 132 5 35 38\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1179-142X", "issue": "11()", "journal": "International medical case reports journal", "keywords": "Graves’ disease; corneal ulcer; ophthalmopathy; orbital decompression; tarsoraphy; thyroid eye disease", "medline_ta": "Int Med Case Rep J", "mesh_terms": null, "nlm_unique_id": "101566269", "other_id": null, "pages": "243-249", "pmc": null, "pmid": "30319289", "pubdate": "2018", "publication_types": "D002363:Case Reports", "references": "2757096;27911423;577380;2765444;16169806;23072549;9336777;10923974;15677945;17891642;16140250;6893929;25198394;17572552;19738586;27099835;17320178;16751042;19028743;11158820;8493010;16914591;10773808;18486219;27828915;10614926;10837384;21997825;15950284;2342809;9924370;17691064;22132843;12368609;20812832", "title": "Orbital decompression in the system of treatment for complicated thyroid eye disease: case report and literature review.", "title_normalized": "orbital decompression in the system of treatment for complicated thyroid eye disease case report and literature review" }

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"21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cataract", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cushingoid", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ISMAILOVA DS, BELOVALOVA IM, GRUSHA YO, SVIRIDENKO NY. ORBITAL DECOMPRESSION IN THE SYSTEM OF TREATMENT FOR COMPLICATED THYROID EYE DISEASE: CASE REPORT AND LITERATURE REVIEW. INT-MED-CASE-REP-J 2018?11:243-249.", "literaturereference_normalized": "orbital decompression in the system of treatment for complicated thyroid eye disease case report and literature review", "qualification": "3", "reportercountry": "RU" }, "primarysourcecountry": "RU", "receiptdate": "20190121", "receivedate": "20190121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15848909, "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" } ]

{ "abstract": "We report the case of a 78-year-old patient with late diagnosis of hyperoxaluria type III (PH3). He developed renal failure after nephrectomy for clear cell papillary renal carcinoma and complained of recurrent urolithiasis for some 30 years, whose aetiology was never identified. Biochemical laboratory investigations of urine and urolithiasis composition revealed marked hyperoxaluria but normal concentrations of urinary glyceric and glycolic acid as well as stones of idiopathic calcium-oxalate appearance. Furthermore, the dietary survey showed excessive consumption of food supplements containing massive amounts of oxalate precursors. However, the persistence of excessive hyperoxaluria after his eating habits was changed leading us to perform molecular genetic testing. We found heterozygous mutations of the recently PH3-associated HOGA1 gene when sequencing PH genes. This is the first description of late diagnosis primary PH3 in a patient with several additional pro-lithogenic factors. This case illustrates the importance of undertaking a complete biological work-up to determine the aetiology of hyperoxaluria. This may reveal underdiagnosed primary hyperoxaluria, even in older patients.", "affiliations": "1 Biothérapies des Maladies Génétiques, Inflammatoires et Cancers, Université de Bordeaux, Bordeaux, France.;1 Biothérapies des Maladies Génétiques, Inflammatoires et Cancers, Université de Bordeaux, Bordeaux, France.;4 Service de Néphrologie Pédiatrique, Centre de Référence Maladies Rénales Rares du Sud-ouest, Centre Hospitalier Universitaire de Bordeaux, Bordeaux Cedex, France.;4 Service de Néphrologie Pédiatrique, Centre de Référence Maladies Rénales Rares du Sud-ouest, Centre Hospitalier Universitaire de Bordeaux, Bordeaux Cedex, France.;5 Département de Pharmacologie Clinique, Centre Hospitalier Universitaire de Bordeaux, France.;6 Service des Maladies Héréditaires du Métabolisme et Dépistage Néonatal, Centre de Biologie et Pathologie Est, CHU de Lyon, Bron, France.;7 Service de Néphrologie Transplantation Dialyse, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.", "authors": "Richard|Emmanuel|E|;Blouin|Jean-Marc|JM|;Harambat|Jérome|J|;Llanas|Brigitte|B|;Bouchet|Stéphane|S|;Acquaviva|Cécile|C|;de la Faille|Renaud|R|", "chemical_list": "D005988:Glyceric Acids; D006016:Glycolates; C031149:glycolic acid; C042971:glyceric acid; D007652:Oxo-Acid-Lyases; C021415:4-hydroxy-2-oxoglutarate aldolase", "country": "England", "delete": false, "doi": "10.1177/0004563216677101", "fulltext": null, "fulltext_license": null, "issn_linking": "0004-5632", "issue": "54(3)", "journal": "Annals of clinical biochemistry", "keywords": "Hyperoxaluria; infrared spectroscopy; kidney stones; lithiasis", "medline_ta": "Ann Clin Biochem", "mesh_terms": "D000368:Aged; D002292:Carcinoma, Renal Cell; D057210:Delayed Diagnosis; D015870:Gene Expression; D005988:Glyceric Acids; D006016:Glycolates; D006801:Humans; D006960:Hyperoxaluria, Primary; D007668:Kidney; D007680:Kidney Neoplasms; D008297:Male; D009154:Mutation; D009392:Nephrectomy; D007652:Oxo-Acid-Lyases; D052878:Urolithiasis", "nlm_unique_id": "0324055", "other_id": null, "pages": "406-411", "pmc": null, "pmid": "27742850", "pubdate": "2017-05", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Late diagnosis of primary hyperoxaluria type III.", "title_normalized": "late diagnosis of primary hyperoxaluria type iii" }

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LATE DIAGNOSIS OF PRIMARY HYPEROXALURIA TYPE III. 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{ "abstract": "Herein, we present a case of successfully treated biopsy-proven Rasamsonia argillacea species complex myocarditis, pericarditis, and pulmonary infection in a 35-year-old male with a history of chronic granulomatous disease. Computed tomography of the chest demonstrated numerous pulmonary nodules and mass-like pulmonary lesions, and subsequent cardiac magnetic resonance imaging demonstrated an infiltrating mass-like lesion within the interventricular septum and pericarditis. Endobronchial, thoracoscopic, and eventual myocardial biopsies with cultures were ultimately reported as positive for R. argillacea species and the patient was treated with tailored antifungal therapy resulting in a significant therapeutic response upon short interval follow-up. This case stresses the importance of recognizing unusual thoracic imaging manifestations of an atypical fungal infection in immunocompromised individuals in order to expedite treatment of an otherwise potentially fatal disease.", "affiliations": "University of Pittsburgh Medical Center, Radiology Suite 200 East Wing, 200 Lothrop Street, Pittsburgh, PA 15213, USA.;University of Pittsburgh Medical Center, Radiology Suite 200 East Wing, 200 Lothrop Street, Pittsburgh, PA 15213, USA.;University of Pittsburgh Medical Center, Radiology Suite 200 East Wing, 200 Lothrop Street, Pittsburgh, PA 15213, USA.;University of Pittsburgh Medical Center, Radiology Suite 200 East Wing, 200 Lothrop Street, Pittsburgh, PA 15213, USA.;University of Pittsburgh Medical Center, Radiology Suite 200 East Wing, 200 Lothrop Street, Pittsburgh, PA 15213, USA.", "authors": "Ocak|Iclal|I|;Bollino|Gideon|G|;Bering|Patrick|P|;Sciortino|Christopher|C|;Cavalcante|Joao|J|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.radcr.2019.03.035", "fulltext": "\n==== Front\nRadiol Case RepRadiol Case RepRadiology Case Reports1930-0433Elsevier S1930-0433(18)30510-710.1016/j.radcr.2019.03.035CardiacRasamsonia argillacea species complex myocarditis in a patient with chronic granulomatous disease Ocak Iclal MDocaki@upmc.edu⁎Bollino Gideon MDBering Patrick MDSciortino Christopher MDCavalcante Joao MDUniversity of Pittsburgh Medical Center, Radiology Suite 200 East Wing, 200 Lothrop Street, Pittsburgh, PA 15213, USA⁎ Corresponding author. ocaki@upmc.edu08 4 2019 6 2019 08 4 2019 14 6 766 770 1 11 2018 28 3 2019 28 3 2019 © 2019 Published by Elsevier Inc. on behalf of University of Washington.2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Herein, we present a case of successfully treated biopsy-proven Rasamsonia argillacea species complex myocarditis, pericarditis, and pulmonary infection in a 35-year-old male with a history of chronic granulomatous disease. Computed tomography of the chest demonstrated numerous pulmonary nodules and mass-like pulmonary lesions, and subsequent cardiac magnetic resonance imaging demonstrated an infiltrating mass-like lesion within the interventricular septum and pericarditis. Endobronchial, thoracoscopic, and eventual myocardial biopsies with cultures were ultimately reported as positive for R. argillacea species and the patient was treated with tailored antifungal therapy resulting in a significant therapeutic response upon short interval follow-up. This case stresses the importance of recognizing unusual thoracic imaging manifestations of an atypical fungal infection in immunocompromised individuals in order to expedite treatment of an otherwise potentially fatal disease.\n\nKeywords\nFungalMypocarditis\n==== Body\nIntroduction\nFungal myocarditis and pericarditis are extremely rare infections, seen more commonly in immunocompromised individuals in the setting of disseminated disease and fungemia rather than isolated cardiac infection [1]. Nonspecific symptoms of fungal myocarditis are malaise, weakness, fever, and night sweats. More specific symptoms of end-organ damage from distal septic embolization may also be seen. The most common causative organisms in myocardial and pericardial fungal infections are Candida and Aspergillus species [2].\n\nIn this case report we are presenting a 35-year-old male patient with a history of chronic granulomatous disease (CGD) and ulcerative colitis complicated by Rasamsonia argillacea species complex infection of the lung, myocardium, and pericardium. To the best of my knowledge, this is the first case report of imaging manifestation of R. argillacea species complex myocarditis, pericarditis, and pulmonary infection.\n\nCase presentation\nThe patient is a 35-year-old male with a history of CGD and ulcerative colitis (prescribed sulfasalazine at the time of admission) who was admitted to the hospital with persistent fevers, night sweats, weight loss, tachycardia, and fatigue. Contrast-enhanced computed tomography (CT) of the chest and abdomen was performed to identify a potential source of infection. CT images at that time demonstrated pulmonary nodules and mass-like lesions in all lobes of both lungs (Fig. 1a and b). Subsequently, the patient underwent an endobronchial ultrasound-guided biopsy of a right upper lobe paramediastinal lesion. The tissue culture was reported positive for Penicillium species. The patient was then discharged on a treatment regimen consisting of trimethoprim/sulfamethoxazole and voriconazole.Fig. 1 Axial CT images in lung window at initial presentation demonstrate a mass-like nodular opacity at the right upper lobe (a) and nodular lesions at the level of the right costophrenic recess (b, black arrows). Panel c (4×) shows a representative hematoxylin-eosin stained section of the biopsy specimen showing organizing, necrotizing, granulomatous, and suppurative pneumonitis with corresponding silver stain highlighting the septate branching hyphae (d, 40×).\n\nFig 1\n\nDue to persistent symptoms, the patient returned to the hospital 1 week later. He then underwent a video-assisted thoracoscopic surgery for biopsy of a right lower lobe nodule that showed necrotizing granulomatous, suppurative, and organizing pneumonia with many septate branching hyphae (Fig. 1c and d). Cultures were again initially reported positive for Penicillium species. His antifungal regimen was then changed to liposomal amphotericin B, trimethoprim/sulfamethoxazole, and posaconazole for presumed treatment failure. During this admission, the patient was also found to have developed a myocardial infiltrating mass-like lesion on a follow-up chest CT study (Fig. 2) and subsequently underwent cardiac magnetic resonance imaging (MRI) for further evaluation. The MRI demonstrated a mass-like lesion arising from the interventricular septum with extension into the epicardial fat, as well as a small pericardial effusion with enhancement of the pericardial surfaces (Fig. 3). Biopsy of the cardiac mass revealed no evidence of malignancy, but some septate branching hyphae were present which could not be further speciated on microscopic examination alone. The patient was discharged home with a treatment regimen of liposomal amphotericin B, posaconazole, and caspofungin.Fig. 2 One week after initial presentation. Axial contrast-enhanced CT images of the thorax shows a pericardial effusion with contrast enhancement of the visceral and parietal pericardium and a mass-like lesion arising from interventricular septum near the apex of the heart (arrow).\n\nFig 2Fig. 3 One week after initial presentation. Short axis contrast-enhanced CT images through the heart (a-d) demonstrate a mass-like lesion arising from the interventricular septum with extension into the epicardial fat (arrow). There is also a small pericardial effusion with enhancement of the pericardial surfaces (black asterisk). A biopsy of the interventricular septum mass demonstrated necrotizing granulomatous and suppurative inflammation (e, hematoxylin and eosin stain, 4×) containing rare septate branching hyphae (f, silver stain, 60×). The hyphae on this specimen were morphologically similar to those seen in the right lower lobe mass (Fig. 1c and d).\n\nFig 3\n\nThe patient was seen at an infectious disease clinic 2 months after initial presentation. Laboratory findings at that time revealed hypokalemia for which the patient was again admitted to the hospital for electrolyte repletion. His hospital course was complicated by acute kidney injury thought to be due to an incorrect formulation of amphotericin B being administered with concomitant use of furosemide, spironolactone, and colchicine. Blood cultures from this hospitalization were negative.\n\nThe patient's tissue cultures of the right lower lobe and cardiac mass eventually finalized as R. argillacea species complex after a total of 3 different hospitalizations, the most recent of which resulting in acute kidney injury. The patient was continued on posaconazole, liposomal amphotericin B, and caspofungin. A short interval follow-up chest CT and cardiac MRI obtained 2 months after initial presentation, and subsequent antifungal therapy (Fig. 4, Fig. 5) demonstrated a decrease in the size of pulmonary nodules, myocardial mass-like lesion, and pericardial effusion, consistent with a therapeutic response.Fig. 4 Two months after the initial presentation and initiation of antifungal therapy. Axial CT images in lung window demonstrate decrease in the size of mass-like nodular opacity at the right upper lobe (a) and nodular lesions at the level of the right costophrenic recess (b, black arrows).\n\nFig 4Fig. 5 Two months after initial presentation and initiation of antifungal therapy. Cardiac MRI images in 4-chamber SSFP (A), myocardial delayed enhancement (B), and short axis Haste (C) sequences show mass-like lesion within interventricular septum, isointense on SSFPE, heterogeneously enhancing on late gadolinium imaging with necrotic regions, hyperintense compared to myocardium on Haste sequence. Corresponding follow-up images (D-F) demonstrate near complete resolution of fungal myocarditis.\n\nFig 5\n\nDiscussion\nR. argillacea species complex have been regularly reported in the literature. As in our case, these fungi are frequently misidentified as Penicillium species [3]. CGD is underlying disease that predisposes to infection or colonization with R. argillacea species complex. CGD is caused by defects in the phagocyte nicotinamide adenine dinucleotide phosphate oxidase resulting in the inability of neutrophils, monocytes, and macrophages to destroy certain microbes [4]. Infections in patients with CGD are generally caused by catalase-positive fungal organisms [5]. CGD patients with fungal infection can have a lower absolute fever and a diminished leukemoid reaction which may result in detection at an advanced stage, as in our case [5]. Given R. argillacea's thermotolerance and resistance to various antifungals, special attention should be paid to chronic colonization of the airways by these fungi in CGD patients [3].\n\nFungal infections typically result after inhalation of spores or hyphae which are commonly found in the air [4]. Pneumonia is the most common manifestation, but patients may also have lung abscesses, empyema, and hilar lymphadenopathy [5]. Fungal pneumonia may spread locally to the ribs and spine, or metastasize to brain. Morphologic diagnosis can be misleading as organisms are often reported to be Penicillium species but may actually be more treatment-refractory R. argillacea species complex [6,7].\n\nFungal myocarditis is believed to be a very rare consequence of disseminated fungemia and is associated with a high mortality rate. Due to its low prevalence and high mortality, fungal myocarditis is infrequently imaged [1]. Therefore, the specific imaging features of fungal myocarditis are not well described, unlike the far more common viral myocarditis [8], [9], [10]. Imaging features of fungal pericarditis manifest as a pericardial effusion with enhancement of the visceral and parietal pericardium (split pericardial sign) [10,11].\n\nThe treatment of fungal cardiac infections is long-term intravenous antifungal agents. Follow-up blood cultures may be useful for monitoring treatment response [5,8]. Although cardiac MR imaging has been established as a useful examination for prognostication in the setting of viral myocarditis, its utility in cases of fungal myocarditis has not yet been shown, as the natural histories of these conditions differ [12].\n\nIn patients with CGD, if we see nodules or mass-like lesion within the lungs and myocardium, R. argillacea species complex fungal pneumonia and fungal myocarditis should be kept in mind as part of the differential diagnosis which is crucial in correct patient management.\n\nAppendix Supplementary materials\nImage, application 1 \n\nCompeting Interests: The authors have no conflicts of interest.\n\nSupplementary material associated with this article can be found, in the online version, at doi:10.1016/j.radcr.2019.03.035.\n==== Refs\nReferences\n1 Uppin M.S. Anuradha S.V. Uppin S.G. Paul T.R. Prayaga A.K. Sundaram C. Fungal infections as a contributing cause of death: an autopsy study Indian J Pathol Microbiol 54 2 2011 344 349 21623087 \n2 Orlowski H.L.P. McWilliams S. Mellnick V.M. Bhalla S. Lubner M.G. Pickhardt P.J. Imaging spectrum of invasive fungal and fungal-like infections RadioGraphics 37 4 2017 1119 1134 28622118 \n3 Giraud S. Favennec L. Bougnoux M.E. Bouchara J.P. Rasamsonia argillacea species complex: taxonomy, pathogenesis and clinical relevance Future Microbiol 8 8 2013 967 978 23902144 \n4 Marciano B.E. Spalding C. Fitzgerald A. Mann D. Brown T. Osgood S. Common severe infections in chronic granulomatous disease Clin Infect Dis 60 8 2015 1176 1183 25537876 \n5 Sergio D Rosenzweig S.M.H. Chronic granulomatous disease: pathogenesis, clinical manifestations, and diagnosis 2017 uptodate \n6 De Ravin S.S. Challipalli M. Anderson V. Shea Y.R. Marciano B. Hilligoss D. Geosmithia argillacea: an emerging cause of invasive mycosis in human chronic granulomatous disease Clin Infect Dis 52 6 2011 e136 e143 21367720 \n7 Machouart M. Garcia-Hermoso D. Rivier A. Hassouni N. Catherinot E. Salmon A. Emergence of disseminated infections due to Geosmithia argillacea in patients with chronic granulomatous disease receiving long-term azole antifungal prophylaxis J Clin Microbiol 49 4 2011 1681 1683 21270214 \n8 Cummings K.W. Bhalla S. Javidan-Nejad C. Bierhals A.J. Gutierrez F.R. Woodard P.K. A pattern-based approach to assessment of delayed enhancement in nonischemic cardiomyopathy at MR imaging Radiographics 29 1 2009 89 103 19168838 \n9 Brett N.J. Strugnell W.E. Slaughter R.E. Acute myocarditis demonstrated on CT coronary angiography with MRI correlation Circ Cardiovasc Imaging 4 3 2011 e5 e6 21586739 \n10 Hoey E.T. Gulati G.S. Ganeshan A. Watkin R.W. Simpson H. Sharma S. Cardiovascular MRI for assessment of infectious and inflammatory conditions of the heart AJR Am J Roentgenol 197 1 2011 103 112 21701017 \n11 Wang Z.J. Reddy G.P. Gotway M.B. Yeh B.M. Hetts S.W. Higgins C.B. CT and MR imaging of pericardial disease Radiographics 23 2003 Spec No:S167-180 \n12 Grun S. Schumm J. Greulich S. Wagner A. Schneider S. Bruder O Long-term follow-up of biopsy-proven viral myocarditis: predictors of mortality and incomplete recovery J Am Coll Cardiol 59 18 2012 1604 1615 22365425\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1930-0433", "issue": "14(6)", "journal": "Radiology case reports", "keywords": "Fungal; Mypocarditis", "medline_ta": "Radiol Case Rep", "mesh_terms": null, "nlm_unique_id": "101467888", "other_id": null, "pages": "766-770", "pmc": null, "pmid": "31011375", "pubdate": "2019-06", "publication_types": "D002363:Case Reports", "references": "14557510;19168838;21270214;21367720;21586739;21623087;21701017;22365425;23902144;25537876;28622118", "title": "Rasamsonia argillacea species complex myocarditis in a patient with chronic granulomatous disease.", "title_normalized": "rasamsonia argillacea species complex myocarditis in a patient with chronic granulomatous disease" }

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RASAMSONIA ARGILLACEA SPECIES COMPLEX MYOCARDITIS IN A PATIENT WITH CHRONIC GRANULOMATOUS DISEASE? DOI: HTTPS://DOI.ORG/10.1016/J.RADCR.2019.03.035. 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"drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PENICILLIUM INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMPHOTERICIN B." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMPHOTERICIN B" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PENICILLIUM INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMPHOTERICIN B, LIPOSOMAL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "COLCHICINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, 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"drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "POSACONAZOLE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CASPOFUNGIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PENICILLIUM INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CASPOFUNGIN" }, { 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"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": "SPIRONOLACTONE." } ], "patientagegroup": null, "patientonsetage": "35", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect product formulation administered", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OCAK I, BOLLINO G, BERING P, SCIORTINO C, CAVALCANTE J. RASAMSONIA ARGILLACEA SPECIES COMPLEX MYOCARDITIS IN A PATIENT WITH CHRONIC GRANULOMATOUS DISEASE. RADIOL-CASE-REP 2019?14(6):766-770.", "literaturereference_normalized": "rasamsonia argillacea species complex myocarditis in a patient with chronic granulomatous disease", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190523", "receivedate": "20190523", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16346446, "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" }, { "companynumb": "US-FRESENIUS KABI-FK201905361", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FUROSEMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "018902", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "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": "FUROSEMIDE (MANUFACTURER UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SPIRONOLACTONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "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": "SPIRONOLACTONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AMPHOTERICIN B" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "FUNGAL INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMPHOTERICIN B." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "COLCHICINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "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": "COLCHICINE." } ], "patientagegroup": null, "patientonsetage": "35", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OCAK I, BOLLINO G, BERING P, SCIORTINO C, CAVALCANTE J. RASAMSONIA ARGILLACEA SPECIES COMPLEX MYOCARDITIS IN A PATIENT WITH CHRONIC GRANULOMATOUS DISEASE. RADIOLOGY CASE REPORTS. 2019 JUN?766-770.", "literaturereference_normalized": "rasamsonia argillacea species complex myocarditis in a patient with chronic granulomatous disease", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190513", "receivedate": "20190513", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16306372, "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-AVION PHARMACEUTICALS, LLC-2073030", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "SPIRONOLACTONE" }, "drugadditional": "3", "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SPIRONOLACTONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FUROSEMIDE" }, "drugadditional": "3", "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FUROSEMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "COLCHICINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "210942", "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": "GLOPERBA" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMPHOTERICIN B" }, "drugadditional": "3", "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMPHOTERICIN B." } ], "patientagegroup": null, "patientonsetage": "35", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OCAK, ICLAL? BOLLINO, GIDEON? BERING, PATRICK? SCIORTINO, CHRISTOPHER? CAVALCANTE, JOAO. RASAMSONIA ARGILLACEA SPECIES COMPLEX MYOCARDITIS IN A PATIENT WITH CHRONIC GRANULOMATOUS DISEASE. RADIOLOGY CASE REPORTS. 14 (6) P.766-770. 06/2019.", "literaturereference_normalized": "rasamsonia argillacea species complex myocarditis in a patient with chronic granulomatous disease", "qualification": null, "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190812", "receivedate": "20190812", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16692320, "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-MYLANLABS-2019M1045282", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "CASPOFUNGIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PENICILLIUM INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CASPOFUNGIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FUROSEMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "018487", "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": "FUROSEMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMPHOTERICIN B" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PENICILLIUM INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMPHOTERICIN B." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SPIRONOLACTONE" }, "drugadditional": "3", "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SPIRONOLACTONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "COLCHICINE" }, "drugadditional": "3", "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "COLCHICINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMPHOTERICIN B" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PENICILLIUM INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMPHOTERICIN B, LIPOSOME" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "POSACONAZOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PENICILLIUM INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "POSACONAZOLE" } ], "patientagegroup": null, "patientonsetage": "35", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Incorrect product formulation administered", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OCAK I, BOLLINO G, BERING P, SCIORTINO C, CAVALCANTE J. RASAMSONIA ARGILLACEA SPECIES COMPLEX MYOCARDITIS IN A PATIENT WITH CHRONIC GRANULOMATOUS DISEASE. RADIOL-CASE-REP 2019?14(6):766-770.", "literaturereference_normalized": "rasamsonia argillacea species complex myocarditis in a patient with chronic granulomatous disease", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190514", "receivedate": "20190514", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16310505, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" } ]

{ "abstract": "Sclerosing pneumocytomas are rare pulmonary neoplasms that are typically benign. However, rare patients experience progressive disease, and therapy targeting specific genetic underpinnings could be an attractive therapeutic option. Recent studies have found recurrent AKT 1 mutations in sclerosing pneumocytoma, but little is known about whether oncogenic fusion genes may also be present.\n\n\n\nTo better understand the genetic background, 10 sclerosing pneumocytomas were subjected to next-generation sequencing cancer mutation panel testing (n = 9) and/or RNA sequencing (n = 3). The patients were all women (average age, 47 years; range, 17-74 years).\n\n\n\nEight patients had solitary sclerosing pneumocytomas, while one had two tumors, and one had many bilateral tumors. Recurrent mutations were noted in genes involved in the mTOR pathway, including AKT1, PIK3R1, and PTEN. AKT1 alterations were particularly common, present in 78%. No recurrent genetic fusions were identified. The patient in our study with multiple bilateral lesions was treated with the mammalian target of rapamycin (mTOR) inhibitor everolimus, with no objective radiographic evidence of treatment response after 4 months.\n\n\n\nOur data further support that abnormal activation of the mTOR pathway is a consistent genetic event in sclerosing pneumocytoma. This warrants further exploration to determine if mTOR pathway inhibitors may be effective in patients with metastatic or recurrent disease.", "affiliations": "Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.;Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.;Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.;Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.;Division of Biomedical Statistics and Informatics, Department of Research Services, Mayo Clinic, Rochester, MN.;Division of Biomedical Statistics and Informatics, Department of Research Services, Mayo Clinic, Rochester, MN.;Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.;Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.;Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.;Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.", "authors": "Boland|Jennifer M|JM|;Lee|Hee Eun|HE|;Barr Fritcher|Emily G|EG|;Voss|Jesse S|JS|;Jessen|Erik|E|;Davila|Jaime I|JI|;Kipp|Benjamin R|BR|;Graham|Rondell P|RP|;Maleszewski|Joseph J|JJ|;Yi|Eunhee S|ES|", "chemical_list": "D014408:Biomarkers, Tumor; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases", "country": "England", "delete": false, "doi": "10.1093/ajcp/aqaa136", "fulltext": null, "fulltext_license": null, "issn_linking": "0002-9173", "issue": "155(3)", "journal": "American journal of clinical pathology", "keywords": "Fusion; Mutation; Sclerosing pneumocytoma; mTOR", "medline_ta": "Am J Clin Pathol", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008875:Middle Aged; D047868:Pulmonary Sclerosing Hemangioma; D012189:Retrospective Studies; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014178:Translocation, Genetic; D055815:Young Adult", "nlm_unique_id": "0370470", "other_id": null, "pages": "397-404", "pmc": null, "pmid": "33145590", "pubdate": "2021-02-11", "publication_types": "D016428:Journal Article", "references": null, "title": "Molecular Genetic Landscape of Sclerosing Pneumocytomas.", "title_normalized": "molecular genetic landscape of sclerosing pneumocytomas" }

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{ "abstract": "Leiomyosarcoma of the stomach is an extremely rare malignancy for which treatment in advanced disease is hardly reported. Here, we report a case of a 48-year-old man with metastatic gastric Leiomyosarcoma who had previously received a combination of gemcitabine and docetaxel followed by pazopanib after detection of metastasis. The patient was started on trabectedin as per protocol and had disease control continuing for 17 cycles of trabectedin. His quality of life and absence of significant toxicities highlight the noncumulative nature of trabectedin and potential benefit in responding cases.", "affiliations": "Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi 110029, India.;Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi 110029, India.;Sachin Sarcoma Society, New Delhi 110036, India.;Sheffield Teaching Hospitals NHS Foundation Trust, Northern General Hospital, Sheffield S5 7AU, UK.;Medkrux Research Group, Mumbai 400064, India.", "authors": "Rastogi|Sameer|S|;Kalra|Kaushal|K|;Manasa|Parisa|P|;Rajawat|Monali|M|;Mehta|Varshil|V|https://orcid.org/0000-0001-5804-9948", "chemical_list": null, "country": "England", "delete": false, "doi": "10.2144/fsoa-2019-0085", "fulltext": "\n==== Front\nFuture Sci OAFuture Sci OAFSOAFuture Science OA2056-5623Future Science Ltd London, UK 10.2144/fsoa-2019-0085Case ReportLong lasting response of trabectedin in patient with gastric leiomyosarcoma with liver metastasis: an update to previous report Rastogi Sameer **1Kalra Kaushal 1Manasa Parisa 2Rajawat Monali 34https://orcid.org/0000-0001-5804-9948Mehta Varshil *451 Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi 110029, India2 Sachin Sarcoma Society, New Delhi 110036, India3 Sheffield Teaching Hospitals NHS Foundation Trust, Northern General Hospital, Sheffield S5 7AU, UK4 Medkrux Research Group, Mumbai 400064, India5 Chelsea and Westminster Hospital NHS Foundation Trust, West Middlesex University Hospital, Isleworth TW7 6AF, UK* Author for correspondence: varshil.mehta@chelwest.nhs.uk** Author for correspondence: samdoc_mamc@yahoo.com09 12 2019 1 2020 09 12 2019 6 1 FSO43218 7 2019 30 9 2019 09 12 2019 © 2019 Varshil Mehta2019This work is licensed under the http://creativecommons.org/licenses/by/4.0/Leiomyosarcoma of the stomach is an extremely rare malignancy for which treatment in advanced disease is hardly reported. Here, we report a case of a 48-year-old man with metastatic gastric Leiomyosarcoma who had previously received a combination of gemcitabine and docetaxel followed by pazopanib after detection of metastasis. The patient was started on trabectedin as per protocol and had disease control continuing for 17 cycles of trabectedin. His quality of life and absence of significant toxicities highlight the noncumulative nature of trabectedin and potential benefit in responding cases.\n\nLay abstract\nLeiomyosarcoma (LMS) is a very rare form of tumor which, when it spreads to other organs, can be dreadful. Here, we report a case of a 48-year-old man who was diagnosed with LMS of the stomach that subsequently affected the liver. Multiple lines of anti-cancer drugs were given to the patient. At present, the patient takes trabectedin and has been tolerating it very well. Most drugs have cumulative toxicity when given for a long period of time but trabectedin does not possess this effect, which is why we feel that trabectedin should be considered as first-line treatment for LMS in the future.\n\nKeywords: \ngastric LMSliposarcomaLMSmetastasispazopanibtrabectedin\n==== Body\nIn the last few years, the landscape of sarcoma management has changed with the approval of new and better agents. After pazopanib was approved in nonadipocytic sarcomas, trabectedin received US FDA approval in October, 2015 for the treatment of advanced L-sarcomas (liposarcoma and leiomyosarcoma [LMS]) in patients previously treated with anthracyclines. LMS is one of the most common soft tissue sarcomas and arises from smooth muscle cells. Both the approval trials of pazopanib and trabectedin had LMS as the most common subtype [1,2].\n\nPatients treated with trabectedin had longer progression-free survival (PFS) than patients who received dacarbazine (4.2 vs 1.5 months; p = 0.001). However, there was no difference in overall survival (OS) in the two arms [2].\n\nTrabectedin has a pleiotropic mechanism of action including the interaction with the minor groove of the DNA double helix, affecting transcription of different genes involved in DNA repair, facilitating lethal DNA strand breaks, directing growth inhibition and resulting in the death of malignant cells. It also displays anti-inflammatory and immunomodulatory properties because of the hinderance of factors that promote tumor growth, angiogenesis and metastasis [3,4]. Some of the most common adverse effects (all grades) of trabectedin in registration trials were nausea (73%), fatigue (67%), neutropenia (49%), increased AAT (39%), vomiting (44%), anemia (39%) etc [2].\n\nHere, we report an unusual case of gastric LMS that had earlier responded to pazopanib [5] and as subsequent therapy had long-lasting response to trabectedin.\n\nCase presentation\nA 48-year-old man having no co-morbidities was diagnosed with LMS of stomach (greater curvature) in his local area and underwent mass excision for the same in December, 2014. The histopathology was suggestive of high-grade LMS. The patient received adjuvant chemotherapy (6 cycles) of doxorubicin. After a treatment-free interval of 18 months, he developed metastasis to the liver in September, 2016. The patient further was given gemcitabine–docetaxel (7 cycles), after which the disease progressed. Subsequently, the patient came to our institute for further therapy. At presentation, he had Eastern Cooperative Oncology Group Performance Status (ECOG PS) 1 and we then started him on pazopanib 400 mg.\n\nThe patient had partial response initially on pazopanib (dosage: 400 mg OD) but after 6 months of therapy, the disease progressed. Hence, he was started on injection trabectedin from February 2018 onwards. Trabectedin was given at the dose of 1.5 mg/m2 on every 21st day (every 3 weeks). Post three cycles of trabectedin, a partial response was observed. After eight cycles, a stable disease was noted in imaging by RECIST 1.1 criteria. He tolerated trabectedin well and had fatigue as the only toxicity (Grade 1), while adverse reactions such as alopecia and mucositis never developed during the treatment. The last cycle of trabectedin was given in May 2019 (17th cycle) and the imaging scans showed stable disease. His current ECOG PS is 1 and doing well on therapy.\n\nThe computed tomography scan before initiation of the treatment displayed the largest lesion with the dimension of 30.0 mm × 22.5 mm (Figure 1A), which subsequently reduced to 20 mm × 10 mm and 16 mm × 14 mm post 3 cycles (Figure 1B) and 17 cycles from the initiation of the therapy (Figure 1C) respectively. The disease is currently stable at 58 months after diagnosis of primary LMS was made.\n\nFigure 1.  Computed tomography scan showing the largest lesion: (A) before start of the treatment; (B) post 3 cycles; (C) post 17 cycles.\nDiscussion\nWe here describe a very rare case of a patient with primary gastric LMS with secondary metastasis to liver, who was treated with multiple lines of chemotherapy. The gastric LMS is an extremely rare malignant tumor, comprising only 1% of all the gastric malignancies. In an analysis of the Surveillance, Epidemiology and End Results (SEER) database in patients with primary gastric LMS diagnosed between 1988 to 2008, the median OS of gastric LMS was significantly higher than gastric adenocarcinoma (36 vs 10 months, p = 0.001) [6].\n\nAs mentioned in previous reports, the closest differential diagnosis of gastric LMS is gastrointestinal stromal tumor; however, the pathology and immunohistochemistry of our patient had been reviewed elaborately and was suggestive of LMS [5]. As this patient responded to a combination of gemcitabine–docetaxel, pazopanib and trabectedin, it is possible that the behavior of gastric LMS is similar to extremity LMS.\n\nThe patient has nonprogressive disease on 17th cycle of trabectedin with preserved quality of life and minimal toxicities, underlining the potential benefit of trabectedin in metastatic LMS. The minimal toxicity profile in our patient further reinforces the fact that the toxicity of trabectedin is non-cumulative as has been shown in previous trials [7–10].\n\nIn the trial by Demetri et al., it was reported that 10% of patients were able to take 12 cycles of trabectdine continuously as compared with 2% of patients which took dacarbazine, thus a considerably smaller number of patients continues beyond 12 cycles [1]. Tavella et al. reported a case of uterine LMS, in which the patient was treated with 30 cycles of trabectedin and had a stable disease till the case was reported [11]. Similarly, in a study by Nteli et al., the patient with uterine LMS had a stable disease till ninth cycle of chemotherapy [12]. In a report by Hauslbauer et al., trabectedin provided 22 months of progression-free time with good quality of life in an elderly man with LMS with multiple comorbidities [13]. In a report by Corrado et al., the best response to trabectedin happened after 9 cycles in a patient with metastatic inguinal LMS, signifying late response even after three to six cycles [14]. To our best knowledge there is no report of use of trabectedin in gastric LMS.\n\nSince only a fraction of patients show clinical improvement after being exposed to trabectedin, it is imperative to use a biomarker in order to delineate the subgroup of the patients that will derive maximum benefit from the study. In a few clinical pharmacogenomic retrospective studies, it was shown that BRCA1 status could be predictive of trabectedin efficacy in sarcoma patients, which was later on refuted in the EORTC 62091 study in which prospective study of BRCA 1 assessment in soft tissue sarcoma was done (BRCA study) [15].\n\nNewer modalities of treatment options available for LMS\nIn the last few years various drugs like olaratumab, eribulin and some immunotherapies have also been tried in LMS. Olaratumab was approved in October 2016 in first-line setting in combination with doxorubicin, based upon a Phase Ib/II trial showing the dramatic OS benefit of 11.8 months as compared with single agent doxorubicin, which was unprecedented, leading to both reassurance and speculations after FDA accelerated approval [16]. This was followed by a Phase III placebo control randomized trial (ANNOUNCE), which used OS as primary end point. However, this trial failed to show OS benefit, with OS 20.4 months in the olaratumab/doxorubicin arm as compared with 29.8 months in the doxorubicin/placebo arm [17].\n\nIn a Phase III trial by Schoffski et al., patients with advanced L-sarcomas who previously received two lines of chemotherapy were randomized to eribulin and dacarbazine [18]. The primary end point was OS while secondary end points were progression-free survival and progression-free rate. There was statistically significant improvement in OS in the eribulin arm as compared with that of darcarbazine in the overall population. As per preplanned subgroup analysis, the benefit was mainly limited to the liposarcoma subgroup as compared with the LMS subgroup. Based upon this, eribulin was approved in for liposarcoma but not LMS [19].\n\nSARC 028 study was a Phase II trial in which ten patients each of pleomorphic undifferentiated sarcoma, LMS, synovial sarcoma and liposarcoma (a total of 40 patients) were given pembrolizumab every 21 days [20]. There was no response in the LMS subgroup indicating that it might not be sensitive to immunotherapy. Similarly, in another Phase II trial evaluating single agent nivolumab, of 12 patients there was not even a single positive response [21]. Recently it has been shown that a small fraction of LMS patients might show ALK gene rearrangement and might be sensitive to ALK inhibitors [22]. Though the advancements in the last few years have had mixed or only marginal success, with each and every trial, the understanding of the disease is definitely getting better.\n\nConclusion & future perspective\nIn the present patient with gastric LMS, trabectedin demonstrated an excellent disease control despite being exposed to multiple lines of chemotherapy. The well-maintained quality of life and minimal toxicity profile is worth highlighting. However, we must keep looking for biomarkers in order to optimize treatment with these novel agents.\n\nExecutive summary\nMetastatic leiomyosarcoma (LMS) remains a disease with a dismal outlook, with an urgent need for new therapies. The last decade has seen major advancement in terms of collaborative studies with newer agents.\n\nTrabectedin is a novel therapeutic agent with a pleotropic mechanism of action approved after two lines of therapy in liposarcoma and LMS.\n\nTrabectadin is a relatively well tolerated chemotherapeutic agent with a noncumulative toxicity profile. Major toxicities are nausea, fatigue, neutropenia, thrombocytopenia, increased alanine amino transferase, vomiting and anemia.\n\nIn our patient with metastatic gastric LMS, the disease was nonprogressive till last follow up after receiving 17 cycles of trabectedin with minimal toxicity.\n\nAs this patient responded to combination of gemcitabine–docetaxel, pazopanib and trabectedin it is possible that the behaviour of gastric LMS is similar to extremity LMS.\n\nFuture research looking for biomarkers to delineate the correct subtype of patient for each therapy holds the key for better patient selection.\n\nAuthor contributions\n\nAll authors contributed equally to the study design and methodology. S Rastogi, K Kalra, P Manasa wrote the first draft. V Mehta and M Rajawat edited the paper. S Rastogi, K Kalra and V Mehta revised the paper.\n\nFinancial & competing interests disclosure\n\nThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.\n\nNo writing assistance was utilized in the production of this manuscript.\n\nEthical conduct of research\n\nThe authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.\n\nOpen access\n\nThis work is licensed under the Creative Commons Attribution 4.0 License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/\n==== Refs\nReferences\nPapers of special note have been highlighted as: • of interest; •• of considerable interest\n\n1. van der Graaf WT , Blay JY , Chawla SP \n\nPazopanib for metastatic soft-tissue sarcoma [PALETTE]: a randomised, double-blind, placebo-controlled Phase 3 trial . Lancet \n379 (9829 ), 1879 –1886 (2012 ). 22595799 • This was the major landmark trial which demontrated the efficacy of pazopanib in metastatic leiomyosarcoma.\n\n\n2. Demetri GD , von Mehren M , Jones RL \n\nEfficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: results of a Phase III randomized multicenter clinical trial . J. Clin. Oncol. \n34 (8 ), 786 –793 (2016 ). 26371143 • This was also a landmark trial which showed the efficacy and safety of trabectedin and provided wonderful option in the treatment of metastatic liposarcomas and leiomyosarcoma.\n\n\n3. D'Incalci M , Jimeno J \nPreclinical and clinical results with the natural marine product ET-743 . Expert Opin. Investig. Drugs. \n12 (11 ), 1843 –1853 (2003 ).\n4. Zewail-Foote M , Hurley LH \nEcteinascidin 743: a minor groove alkylator that bends DNA toward the major groove . J. Med. Chem. \n42 (14 ), 2493 –2497 (1999 ).10411470 \n5. Mehta V , Rajawat M , Rastogi S , Phulware RH , Mezencev R \nLeiomyosarcoma of the stomach with metastasis to the liver: a case report with review of the literature . Future Sci. OA \n4 (2 ), FSO264 (2018 ).29379638 \n6. Moody JS , Kozak KR \nGastric leiomyosarcomas: aSEER analysis . J. Clin. Oncol. \n30 (Suppl. 4 ), 106 –106 (2012 ).\n7. Leporini C , Patane M , Saullo F \n\nA comprehensive safety evaluation of trabectedin and drug–drug interactions of trabectedin-based combinations . Biodrugs \n28 (6 ), 499 –511 (2014 ).25209722 \n8. Baldi GG , Di Donato S , Fargnoli R \n\nComplete response after rechallenge with trabectedin in a patient with previously responding high-grade undifferentiated sarcoma . Anticancer Drugs \n27 (9 ), 908 –1913 (2016 ).27348763 \n9. Martin-Liberal J , Judson I \nSafety evaluation of trabectedin in treatment of soft-tissue sarcomas . Expert Opin. Drug Saf. \n12 (6 ), 905 –911 (2013 ).23937190 \n10. Le Cesne A , Ray-Coquard I , Duffaud F \n\nTrabectedin in patients with advanced soft tissue sarcoma: a retrospective national analysis of the French Sarcoma Group . Eur. J. Cancer \n51 (6 ), 742 –750 (2015 ).25727882 \n11. Tavella K , Villanucci A , Vannini L \n\nStable disease in a patient with metastatic leiomyosarcoma treated with trabectedin . Anticancer Drugs \n28 (4 ), 465 –468 (2017 ).28181940 \n12. Nteli VA , Knauf W , Janton-Klein A , El-Safadi S \nLong-lasting response to trabectedin in a patient with metastatic uterine leiomyosarcoma: a case report . Case Rep. Oncol. \n11 (1 ), 81 –89 (2018 ). 29515415 •• Similar case report showed prolong response of trabectedin in soft tissue sarcoma.\n\n\n13. Haslbauer F \nLong-term progression-free survival in a patient with metastatic leiomyosarcoma of the inguinal region treated with trabectedin . Case Rep. Oncol. \n11 (1 ), 246 –251 (2018 ). 29805376 •• Similar case report showed prolong response of trabectedin in soft tissue sarcoma.\n\n\n14. Corrado G , Salutari V , Fuoco G , Lucidi A , Ferrandina G \nProlonged clinical response to trabectedin in a heavily pretreated patient with advanced uterine leiomyosarcoma: a case report and literature review . Gynecol. Oncol. \n121 (2 ), 416 –417 (2011 ).21324513 \n15. Lorusso D , Scambia G , Pignata S \n\nProspective Phase II trial of trabectedin in BRCA-mutated and/or BRCAness phenotype recurrent ovarian cancer patients: the MITO 15 trial . Ann. Oncol. \n27 (3 ), 487 –493 (2016 ).26681678 \n16. Tap WD , Jones RL , Van Tine BA \n\nOlaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label Phase 1b and randomised phase 2 trial . Lancet. \n388 (10043 ), 488 –497 (2016 ).27291997 \n17. Tap WD , Wagner AJ , Papai Z \n\nANNOUNCE: A randomized, placebo [PBO]-controlled, double-blind, Phase [Ph] III trial of doxorubicin [dox] + olaratumab versus dox + PBO in patients [pts] with advanced soft tissue sarcomas [STS] . J. Clin. Oncol. \n37 (Suppl. 18 ), LBA3 –LBA (2019 ).\n18. Schoffski P , Chawla S , Maki RG \n\nEribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, Phase 3 trial . Lancet. \n387 (10028 ), 1629 –1637 (2016 ).26874885 \n19. Rastogi S , Gupta V \nEribulin approval in advanced liposarcoma – successful drug or a weaker methodology? \nInd. J. Med. Paediatr. Oncol. \n38 (1 ), 2 –3 (2017 ).\n20. Tawbi HA , Burgess M , Bolejack V \n\nPembrolizumab in advanced soft-tissue sarcoma and bone sarcoma [SARC028]: a multicentre, two-cohort, single-arm, open-label, Phase 2 trial . Lancet Oncol. \n18 (11 ), 1493 –501 (2017 ).28988646 \n21. Ben-Ami E , Barysauskas CM , Solomon S \n\nImmunotherapy with single agent nivolumab for advanced leiomyosarcoma of the uterus: Results of a Phase 2 study . Cancer \n123 (17 ), 3285 –3290 (2017 ).28440953 \n22. Davis LE , Nusser KD , Przybyl J \n\nDiscovery and characterization of recurrent, targetable ALK fusions in leiomyosarcoma . Mol. Cancer Res. \n17 (3 ), 676 –685 (2019 ).30518629\n\n", "fulltext_license": "CC BY", "issn_linking": "2056-5623", "issue": "6(1)", "journal": "Future science OA", "keywords": "LMS; gastric LMS; liposarcoma; metastasis; pazopanib; trabectedin", "medline_ta": "Future Sci OA", "mesh_terms": null, "nlm_unique_id": "101665030", "other_id": null, "pages": "FSO432", "pmc": null, "pmid": "31915533", "pubdate": "2019-12-09", "publication_types": "D002363:Case Reports", "references": "21324513;28181940;28988646;14585059;10411470;25209722;28440953;30518629;26874885;28469328;26681678;23937190;22595799;29805376;27291997;26371143;29379638;27348763;25727882;29515415", "title": "Long lasting response of trabectedin in patient with gastric leiomyosarcoma with liver metastasis: an update to previous report.", "title_normalized": "long lasting response of trabectedin in patient with gastric leiomyosarcoma with liver metastasis an update to previous report" }

[ { "companynumb": "IN-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-235735", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "022534", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "LEIOMYOSARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GEMCITABINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "LEIOMYOSARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE." } ], "patientagegroup": null, "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RASTOGI S, KALRA K, MANASA P, RAJAWAT M, MEHTA V. LONG LASTING RESPONSE OF TRABECTEDIN IN PATIENT WITH GASTRIC LEIOMYOSARCOMA WITH LIVER METASTASIS: AN UPDATE TO PREVIOUS REPORT. FUTURE SCI OA. 2019?6(1):FSO432", "literaturereference_normalized": "long lasting response of trabectedin in patient with gastric leiomyosarcoma with liver metastasis an update to previous report", "qualification": "3", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20200210", "receivedate": "20200210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17394590, "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": "Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is an extremely rare cause of hyponatremia post-liver transplantation. A 15-year-old Japanese girl with recurrent cholangitis after Kasai surgery for biliary atresia underwent successful living donor liver transplantation. Peritonitis due to gastrointestinal perforation occurred. Hyponatremia gradually developed but improved after hypertonic sodium treatment. One month later, severe hyponatremia rapidly recurred. We considered the hyponatremia's cause as SIADH. We suspected that tacrolimus was the disease's cause, so we used cyclosporine instead, plus hypertonic sodium plus water intake restriction, which improved the hyponatremia. Symptomatic hyponatremia manifested by SIADH is a rare, serious complication post-liver transplantation.", "affiliations": "Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.", "authors": "Takagi|Kosei|K|;Yagi|Takahito|T|;Shinoura|Susumu|S|;Umeda|Yuzo|Y|;Yoshida|Ryuichi|R|;Nobuoka|Daisuke|D|;Watanabe|Nobuyuki|N|;Kuise|Takashi|T|;Fuji|Tomokazu|T|;Araki|Hiroyuki|H|;Fujiwara|Toshiyoshi|T|", "chemical_list": "D007166:Immunosuppressive Agents; D014667:Vasopressins; D016559:Tacrolimus", "country": "Japan", "delete": false, "doi": "10.18926/AMO/54830", "fulltext": null, "fulltext_license": null, "issn_linking": "0386-300X", "issue": "71(1)", "journal": "Acta medica Okayama", "keywords": "SIADH; hyponatremia; liver transplantation; syndrome of inappropriate antidiuretic hormone secretion; tacrolimus", "medline_ta": "Acta Med Okayama", "mesh_terms": "D000293:Adolescent; D002761:Cholangitis; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007010:Hyponatremia; D007166:Immunosuppressive Agents; D007177:Inappropriate ADH Syndrome; D016031:Liver Transplantation; D011183:Postoperative Complications; D016559:Tacrolimus; D014667:Vasopressins", "nlm_unique_id": "0417611", "other_id": null, "pages": "85-89", "pmc": null, "pmid": "28238015", "pubdate": "2017-02", "publication_types": "D002363:Case Reports", "references": null, "title": "Syndrome of Inappropriate Antidiuretic Hormone Secretion Following Liver Transplantation.", "title_normalized": "syndrome of inappropriate antidiuretic hormone secretion following liver transplantation" }

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SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION FOLLOWING LIVER TRANSPLANTATION. 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"drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "15", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cholangitis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Inappropriate antidiuretic hormone secretion", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Gastrointestinal perforation", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TAKAGI K, YAGI T, SHINOURA S, UMEDA Y, YOSHIDA R, NOBUOKA D, ET AL.. SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION FOLLOWING LIVER TRANSPLANTATION. ACTA MEDICA OKAYAMA. 2017;71(1):85-9", "literaturereference_normalized": "syndrome of inappropriate antidiuretic hormone secretion following liver transplantation", "qualification": "5", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20170316", "receivedate": "20160809", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12637045, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "JP-ACCORD-049223", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "091195", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "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": "TACROLIMUS." }, { "actiondrug": null, "activesubstance": null, "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": "VALACICLOVIR/VALACICLOVIR HYDROCHLORIDE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FLUCONAZOLE" }, "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": "FLUCONAZOLE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "15", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyponatraemia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Inappropriate antidiuretic hormone secretion", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "TAKAGI K, YAGI T, SHINOURA S, UMEDA Y, YOSHIDA R, NOBUOKA D, ET AL. SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION FOLLOWING LIVER TRANSPLANTATION. ACTA MED OKAYAMA. 2017 FEB;71(1):85-89.", "literaturereference_normalized": "syndrome of inappropriate antidiuretic hormone secretion following liver transplantation", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20170320", "receivedate": "20170320", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13349071, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170428" } ]

{ "abstract": "Opportunistic infections are an ongoing concern in patients with autoimmune disease who are being treated with immunosuppressive agents. Nocardiosis is an uncommon opportunistic infection which has been reported in association with immunosuppressed patients and autoimmune disease. It is challenging to diagnose and can have multisystem manifestations. Failure to diagnose and appropriately treat can result in significant mortality. We present a 49 year old woman with systemic lupus erythematosus and neuromyelitis optica spectrum disorder who was treated with mycophenolate mofetil, prednisone and recent plasmapheresis. She developed acute onset of shortness of breath and fevers and was ultimately diagnosed with disseminated nocardiosis with lung, brain and muscle abscesses.", "affiliations": "Department of Medicine/Rheumatology, Brookdale University Hospital and Medical Center, Brooklyn, NY, USA.;Department of Medicine, SUNY Downstate Medical Center, Brooklyn, NY, USA.;Department of Radiology, SUNY Downstate Medical Center, Brooklyn, NY, USA.;Division of Rheumatology, SUNY Downstate Medical Center, Brooklyn, NY, USA.", "authors": "Terebelo|Sima|S|https://orcid.org/0000-0002-3386-4345;Sharif|Sara|S|;Chaudhry|Zeshan A|ZA|;Ginzler|Ellen|E|", "chemical_list": "D015378:Imipenem; D014295:Trimethoprim; D009173:Mycophenolic Acid; D013420:Sulfamethoxazole; D011241:Prednisone", "country": "England", "delete": false, "doi": "10.1177/0961203320976928", "fulltext": null, "fulltext_license": null, "issn_linking": "0961-2033", "issue": "30(2)", "journal": "Lupus", "keywords": "Systemic lupus erythematosus; disseminated nocardiosis; immunosuppresssion; mycophenolate mofetil; neuromyelitis optica spectrum disorder", "medline_ta": "Lupus", "mesh_terms": "D001922:Brain Abscess; D005260:Female; D006801:Humans; D015378:Imipenem; D016867:Immunocompromised Host; D008169:Lung Abscess; D008180:Lupus Erythematosus, Systemic; D008875:Middle Aged; D009173:Mycophenolic Acid; D009471:Neuromyelitis Optica; D009617:Nocardia Infections; D010956:Plasmapheresis; D011241:Prednisone; D013902:Radiography, Thoracic; D013420:Sulfamethoxazole; D014057:Tomography, X-Ray Computed; D014295:Trimethoprim", "nlm_unique_id": "9204265", "other_id": null, "pages": "347-351", "pmc": null, "pmid": "33259737", "pubdate": "2021-02", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Disseminated nocardiosis in an immunosuppressed patient with systemic lupus erythematosus and neuromyelitis optica spectrum disorder.", "title_normalized": "disseminated nocardiosis in an immunosuppressed patient with systemic lupus erythematosus and neuromyelitis optica spectrum disorder" }

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DISSEMINATED NOCARDIOSIS IN AN IMMUNOSUPPRESSED PATIENT WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND NEUROMYELITIS OPTICA SPECTRUM DISORDER. LUPUS.2020. 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"reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "TEREBELO S, SHARIF S, CHAUDHRY ZA, GINZLER E. DISSEMINATED NOCARDIOSIS IN AN IMMUNOSUPPRESSED PATIENT WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND NEUROMYELITIS OPTICA SPECTRUM DISORDER. 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"drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." } ], "patientagegroup": null, "patientonsetage": "49", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Nocardiosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TEREBELO S , SHARIF S, CHAUDHRY ZA, GINZLER E. DISSEMINATED NOCARDIOSIS IN AN IMMUNOSUPPRESSED PATIENT WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND NEUROMYELITIS OPTICA SPECTRUM DISORDER. LUPUS. 2020", "literaturereference_normalized": "disseminated nocardiosis in an immunosuppressed patient with systemic lupus erythematosus and neuromyelitis optica spectrum disorder", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201228", "receivedate": "20201228", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18673282, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210114" }, { "companynumb": "US-ACCORD-210841", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "065416", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTEMIC LUPUS ERYTHEMATOSUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "065416", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUROMYELITIS OPTICA SPECTRUM DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2003", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTEMIC LUPUS ERYTHEMATOSUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "49", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Nocardiosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Brain abscess", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Lung abscess", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Muscle abscess", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Adrenal insufficiency", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Septic embolus", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "TEREBELO S, SHARIF S, CHAUDHRY ZA, GINZLER E. DISSEMINATED NOCARDIOSIS IN AN IMMUNOSUPPRESSED PATIENT WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND NEUROMYELITIS OPTICA SPECTRUM DISORDER. 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"drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTEMIC LUPUS ERYTHEMATOSUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EVIDENCE BASED TREATMENT", 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"drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFEPRIME" } ], "patientagegroup": null, "patientonsetage": "49", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nocardiosis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "TEREBELO S, SHARIF A, CHAUDHRY ZA AND GINZLER E.. DISSEMINATED NOCARDIOSIS IN AN IMMUNOSUPPRESSED PATIENT WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND NEUROMYELITIS OPTICA SPECTRUM DISORDER. 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{ "abstract": "BACKGROUND\nData on outcome of endovascular treatment in patients with acute ischaemic stroke due to large vessel occlusion suffering from intravenous thrombolysis-associated intracranial haemorrhage prior to mechanical thrombectomy remain scarce. Addressing this subject, we report our multicentre experience.\n\n\nMETHODS\nA retrospective analysis of consecutive acute ischaemic stroke patients treated with mechanical thrombectomy due to large vessel occlusion despite the pre-interventional occurrence of intravenous thrombolysis-associated intracranial haemorrhage was performed at five tertiary care centres between January 2010-September 2020. Baseline demographics, aetiology of stroke and intracranial haemorrhage, angiographic outcome assessed by the Thrombolysis in Cerebral Infarction score and clinical outcome evaluated by the modified Rankin Scale at 90 days were recorded.\n\n\nRESULTS\nIn total, six patients were included in the study. Five individuals demonstrated cerebral intraparenchymal haemorrhage on pre-interventional imaging; in one patient additional subdural haematoma was observed and one patient suffered from isolated subarachnoid haemorrhage. All patients except one were treated by the 'drip-and-ship' paradigm. Successful reperfusion was achieved in 4/6 (67%) individuals. In 5/6 (83%) patients, the pre-interventional intracranial haemorrhage had aggravated in post-interventional computed tomography with space-occupying effect. Overall, five patients had died during the hospital stay. The clinical outcome of the survivor was modified Rankin Scale=4 at 90 days follow-up.\n\n\nCONCLUSIONS\nMechanical thrombectomy in patients with intravenous thrombolysis-associated intracranial haemorrhage is technically feasible. The clinical outcome of this subgroup of stroke patients, however, appears to be devastating with high mortality and only carefully selected patients might benefit from endovascular treatment.", "affiliations": "Institute for Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, Germany.;Institute of Neuroradiology, University Hospital Carl Gustav Carus, Germany.;Department of Diagnostic and Interventional Radiology, University Hospital Cologne, Germany.;Department of Neuroradiology, University Hospital Basel, Switzerland.;Neuroradiological Clinic, Klinikum Stuttgart, Germany.;Department of Radiology, Neuroradiology and Nuclear Medicine, Ruhr-University Bochum, Germany.;Institute of Neuroradiology, University Hospital Carl Gustav Carus, Germany.;Department of Diagnostic and Interventional Radiology, University Hospital Cologne, Germany.;Department of Neuroradiology, University Hospital Basel, Switzerland.;Institute for Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, Germany.;Neuroradiological Clinic, Klinikum Stuttgart, Germany.;Department of Radiology, Neuroradiology and Nuclear Medicine, Ruhr-University Bochum, Germany.", "authors": "Styczen|Hanna|H|https://orcid.org/0000-0002-9623-4156;Gawlitza|Matthias|M|;Abdullayev|Nuran|N|;Brehm|Alex|A|;Serna-Candel|Carmen|C|;Fischer|Sebastian|S|;Gerber|Johannes|J|https://orcid.org/0000-0001-7465-8700;Kabbasch|Christoph|C|;Psychogios|Marios-Nikos|MN|;Forsting|Michael|M|;Henkes|Hans|H|;Maus|Volker|V|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1177/19714009211009112", "fulltext": "\n==== Front\nNeuroradiol J\nNeuroradiol J\nNEU\nspneu\nThe Neuroradiology Journal\n1971-4009\n2385-1996\nSAGE Publications Sage UK: London, England\n\n33840277\n10.1177/19714009211009112\n10.1177_19714009211009112\nOriginal Articles\nMechanical thrombectomy in acute ischaemic stroke patients with pre-interventional intracranial haemorrhage following intravenous thrombolysis\nhttps://orcid.org/0000-0002-9623-4156\nStyczen Hanna 1\nGawlitza Matthias 2\nAbdullayev Nuran 3\nBrehm Alex 4\nSerna-Candel Carmen 5\nFischer Sebastian 6\nhttps://orcid.org/0000-0001-7465-8700\nGerber Johannes 2\nKabbasch Christoph 3\nPsychogios Marios-Nikos 4\nForsting Michael 1\nHenkes Hans 5\nMaus Volker 6\n1 Institute for Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, Germany\n2 Institute of Neuroradiology, University Hospital Carl Gustav Carus, Germany\n3 Department of Diagnostic and Interventional Radiology, University Hospital Cologne, Germany\n4 Department of Neuroradiology, University Hospital Basel, Switzerland\n5 Neuroradiological Clinic, Klinikum Stuttgart, Germany\n6 Department of Radiology, Neuroradiology and Nuclear Medicine, Ruhr-University Bochum, Germany\nHanna Styczen, Institute for Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, Hufelandstraße 55, 45122 Essen, Germany. Email: hanna.styczen@uk-essen.de\n12 4 2021\n10 2021\n12 4 2021\n34 5 456461\n© The Author(s) 2021\n2021\nSAGE Publications\nhttps://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution 4.0 License (https://creativecommons.org/licenses/by/4.0/) which permits any 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).\nBackground\n\nData on outcome of endovascular treatment in patients with acute ischaemic stroke due to large vessel occlusion suffering from intravenous thrombolysis-associated intracranial haemorrhage prior to mechanical thrombectomy remain scarce. Addressing this subject, we report our multicentre experience.\n\nMethods\n\nA retrospective analysis of consecutive acute ischaemic stroke patients treated with mechanical thrombectomy due to large vessel occlusion despite the pre-interventional occurrence of intravenous thrombolysis-associated intracranial haemorrhage was performed at five tertiary care centres between January 2010–September 2020. Baseline demographics, aetiology of stroke and intracranial haemorrhage, angiographic outcome assessed by the Thrombolysis in Cerebral Infarction score and clinical outcome evaluated by the modified Rankin Scale at 90 days were recorded.\n\nResults\n\nIn total, six patients were included in the study. Five individuals demonstrated cerebral intraparenchymal haemorrhage on pre-interventional imaging; in one patient additional subdural haematoma was observed and one patient suffered from isolated subarachnoid haemorrhage. All patients except one were treated by the ‘drip-and-ship’ paradigm. Successful reperfusion was achieved in 4/6 (67%) individuals. In 5/6 (83%) patients, the pre-interventional intracranial haemorrhage had aggravated in post-interventional computed tomography with space-occupying effect. Overall, five patients had died during the hospital stay. The clinical outcome of the survivor was modified Rankin Scale=4 at 90 days follow-up.\n\nConclusion\n\nMechanical thrombectomy in patients with intravenous thrombolysis-associated intracranial haemorrhage is technically feasible. The clinical outcome of this subgroup of stroke patients, however, appears to be devastating with high mortality and only carefully selected patients might benefit from endovascular treatment.\n\nAcute ischaemic stroke\nintracranial haemorrhage\nintravenous thrombolysis\nlarge vessel occlusion\nmechanical thrombectomy\ntypesetterts2\n==== Body\npmcBackground\n\nMechanical thrombectomy (MT) in combination with intravenous thrombolysis (IVT) is the standard treatment for patients suffering from acute ischaemic stroke (AIS) due to intracranial large vessel occlusion (LVO) in the anterior circulation.1,2 The particular benefit of IVT in these patients is unknown. As a result, various randomised controlled studies are currently being conducted to determine if MT without IVT is equally effective (SWIFT-DIRECT, NCT03192332; MR CLEAN NO IV, ISRCTN80619088; DIRECT MT, NCT03469206). Recently, the randomised DIRECT-MT trial in China indicated that MT was noninferior to the combined treatment. 3 However, the ongoing SKIP trial in Japan could not establish that skipping IVT was noninferior to the combined approach but was at least associated with a lower risk of intracranial haemorrhage (ICH). 4\n\nSymptomatic intracerebral haemorrhage is the main intracranial complication of IVT with rates reported up to 8.8% according to the European Cooperative Acute Stroke Study II (ECASS II) trial and associated with high mortality rates.5,6 Nevertheless, in primary stroke centres (PSCs), the early initiation of bridging therapy remains the only treatment for patients presenting with AIS before admitting these patients to a MT-capable comprehensive stroke centre (CSC). With increasing numbers of patients treated under the ‘drip and ship’ paradigm, the occurrence of an IVT-associated ICH prior to the endovascular procedure is becoming more likely. 7 Studies analysing the benefit of MT in this subgroup are limited as pre-interventional ICH remains an exclusion criterion for endovascular therapy in clinical trials. 8 Therefore, we aimed to report our multicentre experience with MT in patients with AIS due to LVO suffering from IVT-associated ICH.\n\nMethods\n\nWe conducted a retrospective study of AIS patients undergoing MT at five tertiary care centres in Germany between January 2010–September 2020.\n\nAll patients included in the study were treated with MT due to LVO despite the occurrence of an ICH after initiation of IVT. Inclusion criteria were missing evidence of ICH on baseline imaging, application of IVT and execution of additional imaging prior to the intervention (e.g. due to deterioration of clinical symptoms) using multi-detector or flat-detector computed tomography (CT) with detection of a newly delimited ICH. Extent or location of ICH (parenchymal, subdural or subarachnoid) were not exclusion criteria. Space-occupying effect of a parenchymal haemorrhage was defined as any mass effect on adjacent brain structures such as deep grey matter and gyri with narrowing of sulci, midline shift or brain herniation. Early ischaemic damage was evaluated using Alberta Stroke Program Early CT Score (ASPECTS) on first imaging for the anterior and posterior circulation. In post-interventional ASPECTS areas of intraparenchymal haemorrhage in the affected territory were included in the assessment. Large vessel occlusion was defined as any occlusion in cerebral arteries including distal internal carotid artery (ICA), middle cerebral artery (MCA; M1 and M2 segments), distal vertebral artery, basilar artery (BA) and posterior cerebral artery (P1 segment). Patient demographics, medical history, technical features, angiographic and clinical outcome were noted. The aetiology of the occlusion was based on the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification. In addition, the underlying aetiology for ICH (e.g. neoplasm, aneurysm, cavernoma) and localization of the ICH (in/outside the LVO affected territory) was reviewed. Any progression in size with consecutive increase of perifocal oedema was defined as aggravation of the ICH.\n\nAll patients received IVT and were treated according to the widely accepted selection criteria with a weight-based infusion of alteplase at 0.9 mg/kg over 60 min with a maximum dose of 90 mg. Ten per cent of the total treatment dose was given as a bolus over 1 min. There were no limitations on procedural characteristics including the use of different thrombectomy techniques, which were left to the attending neuroradiologist’s discretion. Endovascular treatment was performed with approved MT devices using stent-retrievers, large-bore aspiration catheters or a combination of both.\n\nComplete reperfusion was defined as the Thrombolysis In Cerebral Infarction (TICI) scale score of three. Successful reperfusion was defined as TICI≥2b. Clinical efficacy outcome was the rate of functional independence measured by the modified Rankin Scale (mRS) and defined as 0–2 at discharge and 90 days. National Institutes of Health Stroke Scale (NIHSS) and mRS grades were assessed by a consultant neurologist. Baseline NIHSS was collected at patients’ admission at the CSC.\n\nAccording to the guidelines of the respective local ethics committees, ethical approval was given when necessary for this anonymous retrospective study, which was conducted in accordance with the Declaration of Helsinki. A patient’s consent for treatment was obtained according to the individual institutional guidelines. Due to the retrospective nature of the study, additional informed consent was deemed unnecessary.\n\nResults\n\nIn total, six patients from five tertiary stroke centres were treated with MT due to LVO suffering from IVT-associated ICH. Procedural characteristics per case are shown in Table 1. Out of six patients, five patients received IVT at a PSC and were subsequently transferred to a CSC for endovascular treatment (‘drip-and-ship’ paradigm). One patient was directly transferred to a CSC (‘mothership’ paradigm’). Alteplase was administered as the full dose in patients treated by the ‘drip-and-ship’ paradigm. Median age was 80 years (interquartile range (IQR) 76–85 years) and 4/6 (67%) patients were female.\n\nTable 1. Detailed demographic, procedural and outcome parameters.\n\nCase\tSex/age\tBaseline medication\tDrip and ship\tOcclusion site\tTOAST\tUnderlying aetiology for ICH\tBaseline ASPECTS\tNIHSS admission\tLocalization of ICH\tICH within the LVO affected territory\tOnset to groin (min)\tOnset to IVT (min)\tOnset to final reperfusion (min)\tFinal TICI\tNumber of manoeuvres\tmRS 90 days\t\n1\tM/78\tAspirin\tYes\tM1\tUndetermined\tUnknown\t8\t22\tIntraparenchymal\tNo\t149\t45\t193\t2a\t2\t6\t\n2\tF/85\tAspirin\tYes\tBA\tCardioembolic\tUnknown\t8\t22\tIntraparenchymal and subdural\tYes\tNA\tNA\tNA\t2b\t3\t6\t\n3\tF/86\tNo\tYes\tDistal ICA\tCardioembolic\tVital cancer\t10\t30\tIntraparenchymal\tYes\t230\t80\t335\t2b\t3\t6\t\n4\tM/70\tAspirin\tYes\tM1\tUndetermined\tUnknown\t8\t20\tIntraparenchymal\tYes\t240\t150\t306\t2b\t1\t4\t\n5\tF/79\tNo\tNo\tBA\tCardioembolic\tUnknown\t8\t12\tIntraparenchymal\tYes\t320\t60\t660\t2a\t8\t6\t\n6\tF/80\tAspirin\tYes\tBA\tLarge artery Sclerosis\tUnknown\t10\t36\tSubarachnoid\tYes\t288\t179\t358\t2b\t1\t6\t\nASPECTS: Alberta Stroke Program Early CT score; BA: basilar artery; F: female; ICA: internal carotid artery; ICH: intracranial haemorrhage; IVT: intravenous thrombolysis; LVO: large vessel occlusion; M: male; min: minutes; mRS: modified Rankin Score; NIHSS: National Institutes of Health Stroke Scale; SAH: subarachnoid haemorrhage; TICI: Thrombolysis In Cerebral Infarction.\n\nLarge vessel occlusion of the BA was detected in 3/6 (50%) patients, two patients suffered from MCA M1 and one patient from distal ICA LVO, respectively. Five out of six (83%) individuals demonstrated cerebral intraparenchymal haemorrhage on pre-interventional CT. Of those, 3/5 (60%) patients suffered from space-occupying haematoma. In one patient, additional subdural haematoma was observed, and one patient suffered from isolated subarachnoid haemorrhage (SAH). Five out of six (83%) ICH events were localised in the LVO affected territory (Figure 1).\n\nFigure 1. (a) Baseline imaging from an octogenarian woman with basilar artery occlusion and dens artery sign (white arrow) on non-contrast computed tomography. Intravenous thrombolysis was given, and the patient was transferred to a comprehensive stroke center. (b) At the beginning of the endovascular procedure a flat detector computed tomography was done due to deterioration of symptoms (National Institute of Health Stroke Scale=22) with evidence of an intraparenchymal haemorrhage in the left occipital lobe (white asterisk). At this timepoint, alteplase was already administered completely. (c)–(e) Mechanical thrombectomy was done with successful recanalization of the basilar artery. The right posterior cerebral artery was chronically occluded. (f) Computed tomography 24 h later showed an aggravation of the intracranial haemorrhage (black asterisk). The patient died due to respiratory failure during the hospital stay.\n\nCardioembolic cause was the most common aetiology for the LVO and found in 3/6 (50%) patients, followed by large artery atherosclerosis (1/6; 17%). Stroke aetiology remained unknown in two patients. The underlying aetiology for the ICH remained undetermined in all patients except for one, for whom further work-up revealed vital cancer, which might have increased the bleeding propensity. Four out of six patients had previous medication with antiplatelet agents.\n\nMedian baseline NIHSS at CSC admission was 22 and median baseline ASPECTS on first imaging was eight. The initial NIHSS at the primary stroke centre was not documented in 5/6 patients. The median interval between (a) onset and IVT was 80 min (IQR 53–165 min), (b) IVT and groin puncture was 107 min (IQR 94–193 minutes) and (c) onset and groin puncture was 240 min (IQR 190–340 min), respectively. The rate of pre-treatment functional independence (mRS≤2) was 50% (3/6).\n\nProcedural and functional outcome\n\nThe median time interval from groin puncture to final reperfusion was 70 min (IQR 61–146 min) and the median number of thrombectomy manoeuvres was three (range 1–8). Successful reperfusion was achieved in 4/6 (67%) patients. None of the six patients were reperfused completely. The median ASPECTS in post-interventional CT was six. In the majority of cases (5/6, 83%), the IVT-associated ICH had aggravated in post-interventional imaging with space-occupying oedema.\n\nProcedure-related, minor SAH had occurred in 1/6 (17%) patients. In one patient, intracranial stenting was performed (Case 6). The patient presented with an occlusion of the proximal BA at a PSC (Figure 2) and after IVT was administered, the patient was transferred to the CSC. As the patients’ status had become impaired, CT imaging was done at the CSC with evidence of slight SAH. The patient was transferred in the angiography suite and the occlusion was recanalised successfully with one aspiration attempt. However, a high-grade stenosis was confirmed in the proximal BA segment, which re-occluded instantly. The operator decided to implant a self-expanding stent with subsequent balloon angioplasty, resulting in good reconstitution of the vessel. As the patient was already pretreated with a daily dose of 100 mg of aspirin, an intravenous infusion of tirofiban was initiated. Four hours later the patient demonstrated wide and fixed pupils bilaterally. An emergency CT scan showed a massive haemorrhage with intraparenchymal, subarachnoid and subdural components. Surgical evacuation was not attempted, and the patient died 2 days later.\n\nFigure 2. An 80-year-old female patient with acute basilar artery occlusion, treated with intravenous thrombolysis at the referring centre (not shown). Upon arrival computed tomography showed a persistent proximal basilar artery thrombosis with reperfusion of the basilar apex (a). Native computed tomography demonstrated a slight subarachnoid haemorrhage in the left temporal region (b). The first angiogram showed persisting occlusion of the proximal third of the basilar artery (c). After one aspiration the vessel was recanalised, but revealed a proximal high-grade stenosis (d), which re-occluded 10 min later. The implantation of a self-expanding stent with following percutaneous transluminal angioplasty led to good reconstitution of the vessel (e). Recanalization of the occluded right P2 segment was not attempted. As the patient was already pretreated with a daily dose of 100 mg of aspirin, an intravenous infusion of tirofiban was initiated with the intention to load the patient with clopidogrel in an overlapping fashion. Four hours later the patient demonstrated wide and fixed pupils bilaterally. An emergency computed tomography scan showed a massive haemorrhage with intraparenchymal, subarachnoid and subdural components. Surgical evacuation was not attempted, and the patient died 2 days later.\n\nOverall, five patients had died during hospital stay. The survivor initially presented with a non-space occupying ICH and achieved a complete resorption of the haemorrhage at discharge; at 90 days, the clinical outcome was moderate an mRS=4 (pre-treatment mRS=2, Case 4).\n\nDiscussion\n\nWe provide the first report of a series of AIS patients with LVO suffering from IVT-associated ICH prior to MT. Our study revealed several findings: (a) the procedure is technically feasible with an adequate rate of successful reperfusion, (b) the mortality rate of these subgroup of patients is high (83%), and (c) the underlying cause for the ICH remains undetermined in most cases.\n\nAs the presence of an intracranial haemorrhage currently represents an exclusion criterion for MT, the decision-making was done individually. In three of the affected individuals, the haemorrhage was not space-occupying (Cases 2, 4 and 6). One patient showed haemorrhage outside the affected territory (Case 1). One patient suffered from a basilar artery occlusion and clinical outcome is known to be devastating if occlusion will not be recanalised (Case 5). In another patient (Case 3), it was the decision of the operator and the neurologist as the patient was in her 80s, but functionally independent prior to the stroke.\n\nSo far, there is one case report about a successful MT in a 75-year-old patient with MCA occlusion and pre-interventional IVT-associated ICH. 8 The underlying cause for the ICH was probable cerebral amyloid angiopathy and the patient was released with an excellent neurological outcome (mRS=0). In comparison with our study, the patient had lower NIHSS at admission (NIHSS=7) and was reperfused completely. In addition, the IVT-associated ICH appeared not to be space-occupying.\n\nThe rate of successful reperfusion in our study was lower compared to the current literature 5 and might be due to several factors. First, the median age of the included patients was 80 years and all patients had arterial hypertension with increased likelihood of difficult vascular access resulting in longer procedure times, lower recanalization rates and poorer outcome. 9 Second, half of the occluded vessels were localised in the posterior circulation. A recent study reported that futile recanalization occurred more frequently in BA occlusions, and predictors of futile recanalization included age, stroke severity, manoeuvre count and intracranial stenting. 10\n\nIn our study, the mortality rate was high with 83% compared to patients with LVO receiving IVT in the anterior circulation with rates up to 15% in the interventional arm (MT and IVT) of the HERMES meta-analysis. 5 It remains unclear whether the devastating clinical outcome in our study was caused by the LVO or the ICH itself. Since the ICHs were space-occupying in the majority of cases, it might have been attributed most likely to the neurological aggravation. However, it has to be mentioned that two of the patients were not reperfused successfully (TICI=2a each), which is also accompanied with poor clinical outcome. 11 In contrast to the deceased, the survivor in our cohort suffered from an M1 occlusion and a small parenchymal haemorrhage, which had resorbed completely at discharge. Although two other patients also showed non-space-occupying ICHs on pre-interventional CT, the clinical outcome was poor due to underlying BA occlusion and an aggravation of the ICHs during the hospital stay. Although the presented number of patients is low, it is conceivable that the extent of baseline ICH and expansion after MT might influence patients’ outcome.\n\nIn this context, blood pressure (BP) control might be one important factor affecting the outcome. On the one hand, moderately elevated BP is associated with good collateral circulation in AIS patients. 12 On the other hand, high BP levels around reperfusion therapy carry an increased risk of ICH. 13 In the status of vessel occlusion, low BP levels may lead to hypoperfusion of ischaemic tissue resulting in greater infarction. 14 In the unlikely event of both, ICH and simultaneous cerebral LVO, the optimal target BP remains indeterminable, since both variations provoke poor neurological outcome.\n\nIn a meta-analysis risk factors for ICH in AIS patients treated with IVT were identified including higher age, higher stroke severity and higher glucose level. 15 The study showed that there was approximately a doubling of the odds of ICH with the presence of a visible acute cerebral ischaemic lesion on pretreatment brain imaging. 15 Some of these baseline factors are also reflected in our cohort regarding high median age, high median baseline NIHSS, a median ASPECTS=8 on baseline imaging, previous antiplatelet agents and comorbidities. From this point of view, it might be reasonable in this subgroup of patients, and more particularly in patients treated by the ‘drip and ship’ paradigm, to enforce a flat detector CT pre-interventionally in case of deterioration of the patients’ status.\n\nThe underlying cause for the IVT-related ICH was undetermined in most cases. This might be due to the fact, that in most patients advanced imaging including post-interventional magnet resonance imaging has not been executed.\n\nIn patients with LVO based on an intracranial atherosclerotic disease the treatment of the underlying stenosis is challenging. In our study, one individual suffered from a slight pre-interventional SAH and an acute high-grade stenosis of the BA. At this point, the risk of progressive bleeding due to the necessity of potent antiplatelet medication must be weighed against re-occlusion of the vessel. The patient in our study was treated with intracranial stenting and peri-interventional administration of tirofiban, which led to a massive intracranial haemorrhage. In these specific cases, alternatively a percutaneous transluminal balloon angioplasty might be a reasonable treatment option with waiving of glycoprotein IIB/IIIA inhibitors administration.\n\nThe main limitation of our study is the retrospective nature including inherent selection bias and the usage of different thrombectomy equipment and techniques. The lack of a control group is a further limitation. As highlighted previously, the presented number of patients is too low to draw definitive conclusions, especially as half of the patients suffered from BA occlusion, which by itself is accompanied with a poorer outcome compared to anterior circulation strokes and might serve as a possible confounder. However, this multicentre study includes the largest number of endovascularly treated LVOs following IVT-associated ICHs in the literature so far.\n\nConclusion\n\nMechanical thrombectomy in patients with IVT-associated ICH is technically feasible. The clinical outcome of these patients appears to be devastating with high mortality and only carefully selected patients might benefit from endovascular treatment. However, until we have data from larger trials, it will always be an individual decision but, finally, it should be the goal to not leave individuals behind that might benefit from endovascular treatment in this particular situation.\n\nAcknowledgements\n\nThe following author contributions were made: conception and design: VM; acquisition of data: MG, NA, AB, HH and VM; analysis and interpretation of data: JG, CK, MP, CSC, SF, MF, HS and VM; drafting the article: HS; all authors have read and approved the manuscript.\n\nConflict of interest: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: HH is co-inventor of the Solitaire FR stent retriever and co-founder and shareholder of Phenox GmbH. The other authors declare that they have no competing interests.\n\nFunding: The author(s) received no financial support for the research, authorship and/or publication of this article.\n\nORCID iDs: Hanna Styczen https://orcid.org/0000-0002-9623-4156\n\nJohannes Gerber https://orcid.org/0000-0001-7465-8700\n==== Refs\nReferences\n\n1 Powers WJ Rabinstein AA Ackerson T , et al . Guidelines for the early management of patients with acute ischemic stroke: 2019 Update to the 2018 guidelines for the early management of acute ischemic stroke: A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2019; 50 : e344–e418.31662037\n2 Turc G Bhogal P Fischer U , et al . European Stroke Organisation (ESO) - European Society for Minimally Invasive Neurological Therapy (ESMINT) guidelines on mechanical thrombectomy in acute ischaemic stroke endorsed by Stroke Alliance for Europe (SAFE). Eur Stroke J 2019; 4 : 6–12.31165090\n3 Yang P Zhang Y Zhang L , et al . Endovascular thrombectomy with or without intravenous alteplase in acute stroke. N Engl J Med 2020; 21 : 1981–1993.\n4 Suzuki K Matsumaru Y Takeuchi M. The randomized study of endovascular therapy with versus without intravenous tissue plasminogen activator in acute stroke with ICA and M1 occlusion (SKIP study). Paper abstract. International Stroke Conference, Los Angeles, USA, 19-21 February 2020.\n5 Goyal M Menon BK van Zwam WH , et al . Endovascular thrombectomy after large-vessel ischaemic stroke: A meta-analysis of individual patient data from five randomised trials. Lancet 2016; 23 : 1723–1731.\n6 Hacke W Kaste M Fieschi C , et al . Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet 1998; 17 : 1245–1251.\n7 Sheth KN Smith EE Grau-Sepulveda MV , et al . Drip and ship thrombolytic therapy for acute ischemic stroke: Use, temporal trends, and outcomes. Stroke 2015; 46 : 732–739.25672784\n8 Weller JM Hattingen E Petzold GC , et al . Successful mechanical thrombectomy in stroke with thrombolysis-associated intracerebral hemorrhage–a case report. J Stroke Cerebrovasc Dis 2019; 28 : 285–287.30529220\n9 Ribo M Flores A Rubiera M , et al . Difficult catheter access to the occluded vessel during endovascular treatment of acute ischemic stroke is associated with worse clinical outcome. J Neurointerv Surg 2013; 5 : i70–i73.23117130\n10 Meinel TR Kaesmacher J Chaloulos-Iakovidis P , et al . Mechanical thrombectomy for basilar artery occlusion: Efficacy, outcomes, and futile recanalization in comparison with the anterior circulation. J Neurointerv Surg 2019; 11 : 1174–1180.31239331\n11 Dekker L Geraedts VJ Hund H , et al . Importance of reperfusion status after intra-arterial thrombectomy for prediction of outcome in anterior circulation large vessel stroke. Interv Neurol 2018; 7 : 137–147.29719551\n12 Rusanen H Saarinen JT Sillanpää N. The association of blood pressure and collateral circulation in hyperacute ischemic stroke patients treated with intravenous thrombolysis. Cerebrovasc Dis 2015; 39 : 130–137.25660943\n13 Anadani M Orabi MY Alawieh A , et al . Blood pressure and outcome after mechanical thrombectomy with successful revascularization. Stroke 2019; 50 : 2448–2454.31318633\n14 Choi KH Kim JM Kim JH , et al . Optimal blood pressure after reperfusion therapy in patients with acute ischemic stroke. Sci Rep 2019; 5 : 5681.\n15 Whiteley WN Slot KB Fernandes P , et al . Risk factors for intracranial hemorrhage in acute ischemic stroke patients treated with recombinant tissue plasminogen activator: A systematic review and meta-analysis of 55 studies. Stroke 2012; 43 : 2904–2909.22996959\n\n", "fulltext_license": "CC BY", "issn_linking": "1971-4009", "issue": "34(5)", "journal": "The neuroradiology journal", "keywords": "Acute ischaemic stroke; intracranial haemorrhage; intravenous thrombolysis; large vessel occlusion; mechanical thrombectomy", "medline_ta": "Neuroradiol J", "mesh_terms": null, "nlm_unique_id": "101295103", "other_id": null, "pages": "456-461", "pmc": null, "pmid": "33840277", "pubdate": "2021-10", "publication_types": "D016428:Journal Article", "references": "25660943;22996959;30529220;32374959;31239331;23117130;30924762;26898852;9788453;25672784;31318633;29719551;30952938;31662037;31165090", "title": "Mechanical thrombectomy in acute ischaemic stroke patients with pre-interventional intracranial haemorrhage following intravenous thrombolysis.", "title_normalized": "mechanical thrombectomy in acute ischaemic stroke patients with pre interventional intracranial haemorrhage following intravenous thrombolysis" }

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{ "abstract": "Chemotherapy-related acute exacerbation (AE) of interstitial lung disease (ILD) is observed in certain patients with non-small cell lung cancer (NSCLC) who have ILD. Although the prognosis of AE-ILD is extremely poor, there are no established risk factors for its occurrence. Therefore, we retrospectively investigated whether high-resolution computed tomography (HRCT) findings could identify risk factors for AE-ILD.\n\n\n\nBetween January 2005 and December 2016, 35 patients with NSCLC who received chemotherapy at Hiroshima University Hospital and were diagnosed with ILD on HRCT were enrolled. The extent of ground-glass attenuation (GGA), reticulation, honeycomb appearance, and emphysema, as well as the presence of micronodules, traction bronchiectasis, and consolidation were evaluated in five levels of the lung bilaterally. The HRCT scores of GGA, reticulation, honeycomb appearance, and emphysema were determined by the following formula: 100 × sum of the extent of the HRCT findings/lung area.\n\n\n\nThirty-five patients underwent various first- to fifth-line chemotherapy regimens. Nine patients (25.7%) developed AE-ILD. The median HRCT scores of GGA and reticulation were significantly higher in patients with AE-ILD than in those without. On univariate analysis, a GGA area score ≥ 24.8, reticulation area score ≥ 19.5, and KL-6 level ≥ 946 U/mL were significant risk factors. Multivariate logistic analysis revealed that only a GGA area score ≥ 24.8 was an independent risk factor of AE-ILD.\n\n\n\nThe GGA area on HRCT is a risk factor for chemotherapy-related AE-ILD. Therefore, this parameter can be used to predict the risk of AE-ILD before administering chemotherapy.", "affiliations": "Department of Respiratory Internal Medicine, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan. ta-masuda@hiroshima-u.ac.jp.;Hiroshima Atomic Bomb Casualty Council, 3-8-6 Sendamachi, Naka-ku, Hiroshima, 730-0052, Japan.;Department of Respiratory Internal Medicine, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.;Department of Respiratory Internal Medicine, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.;Department of Respiratory Internal Medicine, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.;Department of Respiratory Internal Medicine, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.;Department of Emergency and Critical Care Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.;Department of Respiratory Internal Medicine, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.;Department of Respiratory Internal Medicine, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.;Department of Respiratory Internal Medicine, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.", "authors": "Masuda|Takeshi|T|0000-0003-3557-0049;Hirano|Chihiro|C|;Horimasu|Yasushi|Y|;Nakashima|Taku|T|;Miyamoto|Shintarou|S|;Iwamoto|Hiroshi|H|;Ohshimo|Shinichiro|S|;Fujitaka|Kazunori|K|;Hamada|Hironobu|H|;Hattori|Noboru|N|", "chemical_list": "D000970:Antineoplastic Agents", "country": "Germany", "delete": false, "doi": "10.1007/s00280-017-3476-5", "fulltext": null, "fulltext_license": null, "issn_linking": "0344-5704", "issue": "81(1)", "journal": "Cancer chemotherapy and pharmacology", "keywords": "Acute exacerbation; Chemotherapy; High-resolution computed tomography; Interstitial lung disease; Lung cancer", "medline_ta": "Cancer Chemother Pharmacol", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D002289:Carcinoma, Non-Small-Cell Lung; D018450:Disease Progression; D005260:Female; D006801:Humans; D017563:Lung Diseases, Interstitial; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "7806519", "other_id": null, "pages": "131-139", "pmc": null, "pmid": "29143072", "pubdate": "2018-01", "publication_types": "D016428:Journal Article", "references": null, "title": "The extent of ground-glass attenuation is a risk factor of chemotherapy-related exacerbation of interstitial lung disease in patients with non-small cell lung cancer.", "title_normalized": "the extent of ground glass attenuation is a risk factor of chemotherapy related exacerbation of interstitial lung disease in patients with non small cell lung cancer" }

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THE EXTENT OF GROUND-GLASS ATTENUATION IS A RISK FACTOR OF CHEMOTHERAPY-RELATED EXACERBATION OF INTERSTITIAL LUNG DISEASE IN PATIENTS WITH NON-SMALL CELL LUNG CANCER. CANCER CHEMOTHERAPY AND PHARMACOLOGY. 2018?81 (1):131-139.", "literaturereference_normalized": "the extent of ground glass attenuation is a risk factor of chemotherapy related exacerbation of interstitial lung disease in patients with non small cell lung cancer", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180222", "receivedate": "20180222", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14564207, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "JP-TEVA-2018-JP-874456", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "203551", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG ADENOCARCINOMA STAGE IV", "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": "60", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Interstitial lung disease", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MASUDA T, HIRANO C, HORIMASU Y, NAKASHIMA T, MIYAMOTO S, IWAMOTO H, ET AL. THE EXTENT OF GROUND-GLASS ATTENUATION IS A RISK FACTOR OF CHEMOTHERAPY-RELATED EXACERBATION OF INTERSTITIAL LUNG DISEASE IN PATIENTS WITH NON-SMALL CELL LUNG CANCER. CANCER-CHEMOTHER-PHARMACOL 2018?81(1):131-139.", "literaturereference_normalized": "the extent of ground glass attenuation is a risk factor of chemotherapy related exacerbation of interstitial lung disease in patients with non small cell lung cancer", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JM", "receiptdate": "20180402", "receivedate": "20180402", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14706378, "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": "JP-TEVA-2018-JP-874457", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "203551", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG SQUAMOUS CELL CARCINOMA RECURRENT", "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": "64", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Interstitial lung disease", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "MASUDA T, HIRANO C, HORIMASU Y, NAKASHIMA T, MIYAMOTO S, IWAMOTO H, ET AL. THE EXTENT OF GROUND-GLASS ATTENUATION IS A RISK FACTOR OF CHEMOTHERAPY-RELATED EXACERBATION OF INTERSTITIAL LUNG DISEASE IN PATIENTS WITH NON-SMALL CELL LUNG CANCER. CANCER-CHEMOTHER-PHARMACOL 2018?81(1):131-139.", "literaturereference_normalized": "the extent of ground glass attenuation is a risk factor of chemotherapy related exacerbation of interstitial lung disease in patients with non small cell lung cancer", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180402", "receivedate": "20180402", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14706380, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180711" } ]

{ "abstract": "Retinal vascular occlusion after ocular surgery is a rare but serious complication. A history of cardiovascular diseases, retrobulbar anesthesia injection, high intraocular pressure during the perioperative period, and drug toxicity have been reported as possible causative factors. We report here two cases of multiple retinal vascular occlusions after the subconjunctival injection of gentamicin at the end of uncomplicated 25-gauge vitrectomy. Case 1 was a 61-year-old man who developed a macular hole in the right eye. Phacovitrectomy with gas tamponade was performed. On postoperative day (POD) 1, dot hemorrhage was observed on the temporal side of the optic disk. On POD10, macular whitening, retinal hemorrhage, and multiple occlusion of retinal arteries and veins were observed. Case 2 was a 51-year-old woman who was diagnosed with rhegmatogenous retinal detachment in the right eye and underwent phacovitrectomy with gas tamponade. On POD3, macular whitening with cotton wool spots and retinal hemorrhage were observed with macular ischemia owing to occlusion of retinal arteries and veins. In both cases, subconjunctival injection of gentamicin given at the end of surgery was the most suspected cause of retinal vascular occlusion.", "affiliations": "Department of Ophthalmology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.;Department of Ophthalmology, Sapporo City General Hospital, Sapporo, Japan.;Department of Ophthalmology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.;Department of Ophthalmology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.;Department of Ophthalmology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.;Department of Ophthalmology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.", "authors": "Murao|Fumiko|F|;Kinoshita|Takamasa|T|;Katome|Takashi|T|;Sano|Hiroki|H|;Niki|Masanori|M|;Mitamura|Yoshinori|Y|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.1159/000509337", "fulltext": "\n==== Front\nCase Rep Ophthalmol\nCase Rep Ophthalmol\nCOP\nCase Reports in Ophthalmology\n1663-2699 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\n10.1159/000509337\ncop-0011-0473\nCase Report\nSuspected Gentamicin-Induced Retinal Vascular Occlusion after Vitrectomy\nMurao Fumiko a* Kinoshita Takamasa b Katome Takashi a Sano Hiroki a Niki Masanori a Mitamura Yoshinori a aDepartment of Ophthalmology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan\nbDepartment of Ophthalmology, Sapporo City General Hospital, Sapporo, Japan\n*Fumiko Murao, Department of Ophthalmology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto, Tokushima 770-8503 (Japan), murafumitomi@yahoo.co.jp\nMay-Aug 2020 \n11 8 2020 \n11 8 2020 \n11 2 473 480\n28 11 2019 9 6 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.Retinal vascular occlusion after ocular surgery is a rare but serious complication. A history of cardiovascular diseases, retrobulbar anesthesia injection, high intraocular pressure during the perioperative period, and drug toxicity have been reported as possible causative factors. We report here two cases of multiple retinal vascular occlusions after the subconjunctival injection of gentamicin at the end of uncomplicated 25-gauge vitrectomy. Case 1 was a 61-year-old man who developed a macular hole in the right eye. Phacovitrectomy with gas tamponade was performed. On postoperative day (POD) 1, dot hemorrhage was observed on the temporal side of the optic disk. On POD10, macular whitening, retinal hemorrhage, and multiple occlusion of retinal arteries and veins were observed. Case 2 was a 51-year-old woman who was diagnosed with rhegmatogenous retinal detachment in the right eye and underwent phacovitrectomy with gas tamponade. On POD3, macular whitening with cotton wool spots and retinal hemorrhage were observed with macular ischemia owing to occlusion of retinal arteries and veins. In both cases, subconjunctival injection of gentamicin given at the end of surgery was the most suspected cause of retinal vascular occlusion.\n\nKeywords\nGentamicinMacular ischemiaRetinal vascular occlusionVitrectomy\n==== Body\nIntroduction\nA history of cardiovascular disease, retrobulbar anesthesia injection, high intraocular pressure (IOP) during the perioperative period, and drug toxicity have been reported as the possible causative factors of the rare and serious complication of retinal vascular occlusion after intraocular surgery [1, 2, 3].\n\nWe herein report two cases of multiple retinal vascular occlusion after the subconjunctival injection of gentamicin at the end of 25-gauge (25 G) vitrectomy.\n\nCase Presentation\nCase 1\nA 61-year-old man visited our department with a complaint of decreased visual acuity of the right eye for 1 month. A stage 2 macular hole in the right eye was noted (Fig. 1a, b). His decimal best-corrected visual acuity (BCVA) at the first visit was 0.3 in the right eye and 1.0 in the left eye. Furthermore, his IOP was 15 mm Hg in the right eye and 14 mm Hg in the left eye. The axial length was 23.28 mm in the right eye and 23.44 mm in the left eye. No systemic diseases such as diabetes or hypertension were observed. Accordingly, phacovitrectomy with a 20% sulfur hexafluoride (SF6) gas tamponade was performed under retrobulbar anesthesia. At the end of the operation, a subconjunctival injection of gentamicin was administered. Dot hemorrhages were observed on the temporal side of the optic disk on postoperative day (POD) 1. However, neither further hemorrhage nor retinal whitening was observed on POD3, and the patient was discharged. Fundus examination on POD10 revealed blot hemorrhage, mottled retinal whitening in the macula, and cotton wool spots. The patient's BCVA was 0.01 in the right eye and decreased to hand motion during postoperative week 1. Fundus examination and fluorescein angiography (FA) showed multiple disruptions of the vessels surrounding the fovea and occlusion of the macular branch retinal artery on the inferior temporal side. Slight fluorescence leakage on the nasal side of the optic nerve head was observed (Fig. 1c, e). Limaprost alfadex and kallidinogenase were prescribed as antiplatelet and vasodilator therapy, along with an oral steroid. Stellate ganglion block was performed to increase ocular circulation. Progression of arteriovenous occlusion around the macula was observed. The macular hole was finally closed, but the patient's postoperative BCVA was 0.2.\n\nCase 2\nA 51-year-old woman presented with complaints of blurred vision lasting for 6 days. Her decimal BCVA at the first visit was 0.02 in the right eye and 1.2 in the left eye. Her IOP was 13 mm Hg in the right eye and 15 mm Hg in the left eye. Mild cataract was observed in both eyes. The axial length was 26.07 mm in the right eye and 25.88 mm in the left eye. Bullous macula-off retinal detachment was observed in the right eye, with retinal tears in the superior area and temporal inferior area of the retina (Fig. 2a). No systemic diseases such as diabetes or hypertension were observed. Under retrobulbar anesthesia, phacovitrectomy with a 20% SF6 gas tamponade was performed. At the end of the operation, a subconjunctival injection of gentamicin was administered. On POD1, subretinal fluid persisted in the macula, but it was almost absorbed on POD2. Dot bleedings and retinal whitening were observed in the macula on POD3. Blot and flame-shaped hemorrhage and cotton wool spots were observed on POD4 (Fig. 2b, d). FA showed multiple retinal vein filling defects around the macula and tissue staining of the vascular wall. A small nonperfused region was also observed near the laser coagulation spots (Fig. 2c). The patient's BCVA was 50 cm hand motion. The patient was treated with urokinase infusion and oral acetazolamide, but there was no significant improvement in retinal circulation. The retina was reattached. Two months after the operation, her visual acuity was 0.08. There was a central vision defect 16 months after the operation, but local reperfusion of the retinal circulation occurred and the visual acuity improved to 0.8. Within 1.5 months postoperatively, some of the blood vessels located proximal to the optic nerve were reperfused. The distally located blood vessels showed progressive occlusion (Fig. 3a–c). A reperfusion of blood vessels was observed on the nasal superior side of the macula. Optical coherence tomography angiography 1 year after surgery showed a highly damaged capillary network on the superficial capillary plexus (Fig. 3d) and deep capillary plexus (Fig. 3e). The capillaries superior to the macula were less damaged than those inferior to the macula. In visual field examination, a small visual field remained on the temporal inferior side of the central scotoma (Fig. 3f).\n\nRegarding 25 G phacovitrectomy in these two cases, we used a disposable retrobulbar needle for retrobulbar anesthesia. The anesthetic used was a 1:1 mixture of 4–5 mL mepivicaine (2% Carbocaine®) and bupivacaine (0.5% Marcaine®). Compression of the ocular globe was not performed after injection. After phacoemulsification with intraocular lens implantation, the patients underwent 3-port (case 1) and 4-port (case 2) vitrectomy. We used single-use phaco tips, I/A tips, 25 G cutters, and probes. No ethylene oxide gas-sterilized instruments were used. The IOP control system was set from 25 to 30 mm Hg and was reduced to 15 mm Hg during ocular globe compression. Triamcinolone acetonide was used for vitreous staining. Internal limiting membrane peeling was performed in case 1, and retinal photocoagulation around the retinal breaks was performed in case 2. The SF6 gas amount was manually adjusted to 20% before injection. Next, the wound was sutured, and the pressure was confirmed to be at physiological level by digital palpation. At the end of the surgery, subconjunctival injection of gentamicin sulfate (5 mg in 0.5 mL) and dexamethasone (0.8 mg in 0.5 mL) was performed. The total operation time was 40 min for case 1 and 80 min for case 2. There were no intraocular fluctuations in IOP. Postoperatively, both patients were instructed to maintain the prone position.\n\nIn both cases, no vascular abnormalities in the head and neck were found on postoperative magnetic resonance imaging and magnetic resonance angiography, and there were no underlying systemic cardiovascular disorders.\n\nDiscussion/Conclusion\nWe report two cases of multiple retinal vascular occlusions after the subconjunctival injection of gentamicin at the end of 25 G vitrectomy.\n\nIn recent years, there have been reports of subconjunctival gentamicin-induced macular toxicity following sutureless 25 G vitrectomy [4, 5, 6]. Fundus examination showed retinal hemorrhages, edema, and soft exudates on the posterior pole on POD1 [4] or POD3 [5]. In another report, retinal pallor throughout the macula with a macular hole was observed on POD14 [6]. Conway et al. [7] reported on gentamicin-induced retinal toxicity in the primate retina by injecting gentamicin into the vitreous cavity of Cebus navrigatus monkeys. According to the report, gentamicin causes inflammatory changes in the inner layer of the retina in the posterior pole, especially in the nerve fiber layer and the ganglion cell layer. Vascular occlusion occurs secondly owing to granulocyte plug formation around the capillary bed. In the present cases, optical coherence tomography images obtained when retinal opacification appeared showed hyperreflectivity in the inner retinal layers (Fig. 1d and 2e). FA in both cases showed non-filling of the retinal capillaries in the central macula (Fig. 1e and 2c). The distinctive angiographic appearance of shutdown of the capillary bed observed may be the result of irreversible “granulocyte plugging” after the vessel is reopened [7].\n\nWound leak and hypotony promotes exchange of conjunctival fluid with the vitreous fluid, and shaving of the peripheral vitreous tends to cause hypotony owing to insufficient wound closure. In our cases, the wound was sutured, and the pressure was confirmed to be at physiological level by digital palpation before injection of subconjunctival gentamicin. The IOP was within normal tension on the day after operation. However, it is impossible to rule out the possibility that a small amount of gentamicin had flowed into the eye because of insufficiently sutured wounds. Furthermore, a small amount of drug that would not normally cause toxicity may cause retinal damage, as the SF6 gas-filled vitreous cavity contains almost no liquid component [8].\n\nIn case 2, although the central scotoma remained 16 months after the operation, visual acuity improved to 0.8. The reperfusion of capillaries in the nasal superior side of the macula may have improved visual field and visual acuity (Fig. 3) [8].\n\nOther than drug toxicity, postoperative vascular occlusion is caused by post-bulbar anesthesia, gas injection, or increased IOP during and after surgery [1, 2, 3]. In our case, no obvious IOP abnormality was observed during or after surgery, and no problems such as retrobulbar hemorrhage occurred during retrobulbar anesthesia. Fundus findings are different from those of typical central retinal artery occlusion and central retinal vein occlusion [9].\n\nRetinal vascular occlusion after vitrectomy is rare but can be a serious complication that can lead to severe visual impairment. The risks of prophylactic use of subconjunctival injection of gentamicin should be considered, given that no evidence has been reported that prophylactic subconjunctival injection of antibacterial agents can prevent endophthalmitis after vitrectomy [10]. Gentamicin injected under the conjunctiva may flow into the vitreous cavity and induce retinal vascular occlusion, even if all ports are sutured.\n\nStatement of Ethics\nThis case report was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. Written informed consent was obtained from the patients. This study does not include any information which may reveal the patient's identity.\n\nDisclosure Statement\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\nNo funding was received.\n\nAuthor Contributions\nAll authors participated in the analysis of both cases. All authors reviewed and approved the manuscript.\n\nAcknowledgements\nThe authors thank E. Morishita for assistance with ophthalmic examination.\n\nFig. 1 Multimodal imaging including color fundus photography, optical coherence tomography, and FA of case 1 showing a macular hole in the right eye. a Preoperative fundus photograph showing a macular hole. There is no apparent vascular arteriosclerosis. b Preoperative horizontal optical coherence tomography showing a stage 2 macular hole with cysts at the edge of the hole. c Fundus photography 17 days after vitrectomy showing mottled whitening of the macular retina, cotton wool spots, and blot hemorrhages. There are multiple disruptions of the vessels surrounding the fovea. d Horizontal optical coherence tomography through the fovea 17 days after vitrectomy demonstrating thickening and hyperreflectivity of the inner retinal layers. e FA 25 days after vitrectomy showing a nonperfusion area with filling defect in the macular branch of the inferotemporal branch retinal artery and multiple macular arterial occlusion around the fovea. No retinal capillary filling in the central part of the macular even in the late phase was observed.\n\nFig. 2 Multimodal imaging including color fundus photography, optical coherence tomography, and FA of case 2 showing rhegmatogenous retinal detachment in the right eye. a Preoperative fundus photograph showing the bullous macula-off retinal detachment. b Fundus photograph 4 days after vitrectomy showing macular whitening and retinal hemorrhage. Half of the 20% sulfur hexafluoride gas remains. There are two breaks on the upper side, an intentional break below them, and laser photocoagulation spots around these breaks. c FA 4 days after vitrectomy showing an avascular area around the macula and inferior to the intentional break. d Fundus photography 6 days after vitrectomy showing blot retinal hemorrhage, retinal whitening, and cotton wool spots. e Optical coherence tomography through the white arrow in d demonstrating thickening and hyperreflectivity of the inner retinal layers and subfoveal retinal detachment.\n\nFig. 3 FA and optical coherence tomography angiography of case 2. a FA on postoperative day 6 showing multiple retinal vascular filling defects around the macula. There is staining of the arcade vessel wall. The superior half is a mirror image owing to intraocular gas. b FA on postoperative day 12. Supratemporal vessels to the optic disc also show filling defect. c FA on postoperative day 45. The occluded blood vessels located proximal to the optic nerve are reperfused (red arrow), whereas the occlusion of distally located blood vessels have progressed (yellow arrows). d, e Optical coherence tomography angiography 1 year after surgery showing a highly damaged capillary network on the superficial capillary plexus (d) and deep capillary plexus (e). The capillaries superior to the macula are less damaged than those inferior to the macula. f Visual field of the right eye 16 months after the operation. Partial visual field remains on the lower ear side of the central scotoma.\n==== Refs\nReferences\n1 Fischer C Bruggemann A Hager A Callizo Planas J Roider J Hoerauf H Vascular occlusions following ocular surgical procedures: a clinical observation of vascular complications after ocular surgery J Ophthalmol 2017 2017 9120892 28781891 \n2 Tappeiner C Garweg JG Retinal vascular occlusion after vitrectomy with retrobulbar anesthesia-observational case series and survey of literature Graefes Arch Clin Exp Ophthalmol 2011 12 249 (12) 1831 5 21850439 \n3 Russell JF Scott NL Haddock LJ Eaton AM Flynn HW Central retinal artery occlusion on postoperative day one after vitreoretinal surgery Am J Ophthalmol Case Rep 2018 10 12 93 6 30364763 \n4 Cardascia N Boscia F Furino C Sborgia L Gentamicin-induced macular infarction in transconjunctival sutureless 25-gauge vitrectomy Int Ophthalmol 2008 10 28 (5) 383 5 17938870 \n5 Brouzas D Moschos MM Koutsandrea C Davou S Georgalas I Gentamicin-induced macular toxicity in 25-gauge sutureless vitrectomy Cutan Ocul Toxicol 2013 9 32 (3) 258 9 23356777 \n6 Heath Jeffery RC Bowden FJ Essex RW Subconjunctival gentamicin-induced macular toxicity following sutureless 25-gauge vitrectomy Clin Exp Ophthalmol 2017 4 45 (3) 301 4 27683206 \n7 Conway BP Tabatabay CA Campochiaro PA D'Amico DJ Hanninen LA Kenyon KR Gentamicin toxicity in the primate retina Arch Ophthalmol 1989 1 107 (1) 107 12 2910268 \n8 Campochiaro PA Lim JI The Aminoglycoside Toxicity Study Group Aminoglycoside toxicity in the treatment of endophthalmitis Arch Ophthalmol 1994 1 112 (1) 48 53 8285892 \n9 Hayreh SS Central retinal artery occlusion Indian J Ophthalmol 2018 12 66 (12) 1684 94 30451166 \n10 Weiss SJ Adam MK Gao X Obeid A Sivalingam A Fineman MS Endophthalmitis after pars plana vitrectomy: efficacy of intraoperative subconjunctival antibiotics Retina 2018 9 38 (9) 1848 55 29652690\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1663-2699", "issue": "11(2)", "journal": "Case reports in ophthalmology", "keywords": "Gentamicin; Macular ischemia; Retinal vascular occlusion; Vitrectomy", "medline_ta": "Case Rep Ophthalmol", "mesh_terms": null, "nlm_unique_id": "101532006", "other_id": null, "pages": "473-480", "pmc": null, "pmid": "32999678", "pubdate": "2020", "publication_types": "D002363:Case Reports", "references": "17938870;28781891;30364763;30451166;29652690;8285892;21850439;2910268;27683206;23356777", "title": "Suspected Gentamicin-Induced Retinal Vascular Occlusion after Vitrectomy.", "title_normalized": "suspected gentamicin induced retinal vascular occlusion after vitrectomy" }

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SUSPECTED GENTAMICIN?INDUCED RETINAL VASCULAR OCCLUSION AFTER VITRECTOMY. 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{ "abstract": "A 52-year-old obese gentleman presented to the hospital with complaints of fever and shortness of breath for 10 days. He was admitted in the ward and treated for acute exacerbation of asthma. He was shifted to the Intensive Care Unit (ICU) for persistent fever, neck swelling, airway obstruction and desaturation. Ludwig's angina was suspected and computed tomography of neck confirmed it. A difficult airway was anticipated and preceded with surgical tracheostomy. The patient had hypersensitivity reactions to piperacillin/tazobactam; hence, he was treated with clindamycin and metronidazole. The patient improved and was discharged after five days of ICU stay and 12 days of hospitalization. This case summarizes the rare incidence of Ludwig's angina with antibiotic adverse reactions. If angioneurotic edema is coincidental with features of Ludwig's angina, it becomes more challenging. Early identification, securing the airway, and antibiotic administration are the keystone to better survival.", "affiliations": "Department of Critical Care Medicine, Kovai Medical Center and Hospital, Coimbatore, Tamil Nadu, India.;Department of Critical Care Medicine, Kovai Medical Center and Hospital, Coimbatore, Tamil Nadu, India.;Department of Critical Care Medicine, Kovai Medical Center and Hospital, Coimbatore, Tamil Nadu, India.;Department of Critical Care Medicine, Kovai Medical Center and Hospital, Coimbatore, Tamil Nadu, India.", "authors": "Hisham|Mohamed|M|;Sivakumar|Mundilipalayam N|MN|;Senthil Kumar|R S|RS|;Nandakumar|P|P|", "chemical_list": null, "country": "India", "delete": false, "doi": "10.4103/ijccm.IJCCM_189_15", "fulltext": "\n==== Front\nIndian J Crit Care MedIndian J Crit Care MedIJCCMIndian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine0972-52291998-359XMedknow Publications & Media Pvt Ltd India IJCCM-21-17910.4103/ijccm.IJCCM_189_15Case ReportLudwig's Angina: A Nightmare Worsened by Adverse Drug Reaction to Antibiotics Hisham Mohamed Sivakumar Mundilipalayam N. Senthil Kumar R. S. Nandakumar P. Department of Critical Care Medicine, Kovai Medical Center and Hospital, Coimbatore, Tamil Nadu, IndiaAddress for correspondence: Dr. Mohamed Hisham, Department of Critical Care Medicine, Kovai Medical Center and Hospital, Avinashi Road, Coimbatore - 641 014, Tamil Nadu, India. E-mail: hisham_zenith@yahoo.com3 2017 21 3 179 181 Copyright: © 2017 Indian Journal of Critical Care Medicine2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.A 52-year-old obese gentleman presented to the hospital with complaints of fever and shortness of breath for 10 days. He was admitted in the ward and treated for acute exacerbation of asthma. He was shifted to the Intensive Care Unit (ICU) for persistent fever, neck swelling, airway obstruction and desaturation. Ludwig's angina was suspected and computed tomography of neck confirmed it. A difficult airway was anticipated and preceded with surgical tracheostomy. The patient had hypersensitivity reactions to piperacillin/tazobactam; hence, he was treated with clindamycin and metronidazole. The patient improved and was discharged after five days of ICU stay and 12 days of hospitalization. This case summarizes the rare incidence of Ludwig's angina with antibiotic adverse reactions. If angioneurotic edema is coincidental with features of Ludwig's angina, it becomes more challenging. Early identification, securing the airway, and antibiotic administration are the keystone to better survival.\n\nKeywords\nAngioneurotic edemahypersensitivitysubmandibular infection\n==== Body\nINTRODUCTION\nLudwig's angina is a potentially life-threatening infection of the sublingual and submandibular space which involves the neck and floor of the mouth.[1] It is one of the rare medical emergencies in a critical care setting, which could turn out to be devastating if unidentified at the earliest. If angioneurotic edema is coincidental with features of Ludwig's angina, it becomes more challenging. This case report adds more information in managing Ludwig's angina along with antibiotic adverse reactions.\n\nCASE REPORT\nA 52-year-old obese gentleman initially presented to a local hospital with complaints of fever, shortness of breath for 10 days, and wheezing for the last 3 days. He was a teetotaler with a past history of obstructive sleep apnea and asthma. His body mass index was 32.9. He was treated for acute exacerbation of asthma and referred to our hospital. In the ward, he was treated for asthma exacerbation with oxygen by facemask, nebulization (budesonide, ipratropium, and levosalbutamol), and intravenous hydrocortisone (100 mg for every 8 h). Pulmonary function test showed reversible obstructive airway disease. The patient's condition improved and he was planned to be discharged on the third day from hospital admission. On the day of discharge, he developed fever, trismus, dysphagia, submandibular pain, and swelling in the neck causing airway obstruction.\n\nThe patient had enlargement of lymph nodes in the neck and had normal dentition. Examination with fiber-optic laryngoscope revealed congestion of the epiglottis and tongue. Ultrasonography (USG) neck was done which reported enlarged parotid and submandibular glands with cervical lymphadenopathy. The patient became drowsy and was immediately shifted to the Intensive Care Unit (ICU). Suspecting Ludwig's angina, piperacillin/tazobactam (4.5 g for every every six hours) was prescribed.\n\nOn ICU admission, the patient was normotensive, tachycardic (120 beats/min), tachypneic (26 breaths/min), and had a high-grade temperature (101.3°F). His arterial blood gas revealed respiratory acidosis (pH – 7.19, pCO2 – 83.2 mmHg, and HCO3 – 32.1 mEq/L). He had leukocytosis with white blood cell count of 20,300 cells/mm3 (normal range – 4500–12,500 cells/mm3). He was supported with bilevel positive airway pressure. A follow-up fiber-optic laryngoscopy examination confirmed edema of the nasopharynx and oropharynx causing obstruction to the airway with normal glottis. In view of increasing neck swelling and persistent airway obstruction, a difficult intubation was anticipated and preceded with surgical tracheostomy. On the third dose of piperacillin/tazobactam, the patient developed facial edema, redness, and erythematous papules all over the body, and the antibiotic was stopped. The patient was treated with clindamycin (600 mg for every six hours) and metronidazole (500 mg for every eight hours).\n\nComputed tomography (CT) neck was done once the patient was stabilized which revealed extensive subcutaneous and mediastinal emphysema, edematous changes in the subcutaneous and intermuscular planes of neck, mucosa of pharynx, and had cervical lymphadenopathy [Figures 1 and 2].\n\nFigure 1 Coronal computed tomography images showing laryngeal inlet edema with airway compromise and subcutaneous emphysema.\n\nFigure 2 Axial computed tomography images showing laryngeal inlet edema with airway compromise and subcutaneous emphysema.\n\nThe erythematous rashes and facial edema subsided gradually. The patient became afebrile and symptomatically better in the ICU. He was weaned off the ventilator and transferred to the ward after five days of ICU stay. The swelling completely subsided; tracheal tube was decannulated and he was subsequently discharged after 12 days of hospitalization. He was advised to take inhalers (tiotropium, levosalbutamol, and budesonide) and continue clindamycin (600 mg for every six hours) and metronidazole (500 mg for every eight hours) to complete a course of 10 days. The patient was explained about the adverse drug reactions he had during hospitalization. He was also advised to be cautious when he takes any medicines and to reveal the history of drug allergies whenever he visited a doctor. The patient had proper follow-up with the pulmonology outpatient department and remained stable with no further episodes of exacerbation. The patient was instructed to take inhalers regularly.\n\nDISCUSSION\nIn 1836, Wilhelm Frederick von Ludwig defined this submandibular infection.[2] Ludwig's angina is an uncommon, aggressive, rapidly progressing, and fatal infection with high mortality rate if unidentified and not treated appropriately.[34] More than 70% of the cases have odontogenic etiology, while the other causes include foreign body, tonsillitis, epiglottitis, pharyngitis, oral laceration, mandible fracture, endotracheal intubation, traumatic bronchoscopy, malignancy, or surgery.[35] This patient did not have any typical dental history, hence strongly indicates the other causes of Ludwig's angina. The most common causative organisms involved are the oral flora: Streptococcus species, Staphylococcus species, and anaerobes.[6]\n\nClinical manifestations include fever, tachypnea, tachycardia, swelling and pain in the oral cavity and anterior of neck, dysphagia, stridor, hoarseness, and respiratory distress. It can present as a mild infection and evolves quickly to brawny bilateral neck swelling, tongue edema, fever, and dysphagia.[6] Differential diagnosis of Ludwig's angina includes angioneurotic edema, carcinoma, or abscess.[3]\n\nEarly recognition and diagnosis is the cornerstone to successful management of Ludwig's angina. Ensuring the airway is most important in the treatment of Ludwig's angina.[3] Considering that this case had continuous airway obstruction and difficult intubation, he was electively taken for surgical tracheostomy. The choice of antibiotics is equally important. Piperacillin/tazobactam or benzyl penicillin with metronidazole are the preferred first-choice antibiotics in perimandibular infections.[17] For patients allergic to penicillins, alternative treatment includes clindamycin or vancomycin. It becomes graver and challenging when the patient develops hypersensitivity reactions to most of the treatment options. There is high chance of cross-reactivity among the beta-lactam group of antibiotics including penicillins, cephalosporins, and carbapenems, unless reviewed separately for skin testing, graded challenge test, and desensitization.[8] Steroid therapy and epinephrine nebulization are all recommended treatment in airway compromise.[910]\n\nNeck radiography and USG are useful to identify the soft-tissue involvement. After assuring the airway, CT and magnetic resonance imaging (MRI) are useful modalities to define the extent of soft-tissue infection.[3] In this case, CT imaging was done after securing airway; it defined the space infections with great clarity.\n\nCONCLUSION\nEarly identification, securing the airway, and antibiotic administration are the keystone to better survival. The establishment of airway is done by fiber-optic intubation, tracheostomy, or cricothyroidotomy. CT and MRI are useful modalities to define the extent of soft-tissue infection, considered only after assuring the airway. Always remember the alternative antibiotics in case the patient is allergic to penicillin.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Bartlett JG Bartlett JG Auwaerter PG Pham PA Cervical fascial (Perimandibular) space infections John Hopkins ABX Guide 2010 New Delhi Jones and Bartlett Learning 117 8 \n2 Manasia A Madisi NY Bassily-Marcus A Oropello J Kohli-Seth R Ludwig's angina complicated by fatal cervicofascial and mediastinal necrotizing fasciitis IDCases 2016 4 32 3 27077024 \n3 Quereshy FA Baskin J Barbu AM Zechel MA Report of a case of cervicothoracic necrotizing fasciitis along with a current review of reported cases J Oral Maxillofac Surg 2009 67 419 23 19138621 \n4 Chueng K Clinkard DJ Enepekides D Peerbaye Y Lin VY An unusual presentation of Ludwig's angina complicated by cervical necrotizing fasciitis: A case report and review of the literature Case Rep Otolaryngol 2012 2012 931350 22953129 \n5 Kremer MJ Blair T Ludwig angina: Forewarned is forearmed AANA J 2006 74 445 51 17236391 \n6 Costain N Marrie TJ Ludwig's Angina Am J Med 2011 124 115 7 20961522 \n7 Furst IM Ersil P Caminiti M A rare complication of tooth abscess – Ludwig's angina and mediastinitis J Can Dent Assoc 2001 67 324 7 11450295 \n8 Montañez MI Ariza A Mayorga C Fernandez TD Torres MJ Cross- reactivity in betalactam allergy: Alternative treatments Curr Treat Options Allergy 2015 2 141 54 \n9 Parthiban SV Muthukumar RS Alagappan M Karthi M Ludwig's angina: A rare case report Indian J Multidiscip Dent 2012 2 518 21 \n10 Kavarodi AM Necrotizing fasciitis in association with Ludwig's angina – A case report Saudi Dent J 2011 23 157 60 24151421\n\n", "fulltext_license": "CC BY-NC-SA", "issn_linking": "0972-5229", "issue": "21(3)", "journal": "Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine", "keywords": "Angioneurotic edema; hypersensitivity; submandibular infection", "medline_ta": "Indian J Crit Care Med", "mesh_terms": null, "nlm_unique_id": "101208863", "other_id": null, "pages": "179-181", "pmc": null, "pmid": "28400693", "pubdate": "2017-03", "publication_types": "D002363:Case Reports", "references": "27077024;20961522;17236391;22953129;24151421;19138621;11450295", "title": "Ludwig's Angina: A Nightmare Worsened by Adverse Drug Reaction to Antibiotics.", "title_normalized": "ludwig s angina a nightmare worsened by adverse drug reaction to antibiotics" }

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LUDWIG^S ANGINA: A NIGHTMARE WORSENED BY ADVERSE DRUG REACTION TO ANTIBIOTICS. INDIAN-J-CRIT-CARE-MED 2017;21(3):179-181.", "literaturereference_normalized": "ludwig s angina a nightmare worsened by adverse drug reaction to antibiotics", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20170413", "receivedate": "20170413", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13435738, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20170830" } ]

{ "abstract": "Identification of acquired von Willebrand syndrome (AVWS) was key to treating a patient with chronic gastrointestinal (GI) bleeding due to angiodysplasia. After exhausting endoscopic and pharmacological options, the patient was successfully treated with rituximab. A 78-year-old man developed chronic GI bleeding from caecal and jejunal angiodysplasia. Red cell transfusion was required weekly despite argon plasma coagulation. A diagnosis of AVWS was made from analysis of clotting factors. Therapies including von Willebrand factor concentrate, thalidomide and tranexamic acid were unsuccessful. With failed endoscopic therapy and no viable surgical option, the patient was given intravenous immunoglobulins (IVIGs). Haemoglobin remained stable from this point. The impact on the patient and hospital of attending for IVIG every 3 weeks necessitated consideration to longer-term therapy. After a single course of rituximab, no further blood products, IVIG or rituximab were required. This case is the first to describe the use of rituximab in AVWS-associated angiodysplasia.", "affiliations": "Department of Gastroenterology, Weston General Hospital, Weston-super-Mare, UK.;Bristol Haematology Unit, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.;Department of Haematology, Weston General Hospital, Weston-super-Mare, UK.;Bristol Haematology Unit, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.;Department of Gastroenterology, Weston General Hospital, Weston-super-Mare, UK.", "authors": "Hawken|James|J|;Knott|Amy|A|;Alsakkaf|Wesam|W|;Clark|Amanda|A|;Fayyaz|Faisal|F|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1136/flgastro-2018-101116", "fulltext": null, "fulltext_license": null, "issn_linking": "2041-4137", "issue": "10(4)", "journal": "Frontline gastroenterology", "keywords": "angiodysplasia; gastrointestinal bleeding", "medline_ta": "Frontline Gastroenterol", "mesh_terms": null, "nlm_unique_id": "101528589", "other_id": null, "pages": "434-437", "pmc": null, "pmid": "31656571", "pubdate": "2019-10", "publication_types": "D002363:Case Reports", "references": "18208537;21540459;25929157;27778439", "title": "Rituximab to the rescue: novel therapy for chronic gastrointestinal bleeding due to angiodysplasia and acquired von Willebrand syndrome.", "title_normalized": "rituximab to the rescue novel therapy for chronic gastrointestinal bleeding due to angiodysplasia and acquired von willebrand syndrome" }

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{ "abstract": "Impaired fertility is common among patients with chronic organ failure, including end-stage renal disease (ESRD). Women of childbearing age undergoing transplantation may experience rapid return of fertility. Pregnancy posttransplant presents numerous risks for the patient, fetus, and allograft. Maternal risks include hypertension and preeclampsia. Allograft risks include acute rejection and failure of the organ, and fetal risks include miscarriage, birth defects from immunosuppressants, premature delivery, and low birth weight. Belatacept, a selective T cell costimulation blocker, was approved for use in kidney transplant recipients in the United States in 2011. Little is known about the safety of belatacept during pregnancy in humans. We describe 2 cases of successful pregnancy and delivery with the use of belatacept-based immunosuppression. The Transplant Pregnancy Registry International (TPR) is a voluntary registry for transplant recipients who have had pregnancies or fathered a pregnancy posttransplant. To date, these 2 cases are the only known exposures to belatacept that have been reported to the TPR.", "affiliations": "Department of Pharmacy Services, Mercy Health St. Mary's, Grand Rapids, Michigan.;Houston Kidney Consultants, Houston, Texas.;Department of Medicine, Michigan State University, Grand Rapids, Michigan.;Transplant Pregnancy Registry International, Gift of Life Institute, Philadelphia, Pennsylvania.;Transplant Pregnancy Registry International, Gift of Life Institute, Philadelphia, Pennsylvania.;Department of Medicine, Michigan State University, Grand Rapids, Michigan.", "authors": "Combs|Jenna|J|;Kagan|Anna|A|;Boelkins|Mark|M|;Coscia|Lisa|L|;Moritz|Michael|M|;Hofmann|R Michael|RM|", "chemical_list": "D007166:Immunosuppressive Agents; D000069594:Abatacept", "country": "United States", "delete": false, "doi": "10.1111/ajt.14911", "fulltext": null, "fulltext_license": null, "issn_linking": "1600-6135", "issue": "18(8)", "journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons", "keywords": "clinical research/practice; immunosuppressant - fusion proteins and monoclonal antibodies: belatacept; immunosuppression/immune modulation; kidney (allograft) function/dysfunction; kidney disease; kidney transplantation/nephrology; obstetrics and gynecology; pregnancy", "medline_ta": "Am J Transplant", "mesh_terms": "D000069594:Abatacept; D000328:Adult; D005260:Female; D005865:Gestational Age; D005919:Glomerular Filtration Rate; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007166:Immunosuppressive Agents; D007231:Infant, Newborn; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D011247:Pregnancy; D011256:Pregnancy Outcome; D066027:Transplant Recipients", "nlm_unique_id": "100968638", "other_id": null, "pages": "2079-2082", "pmc": null, "pmid": "29719109", "pubdate": "2018-08", "publication_types": "D002363:Case Reports", "references": null, "title": "Belatacept during pregnancy in renal transplant recipients: Two case reports.", "title_normalized": "belatacept during pregnancy in renal transplant recipients two case reports" }

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BELATACEPT DURING PREGNANCY IN RENAL TRANSPLANT RECIPIENTS: TWO CASE REPORTS. AMERICAN JOURNAL OF TRANSPLANTATION. 2018?18(8):2079?2082. DOI: 10.1111/AJT.14911.", "literaturereference_normalized": "belatacept during pregnancy in renal transplant recipients two case reports", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180829", "receivedate": "20180829", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15328984, "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": "PHHY2018US015785", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "65461", "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." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, 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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": "MYCOPHENOLIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALEMTUZUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALEMTUZUMAB" } ], "patientagegroup": null, "patientonsetage": "28", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abortion spontaneous", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Kidney transplant rejection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Maternal exposure during pregnancy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Kidney transplant rejection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "COMBS J, KAGAN A, BOELKINS M, COSCIA L, MORITZ M, HOFMANN RM. BELATACEPT DURING PREGNANCY IN RENAL TRANSPLANT RECIPIENTS: TWO CASE REPORTS. AMERICAN JOURNAL OF TRANSPLANTATION. 2018?1-4", "literaturereference_normalized": "belatacept during pregnancy in renal transplant recipients two case reports", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180612", "receivedate": "20180612", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14998604, "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": "US-TEVA-2018-US-950320", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "65457", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FORMULATION: ENTERIC-COATED", "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": "ENTERIC-COATED MYCOPHENOLIC ACID" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "085084", "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": "6", "activesubstance": { "activesubstancename": "BELATACEPT" }, "drugadditional": null, "drugadministrationroute": "050", "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": "5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BELATACEPT" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "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": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BELATACEPT" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/KG DAYS 0 AND 5 WITH SUBSEQUENT 10 MG/ KG DOSES AT WEEKS 2, 4, 8, AND 12", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BELATACEPT" } ], "patientagegroup": null, "patientonsetage": "28", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Maternal exposure during pregnancy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Normal newborn", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "COMBS J, KAGAN A, BOELKINS M, COSCIA L, MORITZ M, HOFMANN RM. BELATACEPT DURING PREGNANCY IN RENAL TRANSPLANT RECIPIENTS: TWO CASE REPORTS. AM-J-TRANSPLANT 2018?18(8):2079-2082.", "literaturereference_normalized": "belatacept during pregnancy in renal transplant recipients two case reports", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190606", "receivedate": "20190606", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16397606, "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" }, { "companynumb": "US-DRREDDYS-USA/USA/18/0103739", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DILTIAZEM" }, "drugadditional": null, "drugadministrationroute": null, "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": "DILTIAZEM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": null, "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": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "090509", "drugbatchnumb": "UNKNOWN", "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": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "28", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Blood creatinine increased", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abortion spontaneous", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Transplant rejection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug level below therapeutic", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "COMBS J, ANNA K, BOELKINS M, COSCIA L, MORITZ M, HOFMANN M. BELATACEPT DURING PREGNANCY IN RENAL TRANSPLANT RECIPIENTS: TWO CASE REPORTS. AM J TRANSPLANT. 2018?18:2079?82.", "literaturereference_normalized": "belatacept during pregnancy in renal transplant recipients two case reports", "qualification": "3", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20180907", "receivedate": "20180907", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15360052, "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": "PHHY2018US078902", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "80336", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MATERNAL DOSE: 10 MG DAILY", "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": "PREDNISONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BELATACEPT" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "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": "BELATACEPT" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MATERNAL DOSE: 50 MG TWICE DAILY", "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": "AZATHIOPRINE." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Low birth weight baby", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "COMBS J, KAGAN A, BOELKINS M, COSCIA L, MORITZ M, HOFMANN RM. BELATACEPT DURING PREGNANCY IN RENAL TRANSPLANT RECIPIENTS: TWO CASE REPORTS. AMERICAN JOURNAL OF TRANSPLANTATION. 2018?1?4", "literaturereference_normalized": "belatacept during pregnancy in renal transplant recipients two case reports", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180831", "receivedate": "20180831", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15339682, "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-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-06859", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "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": "ENTERIC COATED MYCOPHENOLIC ACID (EC-MPA)" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "203005", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "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": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "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": "3", "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": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "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": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BELATACEPT" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BELATACEPT" } ], "patientagegroup": null, "patientonsetage": "28", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abortion spontaneous", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "COMBS J, KAGAN A, BOELKINS M, COSCIA L, ET AL.. BELATACEPT DURING PREGNANCY IN RENAL TRANSPLANT RECIPIENTS: TWO CASE REPORTS. AMERICAN JOURNAL OF TRANSPLANTATION. 2018?18:2079?2082", "literaturereference_normalized": "belatacept during pregnancy in renal transplant recipients two case reports", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190103", "receivedate": "20190103", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15784682, "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": "PHHY2018US015788", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL 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": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "3", "drugadministrationroute": null, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "80336", "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": "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": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "80336", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL 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": "BELATACEPT" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BELATACEPT" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BELATACEPT" }, "drugadditional": "3", "drugadministrationroute": null, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BELATACEPT" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Maternal exposure during pregnancy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abortion spontaneous", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "COMBS J, KAGAN A, BOELKINS M, COSCIA L, MORITZ M, HOFMANN RM. BELATACEPT DURING PREGNANCY IN RENAL TRANSPLANT RECIPIENTS: TWO CASE REPORTS. AMERICAN JOURNAL OF TRANSPLANTATION. 2018?1-4", "literaturereference_normalized": "belatacept during pregnancy in renal transplant recipients two case reports", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180628", "receivedate": "20180611", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14996862, "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" }, { "companynumb": "US-DRREDDYS-USA/USA/18/0103510", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "090509", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "2013", "drugenddateformat": "602", "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2012", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "4", "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": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2012", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ENTERIC?COATED", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2012", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." } ], "patientagegroup": null, "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Renal impairment", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2013" } }, "primarysource": { "literaturereference": "COMBS J, KAGAN A, BOELKINS M, COSCIA L, MORITZ M, HOFMANN R. BELATACEPT DURING PREGNANCY IN RENAL TRANSPLANT RECIPIENTS: TWO CASE REPORTS. AM J TRANSPLANT. 2018?18 (8):2079?82.", "literaturereference_normalized": "belatacept during pregnancy in renal transplant recipients two case reports", "qualification": "3", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20180907", "receivedate": "20180831", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15337751, "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": "PHHY2018US078899", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": "3", 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null, "drugdosageform": null, "drugdosagetext": null, "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": "BELATACEPT" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": "3", "drugadministrationroute": null, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BELATACEPT" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BELATACEPT" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "80336", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL TRANSPLANT", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "80336", "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Maternal exposure during pregnancy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pre-eclampsia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "COMBS J, KAGAN A, BOELKINS M, COSCIA L, MORITZ M, HOFMANN RM. BELATACEPT DURING PREGNANCY IN RENAL TRANSPLANT RECIPIENTS: TWO CASE REPORTS. AMERICAN JOURNAL OF TRANSPLANTATION. 2018?1?4", "literaturereference_normalized": "belatacept during pregnancy in renal transplant recipients two case reports", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180831", "receivedate": "20180831", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15339681, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-280304", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BELATACEPT" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MILLIGRAM, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BELATACEPT" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "089247", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM, DAILY", "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": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MILLIGRAM, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." } ], "patientagegroup": null, "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pre-eclampsia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Live birth", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "COMBS J, KAGAN A, BOELKINS M, COSCIA L, MORITZ M, HOFMANN RM. BELATACEPT DURING PREGNANCY IN RENAL TRANSPLANT RECIPIENTS: TWO CASE REPORTS. AM J TRANSPLANT.. 2018?18:2079?2082", "literaturereference_normalized": "belatacept during pregnancy in renal transplant recipients two case reports", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210220", "receivedate": "20210220", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18918831, "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" }, { "companynumb": "US-ASTELLAS-2018US037354", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "FORMULATION UNKNOWN", "drugdosagetext": "UNK UNK, UNKNOWN FREQ.", "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": "MYCOPHENOLIC ACID." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ALEMTUZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "FORMULATION UNKNOWN", "drugdosagetext": "UNK UNK, UNKNOWN FREQ.", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALEMTUZUMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "050708", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "FORMULATION UNKNOWN", "drugdosagetext": "UNK UNK, UNKNOWN FREQ.", "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." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "FORMULATION UNKNOWN", "drugdosagetext": "UNK UNK, UNKNOWN FREQ.", "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": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "FORMULATION UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL TRANSPLANT", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DILTIAZEM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "FORMULATION UNKNOWN", "drugdosagetext": "UNK UNK, UNKNOWN FREQ.", "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": "DILTIAZEM." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "FORMULATION UNKNOWN", "drugdosagetext": "UNK UNK, UNKNOWN FREQ.", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL 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": "6", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "FORMULATION UNKNOWN", "drugdosagetext": "UNK UNK, UNKNOWN FREQ. (HIGH DOSE)", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "FORMULATION UNKNOWN", "drugdosagetext": "UNK UNK, UNKNOWN FREQ.", "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": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "28", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Abortion spontaneous", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abdominal discomfort", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Transplant rejection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Immunosuppressant drug level decreased", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "COMBS J, KAGAN A, BOELKINS M, COSCIA L, MORITZ M, HOFMANN RM. BELATACEPT DURING PREGNANCY IN RENAL TRANSPLANT RECIPIENTS: TWO CASE REPORTS. AM. J. TRANSPLANT. 2018?18 (8):2079?82", "literaturereference_normalized": "belatacept during pregnancy in renal transplant recipients two case reports", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180823", "receivedate": "20180823", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15311473, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" }, { "companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2018-049913", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "BELATACEPT" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "125288", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "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" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pre-eclampsia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Live birth", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Maternal exposure during pregnancy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "COMBS J, KAGAN A, BOELKINS M, COSCIA L, MORITZ M, HOFMANN RM. BELATACEPT DURING PREGNANCY IN RENAL TRANSPLANT RECIPIENTS: TWO CASE REPORTS. AMERICAN JOURNAL OF TRANSPLANTATION. 2018", "literaturereference_normalized": "belatacept during pregnancy in renal transplant recipients two case reports", "qualification": "2", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200901", "receivedate": "20180601", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14961923, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201102" } ]

{ "abstract": "The case concerns a 54-year-old woman, with a history of fibromyalgia and normal preoperative ocular and systemic study, who presented with a long-lasting disabling photophobia, after sequential bilateral cataract surgery without complications. Photophobia was accompanied by good uncorrected VA, with no pain or subjective eye discomfort, without migraine or indicators of psychic conflict. It was refractory to any prescribed treatment of the ocular surface, finally responding to oral anticonvulsants (carbamazepine) that are frequently used in neuropathic pain. To the best of our knowledge this is the first reported case of a long-lasting disabling photophobia without pain and good VA after cataract surgery.", "affiliations": "Clínica Oftalmológica Pérez Silguero, Las Palmas de Gran Canaria, Spain; Fundación Hospitalaria San José, Las Palmas de Gran Canaria, Spain. Electronic address: dpsilguero@gmail.com.;Clínica Oftalmológica Pérez Silguero, Las Palmas de Gran Canaria, Spain; Hospital La Paloma, Las Palmas de Gran Canaria, Spain.;Clínica Oftalmológica Pérez Silguero, Las Palmas de Gran Canaria, Spain.;Clínica Oftalmológica Pérez Silguero, Las Palmas de Gran Canaria, Spain.", "authors": "Pérez Silguero|D|D|;Pérez Silguero|M Á|MÁ|;Pérez-Silguero Jiménez|S|S|;Encinas Pisa|P|P|", "chemical_list": null, "country": "Spain", "delete": false, "doi": "10.1016/j.oftale.2020.06.024", "fulltext": null, "fulltext_license": null, "issn_linking": "2173-5794", "issue": "96(8)", "journal": "Archivos de la Sociedad Espanola de Oftalmologia", "keywords": "Cataract surgery; Cirugía de catarata; Dolor neuropático; Fibromialgia; Fibromyalgia; Fotofobia; Neuropathic pain; Photophobia", "medline_ta": "Arch Soc Esp Oftalmol (Engl Ed)", "mesh_terms": "D002386:Cataract; D002387:Cataract Extraction; D005260:Female; D005356:Fibromyalgia; D006801:Humans; D008875:Middle Aged; D009437:Neuralgia; D020795:Photophobia", "nlm_unique_id": "101715860", "other_id": null, "pages": "446-448", "pmc": null, "pmid": "34340785", "pubdate": "2021-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Long-lasting disabling photophobia after uneventful cataract surgery.", "title_normalized": "long lasting disabling photophobia after uneventful cataract surgery" }

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null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VITAMIN A" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Postoperative care", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TOBRAMYCIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Postoperative care", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOBRAMYCIN" } ], "patientagegroup": null, "patientonsetage": "54", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Perez Silguero D, Perez Silguero MA, Perez-Silguero Jimenez S, Encinas Pisa P. Long-lasting disabling photophobia after uneventful cataract surgery. Archivos de la Sociedad Espanola de Oftalmologia. 2021;96(8):446-448", "literaturereference_normalized": "long lasting disabling photophobia after uneventful cataract surgery", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20211230", "receivedate": "20211230", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20258837, "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": "Fifty patients with intermediate- or high-grade non-Hodgkin's lymphoma (NHL) who had relapsed after a complete remission induced by an Adriamycin-containing chemotherapy regimen participated in this prospective pilot study. The patients ranged in age from 16 to 60 years (median 42 years). All patients received dexamethasone, high-dose cytarabine, and cisplatin (DHAP) for two courses at 3- to 4-week intervals. Patients achieving a partial or complete response were scheduled to receive involved-field radiotherapy and high-dose carmustine, etoposide, cytarabine, and cyclophosphamide (BEAC), followed by autologous bone marrow transplantation (ABMT). Among 48 evaluable patients (ie, 1 was lost to follow-up and 1 had no measurable disease) 7 patients obtained a complete response (CR) and another 21 patients achieved partial response (PR), whereas the remaining 20 patients failed. One responder died of treatment-related toxicity, and six others declined ABMT. The patient with no measurable disease did not progress on DHAP and was submitted to ABMT. Twenty-two patients underwent ABMT [20 with BEAC and 2 with cyclophosphamide plus total body irradiation (TBI)] of whom 2 (9%) died of toxicity and 10 relapsed. One patient was a suicide at 28 months post-ABMT in CCR and 9 are alive disease-free 24 months to 32 months (median 30 months) post-ABMT. The actuarial 2-year event-free survival for patients undergoing transplantation is 40%. This prospective multicenter trial documents the ability of DHAP followed by ABMT to produce durable complete remission in a significant proportion of patients with relapsed aggressive NHL. Forty-four percent of all patients with relapsed lymphoma who entered the study actually underwent ABMT and 20% of the total group are projected to be long-term disease-free survivors.", "affiliations": "Bone Marrow Transplant Department, Centre Leon Berard, Lyon, France.", "authors": "Philip|T|T|;Chauvin|F|F|;Armitage|J|J|;Bron|D|D|;Hagenbeek|A|A|;Biron|P|P|;Spitzer|G|G|;Velasquez|W|W|;Weisenburger|D D|DD|;Fernandez-Ranada|J|J|", "chemical_list": "D003561:Cytarabine; D003907:Dexamethasone; D002945:Cisplatin", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0006-4971", "issue": "77(7)", "journal": "Blood", "keywords": null, "medline_ta": "Blood", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D016026:Bone Marrow Transplantation; D002945:Cisplatin; D003131:Combined Modality Therapy; D003561:Cytarabine; D003907:Dexamethasone; D004334:Drug Administration Schedule; D005060:Europe; D005260:Female; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011878:Radiotherapy; D014182:Transplantation, Autologous", "nlm_unique_id": "7603509", "other_id": null, "pages": "1587-92", "pmc": null, "pmid": "2009374", "pubdate": "1991-04-01", "publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Parma international protocol: pilot study of DHAP followed by involved-field radiotherapy and BEAC with autologous bone marrow transplantation.", "title_normalized": "parma international protocol pilot study of dhap followed by involved field radiotherapy and beac with autologous bone marrow transplantation" }

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{ "abstract": "OBJECTIVE\nTo review the literature regarding the interaction among amiodarone therapy, thyroid hormone levels, and warfarin metabolism.\n\n\nMETHODS\nA 73-year-old male with type 2 after describing an unusual case of amiodarone-induced thyrotoxicosis (AIT) who experienced a severe rise in international normalized ratio (INR) values after initiating warfarin therapy due to an unusual combination of excessive thyroid hormones, amiodarone therapy, and a genetic abnormality affecting warfarin metabolism.\n\n\nRESULTS\nGenetic analysis revealed that the patient was CYP2C9*2 wild-type, CYP2C9*3/*3 homozygous mutant, and VKORC1*3/*3 homozygous mutant. A review of the literature revealed that both mutations can independently affect warfarin metabolism. In addition, amiodarone therapy and the presence of thyrotoxicosis per se can affect warfarin metabolism and reduce the dose needed to maintain INR in the therapeutic range. The association of the 2 genetic polymorphisms in a patient with AIT is extremely rare and strongly impairs warfarin metabolism, exposing the patient to a high risk of overtreatment.\n\n\nCONCLUSIONS\nIn patients with AIT, warfarin therapy should be gradually introduced, starting with a very low dose, because of the significant risk of warfarin overtreatment. Whether the genetic analysis of CYP2C9 and VKORC1 polymorphisms should be routinely performed in AIT patients remains conjectural.", "affiliations": "Department of Clinical and Experimental Medicine, Section of Endocrinology, University of Pisa, Pisa, Italy.", "authors": "Tomisti|Luca|L|;Del Re|Marzia|M|;Bartalena|Luigi|L|;Tanda|Maria L|ML|;Pucci|Angelo|A|;Pambianco|Franco|F|;Danesi|Romano|R|;Braverman|Lewis E|LE|;Martino|Enio|E|;Bogazzi|Fausto|F|", "chemical_list": "D000889:Anti-Arrhythmia Agents; D000925:Anticoagulants; D013963:Thyroid Hormones; D014859:Warfarin; D004247:DNA; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D000638:Amiodarone", "country": "United States", "delete": false, "doi": "10.4158/EP13093.RA", "fulltext": null, "fulltext_license": null, "issn_linking": "1530-891X", "issue": "19(6)", "journal": "Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists", "keywords": null, "medline_ta": "Endocr Pract", "mesh_terms": "D000368:Aged; D000638:Amiodarone; D000889:Anti-Arrhythmia Agents; D000925:Anticoagulants; D001189:Aryl Hydrocarbon Hydroxylases; D065729:Cytochrome P-450 CYP2C9; D004247:DNA; D004347:Drug Interactions; D006470:Hemorrhage; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D011110:Polymorphism, Genetic; D012306:Risk; D013963:Thyroid Hormones; D013965:Thyroidectomy; D013971:Thyrotoxicosis; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin", "nlm_unique_id": "9607439", "other_id": null, "pages": "1043-9", "pmc": null, "pmid": "23807523", "pubdate": "2013", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Effects of amiodarone, thyroid hormones and CYP2C9 and VKORC1 polymorphisms on warfarin metabolism: a review of the literature.", "title_normalized": "effects of amiodarone thyroid hormones and cyp2c9 and vkorc1 polymorphisms on warfarin metabolism a review of the literature" }

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], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "69", "reaction": [ { "reactionmeddrapt": "Hyperthyroidism", "reactionmeddraversionpt": "17.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "International normalised ratio increased", "reactionmeddraversionpt": "17.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Blindness", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "17.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Intracardiac thrombus", "reactionmeddraversionpt": "17.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Congestive cardiomyopathy", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOMISTI L, DEL RE M, BARTALENA L, TANDA ML, PUCCI A, PAMBIANCO F, ET AL. EFFECTS OF AMIODARONE, THYROID HORMONES AND CYP2C9 AND VKORC1 POLYMORPHISMS ON WARFARIN METABOLISM: A REVIEW OF THE LITERATURE. . ENDOCR-PRACT 2013; 19(6) 1043-9", "literaturereference_normalized": "effects of amiodarone thyroid hormones and cyp2c9 and vkorc1 polymorphisms on warfarin metabolism a review of the literature", "qualification": "1", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20140818", "receivedate": "20140818", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10390813, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150326" } ]

{ "abstract": "Necrotizing fasciitis (NF) is a progressive inflammatory infection of the fascia that is often aggressive and advances insidiously. NF can be preceded by traumatic injury or surgical intervention or may occur spontaneously. Here, we describe a patient who presented with monomicrobial subacute necrotizing fasciitis due to Serratia marcescens. Dermatology was consulted at the local hospital for suspected cellulitis with no resolution using appropriate antibiotics. Our patient failed to show improvement with antibiotic treatment and experienced an above-the-knee amputation. We have also included a review of the current literature on subacute necrotizing fasciitis and S. marcescens. A case review of 25 patients resulted in rates of 52.1% for overall mortality, 72% for mortality among patients treated with only antibiotics, and 40% for mortality among patients treated with surgical debridement. There needs to be a high suspicion for necrotizing fasciitis even in patients presenting with cellulitis without systemic symptoms. If S. marcescens is isolated, more aggressive treatment may be warranted. More cases of subacute necrotizing fasciitis and S. marcescens need to be reported in the literature to better understand early diagnosis and best management practices.", "affiliations": "Dr. Roberts is with Merit Health Wesley in Hattiesburg, Mississippi.;Dr. Roberts is with Merit Health Wesley in Hattiesburg, Mississippi.;Dr. Roberts is with Merit Health Wesley in Hattiesburg, Mississippi.", "authors": "Roberts|Michael|M|;Crasto|David|D|;Roy|David|D|", "chemical_list": null, "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1941-2789", "issue": "14(1)", "journal": "The Journal of clinical and aesthetic dermatology", "keywords": "Serratia marcescens; Subacute; fasciitis; necrotizing", "medline_ta": "J Clin Aesthet Dermatol", "mesh_terms": null, "nlm_unique_id": "101518173", "other_id": null, "pages": "55-58", "pmc": null, "pmid": "33584969", "pubdate": "2021-01", "publication_types": "D002363:Case Reports", "references": "14513405;26712597;19826154;22401347;27670553;17278065;8879802;22640271;16213592;26548496;9368530;19081644;28650753;21724683;29097860;9079250;15817551;10634026;26294949;3540138;29560288;15550150;26778253;12488837;15474143;22837315;19228540;17910710;1489009;26498285;22584779;24947530;21410101;23315798;15869138;11561811;27031553", "title": "A Case of Subacute Necrotizing Fasciitis due to Serratia marcescens.", "title_normalized": "a case of subacute necrotizing fasciitis due to serratia marcescens" }

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{ "abstract": "BACKGROUND\nIdentifying causes of alemtuzumab induced respiratory symptoms in Multiple Sclerosis (MS) patients is crucial.\n\n\nMETHODS\nWe report a case of diffuse alveolar damage (DAD) in a patient with MS after the first course of alemtuzumab treatment. A 42-year-old female developed progressive non-productive cough and exertional dyspnea 2 months after alemtuzumab treatment. DAD was diagnosed histopathologically by lung biopsy. The patient recovered completely, alemtuzumab was not continued.\n\n\nCONCLUSIONS\nOur case highlights another pathomechanism for non-infective lung-disorders in alemtuzumab treated MS patients. DAD is a potential, albeit rare side effect of alemtuzumab, broadening the spectrum of non-infective lung disorders that should be considered in the diagnostic work-up.", "affiliations": "Neurology and Clinical Neurophysiology, University Hospital of Augsburg, Stenglinstrasse 2, 86156, Augsburg, Germany. antonios.bayas@uk-augsburg.de.;Neurology and Clinical Neurophysiology, University Hospital of Augsburg, Stenglinstrasse 2, 86156, Augsburg, Germany.;Internal Medicine I-Cardiology, University Hospital of Augsburg, Stenglinstrasse 2, 86156, Augsburg, Germany.;General Pathology and Molecular Diagnostics, Medical Faculty, University of Augsburg, Stenglinstrasse 2, 86156, Augsburg, Germany.;Neurology and Clinical Neurophysiology, University Hospital of Augsburg, Stenglinstrasse 2, 86156, Augsburg, Germany.", "authors": "Bayas|Antonios|A|http://orcid.org/0000-0002-7418-9040;Menacher|Martina|M|;Schwaiblmair|Martin|M|;Märkl|Bruno|B|;Naumann|Markus|M|", "chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000074323:Alemtuzumab", "country": "England", "delete": false, "doi": "10.1186/s12883-020-01934-7", "fulltext": "\n==== Front\nBMC Neurol\nBMC Neurol\nBMC Neurology\n1471-2377\nBioMed Central London\n\n1934\n10.1186/s12883-020-01934-7\nCase Report\nAlemtuzumab-associated diffuse alveolar damage – a case report\nhttp://orcid.org/0000-0002-7418-9040\nBayas Antonios antonios.bayas@uk-augsburg.de\n\n1\nMenacher Martina 1\nSchwaiblmair Martin 2\nMärkl Bruno 3\nNaumann Markus 1\n1 grid.419801.5 0000 0000 9312 0220 Neurology and Clinical Neurophysiology, University Hospital of Augsburg, Stenglinstrasse 2, 86156 Augsburg, Germany\n2 grid.419801.5 0000 0000 9312 0220 Internal Medicine I-Cardiology, University Hospital of Augsburg, Stenglinstrasse 2, 86156 Augsburg, Germany\n3 grid.7307.3 0000 0001 2108 9006 General Pathology and Molecular Diagnostics, Medical Faculty, University of Augsburg, Stenglinstrasse 2, 86156 Augsburg, Germany\n23 9 2020\n23 9 2020\n2020\n20 35711 7 2020\n15 9 2020\n© The Author(s) 2020\nOpen AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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 in a credit line to the data.\nBackground\n\nIdentifying causes of alemtuzumab induced respiratory symptoms in Multiple Sclerosis (MS) patients is crucial.\n\nCase presentation\n\nWe report a case of diffuse alveolar damage (DAD) in a patient with MS after the first course of alemtuzumab treatment. A 42-year-old female developed progressive non-productive cough and exertional dyspnea 2 months after alemtuzumab treatment. DAD was diagnosed histopathologically by lung biopsy. The patient recovered completely, alemtuzumab was not continued.\n\nConclusions\n\nOur case highlights another pathomechanism for non-infective lung-disorders in alemtuzumab treated MS patients. DAD is a potential, albeit rare side effect of alemtuzumab, broadening the spectrum of non-infective lung disorders that should be considered in the diagnostic work-up.\n\nKeywords\n\nMultiple sclerosis\nAlemtuzumab\nDiffuse alveolar damage\nCase report\nissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\n\nAlemtuzumab is a humanized monoclonal antibody, which targets the surface molecule CD52 on immune cells (T- and B-cells, monocytes, dendritic cells and thymocytes) and leads to a rapid and significant depletion of those cell types [1]. Well-known side effects include an increased infection rate including respiratory tract infections and secondary autoimmune reactions mainly consisting of thyroid disorders, immune thrombocytopenia, anti-glomerular basement membrane (GBM) disease and membranous glomerulonephritis, which may occur after years of first treatment. Since its approval by the European Medicines Agency (EMA) in 2013, non-infective respiratory tract side effects causing dyspnea have been reported in patients treated with alemtuzumab including diffuse alveolar hemorrhage [2], pneumonitis [3], anti-GBM antibody disease [4] and acute respiratory distress syndrome (ARDS) [5]. Five cases of diffuse alveolar damage (DAD) associated with alemtuzumab have been reported to VigiBase©, the World Health Organization’s international database for suspected adverse drug reactions [6], without providing further details on treated disorders or other potentially confounding factors. Our report describes a patient with DAD after alemtuzumab treatment for MS. Compared to cases of alemtuzumab associated DAD published so far [6], here we present detailed clinical data and results of apparative diagnostics, furthermore histological findings that have so far not been reported in ARDS associated with alemtuzumab treatment [5].\n\nCase presentation\n\nA 42-year-old, non-smoking female with highly active relapsing remitting multiple sclerosis (MS) and no concomitant diseases was first diagnosed in 2008. Interferon beta (IFNB)-1a intramuscularly, injected 03/2008, was stopped due to a suspected allergic reaction, intradermal testing for IFNB-1a and -1b could not exclude an allergic reaction. Glatiramer acetate had to be withdrawn after 4 months (07/2008–11/2008) for elevated liver enzymes. Due to high disease activity natalizumab was initiated in 2009 and stopped in 2012 because of JC-virus antibody positivity, hereafter the patient refused further immunotherapies. After a severe relapse resolving only after plasma exchange (PLEX), treatment with fingolimod was initiated, but stopped after 4 months due to another severe relapse requiring treatment with glucocorticosteroids and again PLEX. After 2 further relapses and magnetic resonance imaging (MRI) activity in 2013, treatment with alemtuzumab was decided.\n\nIn January 2014 alemtuzumab (12 mg daily) was applied over 5 days, methylprednisolone 1 g, dimetindene, ranitidine, acyclovir and ibuprofen were given as concomitant medication. Except of fatigue and a mild bradycardia, infusions were well-tolerated. After 2 months, progressive non-productive cough, exertional dyspnea and general exhaustion developed. C-reactive protein and leucocytes were normal. Computed tomography- (CT-) scan of the lung showed atelectasis in both lower lobes without evidence of atypical pneumonia. Lung function tests showed a high-grade restriction in diffusion capacity (diffusing capacity of the lung for carbon monoxide (DLCO) 45% of normal) as well as a respiratory alkalosis (pH 7.46, pCO2 34.3 mmHg), a respiratory partial insufficiency in ergospirometry (decrease of pO2 from 89 mmHg to 78 mmHg and increase of lactate from 1.0 to 5.5 mmol/l during exercise with 150 watt) and a low-grade restrictive lung disease (vital capacity (VC): 2.75 l, reference: ≥ 3.70 l) without obstructive impairment (FEV1 (forced expiratory volume in 1 s)/VC: 88.7%, reference: ≥ 80.9%). Bronchoalveolar lavage revealed a moderately active inflammation and a reduced CD4/CD8-ratio (0,67; reference ≈ 2) consistent with an extrinsic allergic alveolitis or a damage of pneumocytes due to drug toxicity. However, an extrinsic allergic alveolitis seemed unlikely because of negative specific IgG antibodies. The Prick test and Methacholin provocation test, suggesting an allergic reaction or a hyperreagibility of the bronchial system, were negative. Histopathologically, hyperplasia of alveolar pneumocytes and remnants of hyaline membranes consistent with a diffuse alveolar damage were found in a transbronchial lung biopsy (Fig. 1). There was no evidence for an infectious agent. Renal function, urine test and anti-GBM antibodies indicating an alemtuzumab-associated Goodpasture syndrome, were unremarkable. Platelets and thyroid function were normal, thyroid antibodies were not determined. Fig. 1 Lung biopsy, hematoxylin and eosin stain: a arrows indicate activated pneumocytes, b arrows indicate residual hyaline membranes\n\nBased on these results, a diffuse alveolar damage (DAD) related to alemtuzumab drug toxicity was diagnosed. Respiratory symptoms regressed over few months, no corticosteroids were given. Diffusion capacity in December 2014 and December 2015 had constantly improved (single-breath-methode, DLCO 71,5 and 81% respectively of normal). Blood gas analysis and lung function tests were normal lately.\n\nDue to the increased risk for recurrent toxicity, alemtuzumab was not continued and treatment switched to rituximab (off-label) in January 2015. MS clinical course and MRI controls have been stable since 2014. The disease course and treatments are shown in Fig. 2. Written informed consent for patient information and images to be published was provided by the patient. Fig. 2 Disease course and applied treatments. IFN = interferon; GA = glatiramer acetate; ∇ = relapse; GC = glucocorticosteroids; PLEX = plasma exchange; DAD = diffuse alveolar damage\n\nDiscussion and conclusions\n\nOver the last years, reports of serious adverse events also affecting the lungs have prompted the EMA to amend the label for alemtuzumab [7]. More recently, further cases of treatment-induced lung injury have broadened the spectrum of non-infective respiratory disorders after alemtuzumab treatment in MS [5]. To our knowledge, our case is the first report of DAD in MS after alemtuzumab treatment examined histologically. ARDS as a clinical correlate of DAD after alemtuzumab treatment in MS has recently been published, but lung biopsy is not reported [5]. DAD is characterized by dyspnea and dry cough progressing over a period of days or weeks. High-resolution CT typically shows a combination of ground-glass opacity and consolidation involving predominantly dependent regions or distributed more randomly throughout both lungs [8]. DAD can be induced by infections, inhalational injuries, connective tissue diseases and also drugs [9]. It is the most commonly reported histologic manifestation of drug toxicity usually developing after a few weeks or months [8]. The mortality rate in DAD has been reported to be high. In a series of 58 patients with DAD diagnosed by surgical lung biopsy over a 7-year period, 60% were immunocompromised. In this study, the most common cause of DAD were infections (22%), drugs were found to be causal in 10% of cases. The overall hospital mortality rate associated with DAD was 53%, in the group of drug induced DAD 1 of 6 patients died [9]. In our case, respiratory symptoms occurred 2 months after the alemtuzumab cycle, according to the latency known from other drugs. Fortunately, the patient reported gradually recovered over months without subjective residual symptoms. Apart from atelectasis, the initial CT scan revealed no abnormal findings indicating a milder lung involvement and possibly explaining a less severe disease course.\n\nVarious pathological phenomena underlying DAD have been reported, among them endothelial and alveolar cell injury leading to fluid and cellular exsudation with hyaline membranes and edema [10]. The mechanism underlying alemtuzumab induced DAD is unknown. In diffuse alveolar hemorrhage after alemtuzumab treatment, it has been speculated that alemtuzumab induced effector mechanisms lead to acute inflammation that may damage membranes and cells not expressing CD52 [2].\n\nOur report shows that DAD is a potential, albeit rare side effect of alemtuzumab, broadening the spectrum of non-infective lung disorders that should be considered in the diagnostic work-up.\n\nAbbreviations\n\nMS Multiple sclerosis\n\nDAD Diffuse alveolar damage\n\nGBM Anti-glomerular basement membrane\n\nEMA European Medicines Agency\n\nARDS Acute respiratory distress syndrome\n\nIFNB Interferon beta\n\nPLEX Plasma exchange\n\nMRI Magnetic Resonance Imaging\n\nCT Computed tomography\n\nVC Vital capacity\n\nAcknowledgements\n\nnot applicable.\n\nAuthors’ contributions\n\nAB: Acquired and analyzed data and drafted the manuscript. MM: Acquired and analyzed data, revised the manuscript for intellectual content. MS: Acquired and analyzed data, revised the manuscript for intellectual content. BM: Acquired and analyzed data, revised the manuscript for intellectual content. MN: Analyzed data, revised the manuscript for intellectual content. All authors have read and approved the manuscript.\n\nFunding\n\nOpen Access funding enabled and organized by Projekt DEAL.\n\nAvailability of data and materials\n\nAll data relevant for the case report have been presented in the manuscript. Further, potentially identifying or confidential patient data will not be shared.\n\nEthics approval and consent to participate\n\nNot applicable.\n\nConsent for publication\n\nThe patient gave written consent for their personal or clinical details along with any identifying images to be published in this study.\n\nCompeting interests\n\nAB has received personal compensation from Merck Serono, Biogen, Novartis, TEVA, Roche, Sanofi/Genzyme and Celgene and grants for congress trips and participation from Biogen, TEVA, Novartis, Sanofi/Genzyme, Merck Serono and Celgene.\n\nMM: none. MS has received personal compensation from Actelion, AstraZeneca, Bayer, Berlin-Chemie, Boehringer-Ingelheim, Chiesi, GlaxoSmithKline, Janssen-Cilag, MSD, Novartis und Roche. BM: none. MN: none.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Havrdova E Horakova D Kovarova I Alemtuzumab in the treatment of multiple sclerosis: key clinical trial results and considerations for use Ther Adv Neurol Disord 2015 8 31 45 10.1177/1756285614563522 25584072\n2. Myro AZ Bjerke G Zarnovicky S Diffuse alveolar hemorrhage during alemtuzumab infusion in a patient with multiple sclerosis: a case report BMC Pharmacol Toxicol 2018 19 75 10.1186/s40360-018-0267-5 30454022\n3. Whiteside D Barth S Datta A Pneumonitis secondary to alemtuzumab in a patient with multiple sclerosis - A non-infectious cause of breathlessness Mult Scler Relat Disord 2018 22 139 140 10.1016/j.msard.2018.04.002 29684788\n4. https://pneumotox.com. accessed on april 26th, 2020.\n5. Bianco A Mari PV Larici AR Alemtuzumab-induced lung injury in multiple sclerosis: Learning from adversity in three patients Mult Scler Relat Disord 2020 37 101450 10.1016/j.msard.2019.101450 31675637\n6. Uppsala Monitoring Centre. VigiBase tWHO and reactions. idosad. https://www.who-umc.org/vigibase/vigibase/accessed April, 26th, 2020.\n7. Hartung HP, Mares J, Barnett MH. Alemtuzumab: Rare serious adverse events of a high-efficacy drug. Mult Scler. 2020:1352458520913277. 2020/04/17. 10.1177/1352458520913277.\n8. Myers JL Limper AH Swensen SJ Drug-induced lung disease: a pragmatic classification incorporating HRCT appearances Semin Respir Crit Care Med 2003 24 445 454 10.1055/s-2003-42379 16088564\n9. Parambil JG Myers JL Aubry MC Causes and prognosis of diffuse alveolar damage diagnosed on surgical lung biopsy Chest 2007 132 50 57 10.1378/chest.07-0104 17475632\n10. Kaarteenaho R Kinnula VL Diffuse alveolar damage: a common phenomenon in progressive interstitial lung disorders Pulm Med 2011 2011 531302 10.1155/2011/531302 21637367\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2377", "issue": "20(1)", "journal": "BMC neurology", "keywords": "Alemtuzumab; Case report; Diffuse alveolar damage; Multiple sclerosis", "medline_ta": "BMC Neurol", "mesh_terms": "D000328:Adult; D000074323:Alemtuzumab; D000074322:Antineoplastic Agents, Immunological; D005260:Female; D006801:Humans; D017563:Lung Diseases, Interstitial; D020529:Multiple Sclerosis, Relapsing-Remitting; D011650:Pulmonary Alveoli", "nlm_unique_id": "100968555", "other_id": null, "pages": "357", "pmc": null, "pmid": "32967641", "pubdate": "2020-09-23", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "30454022;21637367;29684788;25584072;16088564;32298205;31675637;17475632", "title": "Alemtuzumab-associated diffuse alveolar damage - a case report.", "title_normalized": "alemtuzumab associated diffuse alveolar damage a case report" }

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"drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CORTICOSTEROID NOS" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RELAPSING-REMITTING MULTIPLE SCLEROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CORTICOSTEROID NOS" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dyspnoea exertional", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pneumonitis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Bradycardia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diffuse alveolar damage", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Atelectasis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Respiratory alkalosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cough", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hyperplasia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Restrictive pulmonary disease", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lung diffusion disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2014" } }, "primarysource": { "literaturereference": "BAYAS ET AL.. ALEMTUZUMAB-ASSOCIATED DIFFUSE ALVEOLAR DAMAGE - A CASE REPORT.. BMC NEUROLOGY. 2020?20:357", "literaturereference_normalized": "alemtuzumab associated diffuse alveolar damage a case report", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20201005", "receivedate": "20201005", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18342095, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210113" } ]

{ "abstract": "To report a case of bilateral acute angle-closure glaucoma associated with hyponatremia in the setting of chlorthalidone use and SARS-CoV-2 infection, and to demonstrate the challenges of managing this patient given her infectious status.\n\n\n\nThis was a case report.\n\n\n\nA 65-year-old woman taking chlorthalidone for hypertension presented to the emergency room with headache, pain, and blurry vision in both eyes and was found to be in bilateral acute angle closure. On laboratory investigation, she was severely hyponatremic and also tested positive for SARS-CoV-2. B-scan ultrasound demonstrated an apparent supraciliary effusion in the right eye. Following stabilization of her intraocular pressures with medical management, she ultimately underwent cataract extraction with iridectomies and goniosynechiolysis in both eyes.\n\n\n\nWe report a rare case of bilateral acute angle-closure glaucoma associated with hyponatremia. Chlorthalidone use and perhaps SARS-CoV-2 infection may have contributed to this electrolyte abnormality and unique clinical presentation. In addition, we discuss the challenges of managing this complex patient with active SARS-CoV-2 infection during the pandemic.", "affiliations": "Department of Ophthalmology, Columbia University Irving Medical Center, New York, NY.;Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA.;Department of Ophthalmology, Columbia University Irving Medical Center, New York, NY.;Department of Ophthalmology, Columbia University Irving Medical Center, New York, NY.;Department of Ophthalmology, Columbia University Irving Medical Center, New York, NY.;Department of Ophthalmology, Columbia University Irving Medical Center, New York, NY.;Department of Ophthalmology, Columbia University Irving Medical Center, New York, NY.;Department of Ophthalmology, Columbia University Irving Medical Center, New York, NY.", "authors": "Krawitz|Brian D|BD|;Sirinek|Portia|P|;Doobin|David|D|;Nanda|Tavish|T|;Ghiassi|Maryam|M|;Horowitz|Jason D|JD|;Liebmann|Jeffrey M|JM|;De Moraes|Carlos G|CG|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1097/IJG.0000000000001763", "fulltext": null, "fulltext_license": null, "issn_linking": "1057-0829", "issue": "30(3)", "journal": "Journal of glaucoma", "keywords": null, "medline_ta": "J Glaucoma", "mesh_terms": "D000208:Acute Disease; D000368:Aged; D000086382:COVID-19; D015897:Comorbidity; D005260:Female; D015812:Glaucoma, Angle-Closure; D006801:Humans; D007429:Intraocular Pressure; D032801:Iridectomy; D058873:Pandemics; D000086402:SARS-CoV-2", "nlm_unique_id": "9300903", "other_id": null, "pages": "e50-e53", "pmc": null, "pmid": "33337718", "pubdate": "2021-03-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "The Challenge of Managing Bilateral Acute Angle-closure Glaucoma in the Presence of Active SARS-CoV-2 Infection.", "title_normalized": "the challenge of managing bilateral acute angle closure glaucoma in the presence of active sars cov 2 infection" }

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"drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PILOCARPINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CHLORTHALIDONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "207813", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "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": "CHLORTHALIDONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyponatraemia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Angle closure glaucoma", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "KRAWITZ BD, SIRINEK P, DOOBIN D, NANDA T, GHIASSI M, HOROWITZ JD, ET AL.. THE CHALLENGE OF MANAGING BILATERAL ACUTE ANGLE?CLOSURE GLAUCOMA IN THE PRESENCE OF ACTIVE SARS?COV?2 INFECTION.. J?GLAUCOMA. 2021?30(3):E50?E53", "literaturereference_normalized": "the challenge of managing bilateral acute angle closure glaucoma in the presence of active sars cov 2 infection", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210601", "receivedate": "20210601", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19358232, "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" }, { "companynumb": "US-AMNEAL PHARMACEUTICALS-2021-AMRX-00169", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CHLORTHALIDONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "207204", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CHLORTHALIDONE." } ], "patientagegroup": null, "patientonsetage": "65", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Angle closure glaucoma", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hyponatraemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KRAWITZ B.D., SIRINEK P., DOOBIN D.,ET.AL. THE CHALLENGE OF MANAGING BILATERAL ACUTE ANGLE CLOSURE GLAUCOMA IN THE PRESENCE OF ACTIVE SARS?COV?2 INFECTION. JOURNAL OF GLAUCOMA. 2020", "literaturereference_normalized": "the challenge of managing bilateral acute angle closure glaucoma in the presence of active sars cov 2 infection", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210122", "receivedate": "20210122", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18775100, "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": "IN-ALKEM LABORATORIES LIMITED-IN-ALKEM-2020-09334", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CHLORTHALIDONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "213412", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CHLORTHALIDONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BRIMONIDINE TARTRATE\\TIMOLOL MALEATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIMOLOL?BRIMONIDINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BIMATOPROST" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BIMATOPROST." } ], "patientagegroup": null, "patientonsetage": "65", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Choroidal detachment", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Angle closure glaucoma", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KRAWITZ BD, SIRINEK P, DOOBIN D, NANDA T, ET AL.. THE CHALLENGE OF MANAGING BILATERAL ACUTE ANGLE CLOSURE GLAUCOMA IN THE PRESENCE OF ACTIVE SARS?COV?2 INFECTION. JOURNAL OF GLAUCOMA. 2020?UNK:UNK", "literaturereference_normalized": "the challenge of managing bilateral acute angle closure glaucoma in the presence of active sars cov 2 infection", "qualification": "3", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20210107", "receivedate": "20210107", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18709321, "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" } ]

{ "abstract": "Chronic inflammatory demyelinating polyneuropathy (CIDP) is a disorder in which early effective treatment is important to minimize disability from axonal degeneration. It has been suggested that some patients with CIDP may benefit from rituximab therapy, but there is no definitive evidence for this.\n\n\n\nBaseline and post-rituximab-therapy neuromuscular Medical Research Council (MRC) sum scores, Inflammatory Neuropathy Cause and Treatment (INCAT) disability score, and functional status were assessed in 11 patients with refactory CIDP.\n\n\n\nThe MRC sum score, INCAT disability score, and functional status improved in all patients after rituximab therapy.\n\n\n\nOur study provides evidence of the efficacy of rituximab therapy in at least some patients with CIDP. A placebo-controlled study to assess the effectiveness of rituximab therapy in CIDP with and without nodal antibodies is required to identify disease markers that predict responsiveness.", "affiliations": "Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona.;Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona.;Department of Neurology, University of Minnesota, Minneapolis, Minnesota.;Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona.;Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona.;Department of Neurology, University of Minnesota, Minneapolis, Minnesota.;Department of Neurology, University of Minnesota, Minneapolis, Minnesota.;Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas.;Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas.;Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas.", "authors": "Muley|Suraj A|SA|;Jacobsen|Bill|B|;Parry|Gareth|G|;Usman|Uzma|U|;Ortega|Erik|E|;Walk|David|D|;Allen|Jeff|J|;Pasnoor|Mamatha|M|;Varon|Matthew|M|;Dimachkie|Mazen M|MM|", "chemical_list": "D005938:Glucocorticoids; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D000069283:Rituximab; D003520:Cyclophosphamide; D009173:Mycophenolic Acid; D001379:Azathioprine", "country": "United States", "delete": false, "doi": "10.1002/mus.26804", "fulltext": null, "fulltext_license": null, "issn_linking": "0148-639X", "issue": "61(5)", "journal": "Muscle & nerve", "keywords": "CIDP; neuropathy; refractory; rituximab; treatment", "medline_ta": "Muscle Nerve", "mesh_terms": "D000328:Adult; D000368:Aged; D001379:Azathioprine; D002183:Canes; D003520:Cyclophosphamide; D005260:Female; D061826:Foot Orthoses; D005938:Glucocorticoids; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D008297:Male; D008875:Middle Aged; D051346:Mobility Limitation; D009173:Mycophenolic Acid; D010951:Plasma Exchange; D020277:Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; D011782:Quadriplegia; D000069283:Rituximab; D017211:Treatment Failure; D016896:Treatment Outcome; D014853:Walkers", "nlm_unique_id": "7803146", "other_id": null, "pages": "575-579", "pmc": null, "pmid": "31922613", "pubdate": "2020-05", "publication_types": "D016428:Journal Article", "references": null, "title": "Rituximab in refractory chronic inflammatory demyelinating polyneuropathy.", "title_normalized": "rituximab in refractory chronic inflammatory demyelinating polyneuropathy" }

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{ "abstract": "Nintedanib, a tyrosine kinase inhibitor, is approved for the treatment of idiopathic pulmonary fibrosis. We report a case of left ventricular dysfunction in a patient with idiopathic pulmonary fibrosis treated with nintedanib, which recovered after cessation of nintedanib. Nintedanib may induce left ventricular dysfunction, and early recognition is important since this condition is potentially reversible.", "affiliations": "Department of Pulmonary Medicine, Thoracic Center St. Luke's International Hospital Tokyo Japan.;Department of Pulmonary Medicine, Thoracic Center St. Luke's International Hospital Tokyo Japan.", "authors": "Imai|Ryosuke|R|https://orcid.org/0000-0002-3129-916X;Tomishima|Yutaka|Y|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1002/rcr2.533", "fulltext": "\n==== Front\nRespirol Case RepRespirol Case Rep10.1002/(ISSN)2051-3380RCR2Respirology Case Reports2051-3380John Wiley & Sons, Ltd Chichester, UK 10.1002/rcr2.533RCR2533Case ReportCase ReportsLeft ventricular dysfunction in an idiopathic pulmonary fibrosis patient on nintedanib Cardiac dysfunction by nintedanibR. Imai & Y. TomishimaImai Ryosuke https://orcid.org/0000-0002-3129-916X\n1\nimai.rysk@gmail.com Tomishima Yutaka \n1\n\n1 \nDepartment of Pulmonary Medicine, Thoracic Center\nSt. Luke's International Hospital\nTokyo\nJapan\n* Correspondence\n\nRyosuke Imai, Department of Pulmonary Medicine, Thoracic Center, St. Luke's International Hospital, 9‐1, Akashi‐cho, Chuo City, Tokyo 104‐8560, Japan. E‐mail: imai.rysk@gmail.com\n13 2 2020 3 2020 8 2 10.1002/rcr2.v8.2e0053319 11 2019 15 1 2020 20 1 2020 © 2020 The Authors. Respirology Case Reports published by John Wiley & Sons Australia, Ltd on behalf of The Asian Pacific Society of RespirologyThis is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Nintedanib, a tyrosine kinase inhibitor, is approved for the treatment of idiopathic pulmonary fibrosis. We report a case of left ventricular dysfunction in a patient with idiopathic pulmonary fibrosis treated with nintedanib, which recovered after cessation of nintedanib. Nintedanib may induce left ventricular dysfunction, and early recognition is important since this condition is potentially reversible.\n\nWe report a case of left ventricular dysfunction in a patient with idiopathic pulmonary fibrosis treated with nintedanib, which recovered after cessation of nintedanib. Nintedanib may induce left ventricular dysfunction, and early recognition is important since this condition is potentially reversible.\n\n\nIdiopathic pulmonary fibrosisleft ventricular dysfunctionnintedanib source-schema-version-number2.0cover-dateMarch 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.7.5 mode:remove_FC converted:13.02.2020\n\n\nImai , R \n, \nTomishima , Y \n. (2020 ) Left ventricular dysfunction in an idiopathic pulmonary fibrosis patient on nintedanib . Respirology Case Reports , 8 (2 ), e00533\n10.1002/rcr2.533 \n\n\n\nAssociate Editor: Nicole Goh\n==== Body\nIntroduction\nNintedanib is an intracellular multi‐target tyrosine kinase inhibitor (TKI), whose targets include platelet‐derived growth factor receptors α and β, vascular endothelial growth factor receptors 1, 2, 3, and fibroblast growth factor receptors 1, 2, and 3 1. The use of nintedanib has been demonstrated to significantly reduce disease progression in idiopathic pulmonary fibrosis (IPF) 2 but serious adverse cardiovascular events can occur 3. We report the first case of left ventricular (LV) dysfunction in a patient with IPF on nintedanib.\n\nCase Report\nAn 85‐year‐old Japanese man presented to our clinic with increasing dyspnoea on exertion over 6 months. He had a history of bladder cancer (pT1N0M0, stage IA), in remission at the time of presentation having had transurethral removal of the bladder tumour followed by intravesical Bacillus Calmette‐Guerin therapy. He also had a history of hypertension well controlled with amlodipine and candesartan, hypothyroidism treated with levothyroxine, and chronic kidney disease. He was a former smoker with a 27 pack‐year history and used to work for a catering company without any specific exposures. He had no previous history of LV dysfunction. On respiratory examination, his SpO2 was 95% on room air, and he had fine crackles at his lung bases. Cardiac examination was unremarkable with no features of cardiac failure. Chest X‐ray showed bilateral reticular changes (Fig. 1A). Chest CT demonstrated changes consistent with a usual interstitial pneumonia pattern, with bilateral reticulation, and minor ground glass opacities with mild honeycombing in both lower bases (Fig. 1C–E). Laboratory testing revealed elevated Krebs von den Lungen‐6 level (2117 U/mL, normal 0–500 U/mL). Pulmonary function tests demonstrated a restrictive ventilatory defect with a moderate reduction in gas transfer capacity. Forced vital capacity was 73.9% of predicted and the diffusion capacity of carbon monoxide was 54.5% of predicted.\n\nFigure 1 Before nintedanib treatment, chest X‐ray demonstrated reticulation, especially in the basal parts of the lung (A). Alveolar oedema developed with cardiac enlargement and bilateral pleural fluid at admission (B). Chest computed tomography showed usual interstitial pneumonia pattern with reticular opacities associated with traction bronchiectasis with peripheral and lower lobe predominance (C–E).\n\nAuto‐antibodies including anti‐nuclear antibodies, rheumatoid factor, myositis panel, scleroderma panel, and anti‐cyclic citrullinated peptide were negative. The patient was diagnosed with IPF based on the chest computed tomography findings and a negative autoimmune screen in the appropriate clinical setting. He was started on nintedanib 200 mg/day, which was later increased to 300 mg/day. Two months after the initiation of nintedanib, the patient presented to our clinic with a three‐day history of dyspnoea at rest and orthopnoea. On examination, blood pressure was 167/58 mmHg, heart rate was 87/min and regular, and he had bilateral pitting oedema in his lower extremities. Laboratory tests revealed no elevation of creatine kinase‐MB (14 U/L, normal <30 U/L), mild elevation of troponin T (0.063 ng/mL, normal <0.014 ng/mL) and elevation of N‐terminal pro‐brain natriuretic peptide (23,908 pg/mL, normal <125 pg/mL). Full blood count was unremarkable, thyroid hormone levels were within normal limits, and a septic screen including laboratory markers of infection was negative. Electrocardiogram showed no ST‐T wave changes but a widened QRS‐complex (Fig. 2). Chest X‐ray showed widespread bilateral infiltrates in the lung fields (Fig. 1B). Transthoracic echocardiogram showed global hypokinesia with an LV ejection fraction (LVEF) of 34% (Video S1), which was 69% before the initiation of nintedanib. Cardiac catheterization revealed no significant coronary stenosis. He was diagnosed with congestive heart failure probably due to nintedanib.\n\nFigure 2 Patient's electrocardiogram before nintedanib treatment (A). It changed in left ventricular systolic dysfunction (B). QRS duration was 116 ms before nintedanib treatment and 124 ms at admission.\n\nAfter admission, nintedanib was stopped and furosemide, nitroglycerin, candesartan, and carvedilol were started. The patient improved significantly and was discharged from hospital at day 18. His LVEF recovered to 41% on day 8 of his hospital stay, and to 58% three months after his acute presentation. The patient continues to receive follow‐up in the outpatient clinic to monitor LV function and his IPF and he has not experienced heart failure since his discharge.\n\nDiscussion\nWe report a case of an 85‐year‐old man with LV dysfunction likely caused by nintedanib. The LV function was initially normal, declined after nintedanib treatment, and then improved after cessation of nintedanib and initiation of standard heart failure management. Extensive tests were performed to exclude known causes of heart failure. It has previously been reported that TKIs such as imatinib or sunitinib can cause cardiovascular side effects including heart failure, LV dysfunction, conduction abnormalities, QT prolongation, acute coronary syndromes, myocardial injury, arterial thrombosis, and hypertension 4. Patients with significant cardiovascular disease were actively excluded from the nintedanib trials in IPF 2 but follow‐up of the long‐term use of nintedanib in IPF haas been associated with major adverse cardiovascular events in the order of 3.6 events per 100 patient exposure‐years 3.\n\nNintedanib, which is presently approved for the use in IPF, will likely be approved for other forms of fibrotic lung diseases in the future. Therefore, the use of nintedanib will increase over time, warranting further investigation into its clinical and biological effects.\n\nIn conclusion, LV dysfunction may develop as an adverse event from the use of nintedanib, and early recognition is important since this condition is potentially reversible upon cessation of the drug.\n\nDisclosure Statement\nAppropriate written informed consent was obtained for publication of this case report and accompanying images.\n\nSupporting information\n\nVideo S1. Parasternal long axis view of echocardiogram obtained at admission showing global hypokinesia with a left ventricular ejection fraction of 34%.\n\nClick here for additional data file.\n==== Refs\nReferences\n1 \n\nRicheldi \nL \n, \nCostabel \nU \n, \nSelman \nM \n, et al. 2011 \nEfficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis . N. Engl. J. Med. \n365 :1079 –1087 .21992121 \n2 \n\nRicheldi \nL \n, \ndu Bois \nRM \n, \nRaghu \nG \n, et al. 2014 \nEfficacy and safety of nintedanib in idiopathic pulmonary fibrosis . N. Engl. J. Med. \n370 :2071 –2082 .24836310 \n3 \n\nCrestani \nB \n, \nHuggins \nJT \n, \nKaye \nM \n, et al. 2019 \nLong‐term safety and tolerability of nintedanib in patients with idiopathic pulmonary fibrosis: results from the open‐label extension study, INPULSIS‐ON . Lancet Respir. Med. \n7 :60 –68 .30224318 \n4 \n\nChen \nMH \n, \nKerkelä \nR \n, and \nForce \nT \n. 2008 \nMechanisms of cardiac dysfunction associated with tyrosine kinase inhibitor cancer therapeutics . Circulation \n118 :84 –95 .18591451\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2051-3380", "issue": "8(2)", "journal": "Respirology case reports", "keywords": "Idiopathic pulmonary fibrosis; left ventricular dysfunction; nintedanib", "medline_ta": "Respirol Case Rep", "mesh_terms": null, "nlm_unique_id": "101631052", "other_id": null, "pages": "e00533", "pmc": null, "pmid": "32082576", "pubdate": "2020-03", "publication_types": "D002363:Case Reports", "references": "18591451;21992121;24836310;30224318", "title": "Left ventricular dysfunction in an idiopathic pulmonary fibrosis patient on nintedanib.", "title_normalized": "left ventricular dysfunction in an idiopathic pulmonary fibrosis patient on nintedanib" }

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{ "abstract": "BACKGROUND\nPlasmodium ovale is one of the causative agents of human malaria. Plasmodium ovale infection has long been thought to be non-fatal. Due to its lower morbidity, P. ovale receives little attention in malaria research.\n\n\nMETHODS\nTwo Malaysians went to Nigeria for two weeks. After returning to Malaysia, they fell sick and were admitted to different hospitals. Plasmodium ovale parasites were identified from blood smears of these patients. The species identification was further confirmed with nested PCR. One of them was successfully treated with no incident of relapse within 12-month medical follow-up. The other patient came down with malaria-induced respiratory complication during the course of treatment. Although parasites were cleared off the circulation, the patient's condition worsened. He succumbed to multiple complications including acute respiratory distress syndrome and acute renal failure.\n\n\nRESULTS\nSequencing of the malaria parasite DNA from both cases, followed by multiple sequence alignment and phylogenetic tree construction suggested that the causative agent for both malaria cases was P. ovale curtisi.\n\n\nCONCLUSIONS\nIn this report, the differences between both cases were discussed, and the potential capability of P. ovale in causing severe complications and death as seen in this case report was highlighted.\n\n\nCONCLUSIONS\nPlasmodium ovale is potentially capable of causing severe complications, if not death. Complete travel and clinical history of malaria patient are vital for successful diagnoses and treatment. Monitoring of respiratory and renal function of malaria patients, regardless of the species of malaria parasites involved is crucial during the course of hospital admission.", "affiliations": "Tropical Infectious Disease Research and Education Center (TIDREC), Department of Parasitology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia. lauyeeling@um.edu.my.", "authors": "Lau|Yee-Ling|YL|;Lee|Wenn-Chyau|WC|;Tan|Lian-Huat|LH|;Kamarulzaman|Adeeba|A|;Syed Omar|Sharifah Faridah|SF|;Fong|Mun-Yik|MY|;Cheong|Fei-Wen|FW|;Mahmud|Rohela|R|", "chemical_list": "D000962:Antimalarials; D016054:DNA, Protozoan; D012337:RNA, Ribosomal, 18S", "country": "England", "delete": false, "doi": "10.1186/1475-2875-12-389", "fulltext": "\n==== Front\nMalar JMalar. JMalaria Journal1475-2875BioMed Central 1475-2875-12-3892418031910.1186/1475-2875-12-389Case ReportAcute respiratory distress syndrome and acute renal failure from Plasmodium ovale infection with fatal outcome Lau Yee-Ling 1lauyeeling@um.edu.myLee Wenn-Chyau 1leewc_88@hotmail.comTan Lian-Huat 2hutan07@gmail.comKamarulzaman Adeeba 3adeeba@um.edu.mySyed Omar Sharifah Faridah 3shfaridah@um.edu.myFong Mun-Yik 1fongmy@um.edu.myCheong Fei-Wen 1fwcheong18@hotmail.comMahmud Rohela 1rohela@ummc.edu.my1 Tropical Infectious Disease Research and Education Center (TIDREC), Department of Parasitology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia2 Sunway Medical Centre, Bandar Sunway, 46150 Petaling Jaya, Selangor, Malaysia3 Department of Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia2013 4 11 2013 12 389 389 3 8 2013 24 10 2013 Copyright © 2013 Lau et al.; licensee BioMed Central Ltd.2013Lau et al.; licensee BioMed Central Ltd.This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nPlasmodium ovale is one of the causative agents of human malaria. Plasmodium ovale infection has long been thought to be non-fatal. Due to its lower morbidity, P. ovale receives little attention in malaria research.\n\nMethods\nTwo Malaysians went to Nigeria for two weeks. After returning to Malaysia, they fell sick and were admitted to different hospitals. Plasmodium ovale parasites were identified from blood smears of these patients. The species identification was further confirmed with nested PCR. One of them was successfully treated with no incident of relapse within 12-month medical follow-up. The other patient came down with malaria-induced respiratory complication during the course of treatment. Although parasites were cleared off the circulation, the patient’s condition worsened. He succumbed to multiple complications including acute respiratory distress syndrome and acute renal failure.\n\nResults\nSequencing of the malaria parasite DNA from both cases, followed by multiple sequence alignment and phylogenetic tree construction suggested that the causative agent for both malaria cases was P. ovale curtisi.\n\nDiscussion\nIn this report, the differences between both cases were discussed, and the potential capability of P. ovale in causing severe complications and death as seen in this case report was highlighted.\n\nConclusion\nPlasmodium ovale is potentially capable of causing severe complications, if not death. Complete travel and clinical history of malaria patient are vital for successful diagnoses and treatment. Monitoring of respiratory and renal function of malaria patients, regardless of the species of malaria parasites involved is crucial during the course of hospital admission.\n\nPlasmodium ovale curtisiImported malariaAcute respiratory distress syndromeAcute renal failureDeath\n==== Body\nBackground\nAcute respiratory distress syndrome (ARDS) is one of the severe complications of malaria\n[1]. ARDS in falciparum malaria has been intensively studied\n[2-4]. However, ARDS is not restricted solely to Plasmodium falciparum infection. This potentially grave complication has also been reported in malaria caused by Plasmodium vivax, Plasmodium malariae, Plasmodium knowlesi and Plasmodium ovale[5-12]. Due to its limited geographical distribution\n[13], as well as the much lower morbidity\n[14], P. ovale has been overshadowed by other human malaria parasites in the field of medicine and medical research. Nevertheless, recent studies have shown that ovale malaria is caused by two genetically distinct subspecies, P. ovale curtisi and P. ovale wallikeri[15-18].\n\nIn this report, two cases of P. ovale infection acquired from the same location were presented. Both cases ended with different outcome, and two interesting turning points were ARDS complication and acute renal failure.\n\nMethods\nCase presentation\nTwo Malaysian acquaintances (patients A and B) went to Victoria Island, Nigeria together for a two-week working trip. Lariam® (mefloquine) was used as anti-malarial prophylaxis for the trip. They fell sick after returning to Malaysia and were admitted to different hospitals. Their cases are presented as follows:\n\nCase A (Isolate MAL-2)\nAbout two months after the trip to Nigeria, patient A (52-year-old Chinese male) was admitted to a hospital due to five consecutive days of fever with chills and rigours. He was jaundiced, anorexic and febrile with body temperature of 37.7°C upon admission. He had mild cough, blood pressure of 110/66 mm Hg, pulse rate of 98 beats per minute (BPM) with peak bilirubin level of 45 μmol/L and hepatosplenomegaly. His lung examination was normal. His urine was tea-coloured. Ultrasound study confirmed the findings of hepatosplenomegaly with signs of chronic cholecystitis and cholelithiasis. Initial haematological investigation showed that he was thrombocytopaenic (37,000/μl) with normal white blood cell (WBC) count (5,800 cells/μl) and haemoglobin level of 13.9 g/dL. He had not travelled to any other places after the trip to Nigeria. The patient had a past history of malaria for three times. The last episode of malaria was six months prior to present admission. However, the species of malaria parasites for the previous malaria episodes was not known. The patient also had an underlying condition of hypertension. Besides, he was a heavy alcohol consumer. Clinical findings on patient A upon admission are summarized in Table \n1.\n\nTable 1 Summary of initial clinical findings on patient A and B upon admission\n\nTest (unit)\tPatient A\tPatient B\t\n{normal range}\t(Isolate MAL-2)\t(Isolate MAL-1)\t\nBlood Pressure (mmHg) {90/60 - 130/80}\t110/66\t102/55\t\nPulse rate (BPM) {60 - 100}\t98\t60\t\nParasitemia (%)\t0.10#\t0.18\t\nHaemoglobin (g/dL) {male: 13.5 - 17.5}\t13.9\t12.4\t\nTWBC (× 103cells/μl) {4.5 - 11.0}\t5.8\t3.1\t\nPlatelet (× 103/μl) {150.0 - 450.0}\t37.0\t65.0\t\nSerum creatinine (μmol/L) {60 - 110}\t82.0\t107.0\t\nSerum urea (mmol/L) {2.5 - 6.4}\t9.0\t6.5\t\nTotal serum bilirubin (μmol/L) {<17}\t45.0\t16.0\t\nAST (IU/L) {15.0 - 37.0}\t47.0\t47.0\t\nALT (IU/L) {30.0 - 65.0}\t29.0\t39.0\t\nRandom plasma glucose (mmol/L) {<11.1}\t6.4\t9.5\t\nValues in {} indicate the normal range of the respective event investigated, corresponding to the age and gender of patient.\n\nTWBC = total white blood cell count; AST = aspartate aminotransferase; ALT = alanine aminotransferase.\n\nValue marked with “#” was not obtained upon patient’s admission to the hospital.\n\nPatient A was treated immediately for cholecystitis with intravenous (IV) ceftriaxone 2 g daily and IV metronidazole 500 mg thrice daily by the attending gastroenterologist. However, his fever and thrombocytopaenia persisted, and WBC count dropped progressively. On day 5 of admission, blood smears were prepared and examined under the microscope. “Plasmodium vivax-like” parasites were found with parasitaemia of 0.10%. Further microscopic examination by a referral diagnostic centre subsequently indicated that this was a mono-infection of P. ovale. This was confirmed with nested PCR technique using primers developed from the 18S ribosomal RNA (18S rRNA) gene as applied by previous reports\n[19-21], coupled with sequencing analysis using Basic Local Alignment Search Tool (BLAST)\n[22]. Meanwhile, bacteriological culture diagnoses from patient’s blood samples were negative.\n\nHe was treated with a course of six doses of Riamet® (artemether and lumefantrine), four tablets per dose, and primaquine for two weeks. Patient A responded well to the anti-malarial treatment clinically and biochemically. Patient’s parasitaemia dropped to 0.06% the following day. Malaria parasites were cleared in less than 48 hours after initiation of Riamet® treatment. He was discharged well on day 8 of hospitalization. He remained well without relapse of malaria throughout his medical follow-up of 12 months with the hospital.\n\nCase B (Isolate MAL-1)\nAround six months after the trip to Nigeria, patient B (59-year-old Chinese male) fell sick and went to a private hospital. He was then referred to a tertiary referral hospital. Upon admission to the referral hospital, he gave a history of intermittent fever with rigours, myalgia and nausea for ten days. His blood pressure upon admission was 102/55 mm Hg, with pulse rate of 60 BPM. Plasma glucose level was 9.5 mmol/L. Jaundice and hepatosplenomegaly were not detected. He was alert and conscious. His lung examination was normal. He made a one-day-trip to Kota Kinabalu, Sabah, three months before the admission. He had no known medical illness and no known history of acquiring malaria. Initial haematological investigation revealed that he was thrombocytopaenic (65,000/μl) with low WBC count (3,100 cells/μl) and haemoglobin level of 12.4 g/dL. Malaria parasites were detected in his blood, with parasitaemia of 0.18%. The species was identified as P. ovale, which was further ascertained with nested PCR as mentioned in the previous section. Clinical findings on patient B upon admission are summarized in Table \n1, and more clinical details on patient B throughout his hospital stay is available in Table \n2.\n\nTable 2 Clinical details on patient B (Isolate MAL-1) throughout his hospital stay\n\nDay\tBP (mmHg)\tHb (g/dL)\tPlt (×10\n3\n/μl)\tTSB (μmol/L)\tAST (IU/L)\tALT (IU/L)\tSCr (μmol/L)\tBlood bacteriological & fungal culture\tAnti-malarials\tAntibiotics\tAdditional notes\t\n1\t102/55\t12.4\t65\t16\t47\t39\t100\tN/A\tN/A\tN/A\tPR 60 BPM; SPO2 97% RA; loss of appetite; Lungs: clear\t\n2\t92/52\tN/A\tN/A\tN/A\tN/A\tN/A\t107\tN/A\tChloroquine\tN/A\tPR 70 BPM; Lungs: clear;\t\nPrimaquine\tDengue IgM negative\t\n3\t118/66\tN/A\t107\t13\t88\t71\t112\tN/A\tChloroquine\tN/A\tPR 70 BPM; SPO2 98% RA;\t\nPrimaquine\tLungs: minimal basal crepitations\t\n4\t106/60\t10.5\t120\t13\t50\t90\t101\tNegative\tArtesunate\tCeftriaxone\tPR 66 BPM; Haemoptysis, epistaxis, shortness of breath; CXR: bilateral haziness\t\nQuinine\t\n5\t115/56\t11.2\t170\t8\t56\t62\t114\tN/A\tArtesunate\tCeftriaxone\tBlood smear: negative for malaria parasites; Transferred to ICU\t\n6\t104/50\t9.4\t183\t6\t58\t43\t139\tNegative\tArtesunate\tTazocin®\tBlood smear: negative for malaria\t\n7\t95/56\t10.3\t197\t9\t46\t42\t215\tNegative\tArtesunate\tTazocin®\tBlood smear: negative for malaria\t\n8\t102/70\t9.4\t178\t8\t88\t43\t291\t \tArtesunate\tTazocin®\tBlood smear: negative for malaria; respiratory acidosis\t\nPrimaquine\t\n9\t143/64\t9.0\t184\t7\t49\t39\t297\tNegative\tArtesunate\tTazocin®\tBlood smear: negative for malaria\t\n10\t170/60\t8.5\t199\t10\t54\t48\t316\tN/A\tArtesunate\tTazocin®\tBlood smear: negative for malaria\t\n11\t165/68\t8.1\t231\t8\t99\t81\t301\tN/A\tN/A\tTazocin®\tFerritin blood test: 2,118 ng/ml\t\n12\t200/78\t8.1\t288\t13\t128\t148\t309\tNegative\tN/A\tVancomycin\t \t\nImipenem\t\n13\t160/60\t6.8\t311\t16\t137\t190\t392\tN/A\tN/A\tVancomycin\tHemolysis screening: negative;\t\nImipenem\tCXR: worsening\t\n14\t170/63\t9.1\t265\t13\t47\t106\t408\tN/A\tN/A\tVancomycin\t \t\nImipenem\t\n15\t135/51\t9.5\t270\t22\t65\t74\t472\tPositive for Enterobacter cloacae\tN/A\tVancomycin\tRigours; acidosis (resp. & met.)\t\nImipenem\tABG: pH 7.128; pCO2 59.5 mmHg;\t\nSLED 4 hours\t\n16\t111/45\t9.1\t225\t19\t43\t51\t413\tN/A\tN/A\tVancomycin\tCVVHD\t\nImipenem\t\n17\t134/57\t7.5\t179\t29\t109\t65\t424\tN/A\tN/A\tVancomycin\tSeizures; SLED 8 hours\t\nMeropenem\t\n18\t135/55\t7.3\t178\t30\t38\t40\t320\tN/A\tN/A\tMeropenem\tGentle HD 4 hours\t\n19\t130/56\t9.0\t204\t34\t40\t30\t404\tN/A\tN/A\tMeropenem\tGentle HD 4 hours\t\n20\t147/61\t8.6\t207\t25\t43\t26\t403\tN/A\tN/A\tMeropenem\tSevere resp. acidosis; met. acidosis; gentle HD 4 hours\t\n21\t140/54\tN/A\tN/A\tN/A\tN/A\tN/A\t427\tN/A\tN/A\tMeropenem\tGentle HD 3 hours\t\n22\t102/48\t9.3\t166\t39\t296\t119\t401\tN/A\tN/A\tMeropenem\tWorsening hypoxia; hypotensive; Gentle HD 6 hours\t\n23\tN/A\tN/A\tN/A\t22\t136\t109\t314\tN/A\tN/A\tN/A\tAsystole; death\t\nN/A = not available; BP = blood pressure; Hb = haemoglobin; Plt = platelet; TSB = total serum bilirubin; AST = aspartate aminotransferase; ALT = alanine aminotransferase; SCr = serum creatinine; BP = blood pressure; BPM = beats per minute; PR = pulse rate; SPO2 = blood oxygen saturation; RA = room air; IgM = immunoglobulin M; CXR = chest X-ray; ICU = intensive care unit; resp. = respiratory; met. = metabolic; ABG = arterial blood gas; pCO2 = partial pressure of carbon dioxide; SLED = sustained low efficiency dialysis; CVVHD = continuous veno-venous haemodialysis; HD = haemodialysis.\n\nAnti-malaria therapy course of chloroquine (chloroquine phosphate 150 mg base) and primaquine (30 mg) was started on patient B. However, he was still febrile (38.4°C) 24 hours later. On day 3 of the admission, patient B developed loose stools and lung examination revealed fine basal crepitations. Blood smear examination showed that the malaria parasites were not cleared. In the morning of day 4, he complained of feeling breathless and lethargic. His body temperature surged to 39.2°C. With presence of basal crepitations, an initial diagnosis of pneumonia was made and IV ceftriaxone was added into the course of treatment.\n\nHowever, later that day in the afternoon, the patient developed worsening dyspnea, haemoptysis, and subsequently epistaxis. Chest X-ray examination showed bilateral haziness up to the upper zone, which was suggestive of pulmonary haemorrhage. Haematological investigation showed that his platelet count was 120,000/μl and the malaria parasite load was reduced to 0.03%. Despite the lowering of parasitaemia, patient B progressed into respiratory failure. He was intubated and ventilated. His anti-malarial treatment was changed to IV quinine 850 mg (1 dose) and subsequently to IV artesunate 160 mg (for 7 days). Furosemide was given to the patient for presumed pulmonary oedema.\n\nOn day 5 of the admission, malaria parasites were completely cleared. However, patient was still febrile with temperature of 40.8°C. He was transferred to intensive care unit. On day 6, patient B was oliguric. Increased level of creatinine and worsening of respiratory acidosis were noted. The patient had developed acute kidney injury (AKI) secondary to overwhelming sepsis. Hypotensive episodes were encountered. Therefore inotropic support was initiated. His antibiotic regime was changed to IV Tacocin® (tazobactam and piperacilin).\n\nOn day 12, patient B was still febrile with little improvement on his lung function. He was still dependent on the ventilator. IV Tacocin® was replaced by IV vancomycin and imipenem empirical treatment. All the five sets of bacteriological blood cultures and one set of fungal culture requested earlier on different days came back as negative. Nevertheless, dialysis was started on day 15 due to oliguric AKI with worsening acidosis (mixed respiratory and metabolic). Dialysis was performed on daily basis till the end of his life.\n\nOn day 17, bacteriological culture from patient’s blood sample that was collected on day 15 was positive for Enterobacter cloacae, which was sensitive to carbapenems. Hence, the imipenem therapy was continued. However, due to epileptic seizures suffered by the patient on day 17, the antibiotic regime was subsequently replaced with meropenem. A computerized tomography (CT) scanning on the patient’s brain showed no abnormality. Another thorax CT scanning showed extensive bilateral lung consolidation and loculated pleural effusion. His fever persisted, and he was on prolonged ventilation with difficulty in weaning off. His condition continued to deteriorate. He went into recalcitrant atrial fibrillation on day 22 and required tripleinotropic support. Further blood bacteriological and fungal cultures were all negative. On the 23rd day of hospital admission, he went into asystole and succumbed to P. ovale infection with ARDS, acute renal failure, metabolic acidosis, and nosocomial sepsis.\n\nConsent\nConsent was granted by patient/ patient’s family for the publication of these case reports.\n\nPost-clinical analysis and interpretation\nPlasmodium ovale is not found locally in Malaysia. Alignment of short segments from 18S rRNA gene sequences of these two cases, i.e. isolate MAL-1 (GenBank accession number KF192072) and isolate MAL-2 (GenBank accession number KF192073) with 18S rRNA gene sequences of other isolates of P. ovale spp. that were available in GenBank (accession number L48986, JF894403, JF894405, GQ183051, JF894407, JF894410, M19172) were conducted. The multiple sequence alignment showed that the aetiological agents of the two cases in this case report were P. ovale curtisi (Figure \n1). The clustering of these two isolates with P. ovale curtisi can be visualized clearly via a simple phylogenetic tree constructed using neighbour-joining method (bootstrap = 1000) as described previously\n[23] (Figure \n2).\n\nFigure 1 Multiple sequence alignment of short segments from 18S rRNA gene sequences of Plasmodium ovale spp. isolates. The isolate MAL-1 (GenBank accession number KF192072) and isolate MAL-2 (GenBank accession number KF192073) in this report were indicated as P. ovale curtisi, as shown by the high nucleotide sequence similarity shared between these two isolates and gene sequences of other P. ovale curtisi isolates (GenBank accession number JF894403, JF894405, L48986) that were available in GenBank. Gene sequences of P. ovale wallikeri from GenBank (GenBank accession number JF894407, JF894410) were used in this multiple sequence alignment as well. Position of nucleotides is based on sequences of isolate MAL-1.\n\nFigure 2 Phylogenetic tree based on a short segment of 18S rRNA gene sequences of Plasmodium spp. isolates. Isolate MAL-1 (accession number KF192072) and isolate MAL-2 (accession number KF192073) in this report clustered with P. ovale curtisi isolates, clearly indicating that these two cases were caused by P. ovale curtisi. The tree is constructed using the Neighbor-Joining method (bootstrap = 1000). GenBank accession number is given after each isolate’s name. The 18S rRNA gene sequences of P.falciparum isolate (GenBank accession number M19172) was used as outgroup.\n\nA case of ovale malaria imported from Nigeria was previously reported in Malaysia\n[24], and these are another two imported cases of P. ovale infection. Unlike the previous case report, which involved a Nigerian student (imported patient) who showed no complications\n[24], both cases reported here involved Malaysians that acquired malaria from a trip to Nigeria (imported infection), and one showed severe complications that were ultimately fatal. Interestingly, both patients had taken anti-malarial prophylaxis during their trip to Nigeria. Nevertheless, they still contracted malaria. This may be due to usage of the prophylactic drugs without properly following the instructions or low compliance during the trip. Another reason for failed protective effect of anti-malaria chemoprophylaxis against P. ovale infection is the ability of P. ovale to form hypnozoites, which can survive chemoprophylaxis\n[18].\n\nIn case A, there was a delay in malaria diagnosis. This case is a good example of clinical setting where malaria tends to be overlooked at the initial stage of medical investigation due to low level of suspicion. From the initial haematological investigation, all but one (platelet count) showed values within the normal range. In many hospital settings, especially those of urban areas and non-malaria endemic regions, such investigation outcome usually carries a thin possibility of instigating a blood film microscopic examination. Indeed, a case of traveller’s malaria that developed into severe complications due to delayed diagnosis was reported in Croatia recently\n[25]. The available reported malaria with delayed diagnoses may just be a tip of the iceberg; and such incident may happen more frequently than expected. Thus malaria should have been suspected if patient presented with fever, thrombocytopaenia, and showed history of travelling to malaria-endemic areas within the past one year. The long period between travel to malaria endemic country and disease onset may also contribute to delay in diagnosis, and subsequently the appropriate treatment. The late onset of symptoms due to long latency period provides challenges to clinical diagnoses upon admission. As mentioned previously, P. ovale spp. can form hypnozoites and result in long latency\n[18,26], which can be seen in the two cases presented here.\n\nPatient B succumbed to the malaria infection and he did not have any medical problems prior to the illness. Patient A, who is a heavy drinker, was known to have hypertension even before the infection, survived. One possible explanation for this is the partial immunity gained by patient A from previous incidents of malaria. People who have past history of acquiring falciparum malaria and those staying in malaria-endemic regions are known to show less severe symptoms during subsequent malaria infections compared to people who are from non-malaria endemic regions (malaria-naïve)\n[27]. Indeed, such protective effect of acquired partial immunity via previous exposure to malaria was noted and mentioned in previous reports on falciparum and vivax malaria-related ARDS\n[5,28,29]. Furthermore, malaria related pulmonary complications are often seen in non-immune patients\n[30]. Patient A might be partially protected against severe complications due to previous exposure to malaria. Patient B did not have prior exposure to malaria, and therefore, he suffered and succumbed to the severe complications in his first attack of malaria infection. Even so, pathogenesis of ovale malaria is not intensively studied and protection against ovale malaria complications conferred by previous exposure has not been investigated. Therefore, more investigations are needed to validate this postulation.\n\nOne important note worth mentioning here is the trend of ARDS onset and development in this case. Similar to the situation of malaria-induced ARDS reported previously\n[10,31,32], patient B showed normal breathing without wheezing and crepitations upon admission, but his respiratory function deteriorated towards the grave complication of ARDS afterwards. Therefore, physicians should pay close attention to the respiratory condition of every admitted malaria case. Moreover, malaria is regarded as one of the important causes of ARDS\n[1].\n\nIn case B, nosocomial Enterobacter cloacae infection was diagnosed during the course of his hospital stay. Here, bacterial infection was ruled out as the primary cause of ARDS in patient B as the bacteriological culture showed positive results as late as day 15, whereas he showed symptoms of acute lung injury as early as day 4. Undoubtedly, the bacterial infection that occurred at such critical timing would worsen the health condition of the patient, which acted as the secondary contributing factor towards the fatal end for this case. Another point worth mentioning was the onset of the ARDS symptoms after the initiation of anti-malarial therapy, which was similar to many cases of malaria-associated ARDS reported previously\n[9,10,30-34]. The pulmonary injury seen in this case was likely to be a post-treatment related pulmonary inflammation. Nonetheless, a few case reports of malaria-induced ARDS with pre-treatment onset were described previously\n[5,35]. In addition, quinine was known to be capable of inducing pulmonary injury\n[34]. Hence, the quinine therapy that was briefly applied on the patient may contribute to the worsening of his lung injury. Nevertheless, quinine therapy was immediately replaced with artesunate within the same day.\n\nThrombocytopaenia was seen in both cases. Such phenomenon has been observed in patients infected with P. falciparum, P. vivax, and P. knowlesi[8,21,36-39]. Thrombocytopaenia may serve as a contributing factor, instead of a primary cause of malaria-related severe pulmonary injury. Indeed, the platelet reading of patient A (survived case) was lower than that of patient B (fatal case) upon admission. Other events that are believed to contribute towards acute pulmonary injuries include: host immunologic responses\n[34], rosetting phenomenon, which is found in all four species of human malaria parasites\n[40-44], and sequestration that is found in P. falciparum and to a lesser, but significant extent, P. vivax[45]. This event may account for the much higher prevalence of ARDS complications seen in falciparum malaria. Nonetheless, the pathophysiology of malaria-associated ARDS is not completely understood\n[1,10,30].\n\nAnother aspect of this fatal case of P. ovale infection that deserves attention is the acute renal failure. Acute renal failure is another potentially fatal complication in malaria\n[25,46,47]. However, such complication is reported mostly in falciparum malaria\n[47-49], the newly emerging knowlesi malaria\n[21,50], and occasionally, in a few cases of P. vivax and P. malariae infections\n[51,52]. A fatal case of vivax malaria with acute renal failure was reported recently\n[53]. This is by far the first reported case of P. ovale infection with acute renal injury. In case B, the patient suffered renal injury a few days before he came down with nosocomial sepsis. Therefore, the acute renal injury seen in this case was less likely to be caused by nosocomial sepsis. Nevertheless, the nosocomial sepsis might act as the secondary contributing factor towards the renal failure in this patient. Besides, the medications used on the patient such as vancomycin is potentially nephrotoxic\n[54], thus serving as another potential contributing factor that worsened the acute renal injury. Hence, such therapy was discontinued.\n\nApart from the differences in pathological development of both cases, the anti-malaria treatment regimes used in both cases were dissimilar as well. For patient A, Riamet® with primaquine was used whereas for patient B, chloroquine and primaquine were prescribed at the initial stage of treatment. Parasites were not detected from patient A’s blood smear in less than 48 hours after initiation of antimalarial treatment. On the other hand, complete parasite clearance could only be declared on patient B after switching the medication to quinine and artesunate. Consequently, the parasite clearance took as long as five days to accomplish. Parasite clearance was much faster in treatment strategy using the artemether-lumefantrine-primaquine combination than that of chloroquine-primaquine combination. Indeed, artemisinin-based combination therapy (ACT) has been proven to show high efficacy in treating falciparum malaria\n[55] and non-falciparum malaria\n[56]. The much slower parasite clearance by chloroquine-based treatment may be due to the stage-specific anti-malarial property of chloroquine. As shown by previous studies, the trophozoites of P. vivax, P. malariae and P. ovale are relatively insusceptible to chloroquine\n[57-59]. Therefore, ACT such as Riamet® can serve as an effective first line treatment even for non-falciparum malaria.\n\nSevere ovale malaria is not commonly found. There are a few reports of P. ovale infection with ARDS\n[9-12], and one case of ovale malaria with splenic complication\n[60]. Fatal ovale malaria is even rarer. A fatal case of ovale malaria involving a young Moroccan soldier was reported recently\n[12]. Interestingly, this ovale malaria casualty also suffered ARDS complication. This recent case report and our report show that P. ovale is capable of causing severe complications and death. For that reason, patients with P. ovale infection should not be regarded as “ultimately benign” and taken lightly, particularly in the non-immune travellers. In view of this, travel history as well as past history of acquiring malaria in patients with fever must be recorded in detail to assist in the diagnosis and management of travellers’ malaria and severe malaria.\n\nConclusion\nTwo imported cases of P. ovale infections with different pathological progress were reported. Plasmodium ovale is potentially capable of causing severe complications, if not death. In view of the differences between these two cases, complete clinical history of malaria patient, especially the travel history and history of malaria exposure are vital for successful treatment. Monitoring of respiratory and renal function of malaria patients, regardless of the species of malaria parasites involved is important during the course of hospital admission. In addition, ACT such as Riamet® should be applied to malaria patients regardless of the species of aetiological agents for prompt and efficient treatment.\n\nCompeting interests\nThe authors declared that they have no competing interests.\n\nAuthors’ contributions\nWCL, YLL, and RM collected, analysed and interpreted the data. LHT, AK and SFSO collected blood samples, conducted clinical diagnoses and treatment intervention. FWC conducted and processed molecular diagnoses. MYF constructed and analysed phylogenetic tree. WCL, YLL, LHT and RM arranged the data, conceptualized and prepared the manuscript. All authors read and approved the final manuscript.\n\nAcknowledgements\nYLL, MYF, RM and FWC were supported by University of Malaya High Impact Research (HIR) Grant UM-MOHE (UM.C/625/1/HIR/MOHE/CHAN/14/3) from the Ministry of Higher Education, Malaysia. WCL was supported by University of Malaya Student Research Grant PV044/2012A. 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TT do Rosário VE Arez AP Pinto J Michon P Escalante AA Nosten F Burke M Lee R Blaze M Dan Otto T Barnwell JW Pain A Williams J White NJ Day NPJ Snounou G Lockhart PJ Chiodini PL Imwong M Polley SD Two nonrecombining sympatric forms of the human malaria parasite Plasmodium ovale occur globally J Infect Dis 2010 201 1544 1550 10.1086/652240 20380562 \nSutherland CJ Polley SD Tibayrenc M Genomic Insights into the Past, Current and Future Evolution of Human Parasites of the Genus Plasmodium Genetics and Evolution of the Infectious Diseases 2011 London: Elsevier 607 635 \nCalderaro A Piccolo G Gorrini C Montecchini S Rossi S Medici MC Chezzi C Snounou G A new real-time PCR for the detection of Plasmodium ovale wallikeri PLoS One 2012 7 e48033 10.1371/journal.pone.0048033 23110165 \nNolder D Oguike MC Maxwell-Scott H Niyazi HA Smith V Chiodini PL Sutherland CJ An observational study of malaria in British travellers: Plasmodium ovale wallikeri and Plasmodium ovale curtisi differ significantly in the duration of latency BMJ Open 2013 3 e002711 10.1136/bmjopen-2013-002711 23793668 \nSingh B Kim Sung L Matusop A Radhakrishnan A Shamsul SS Cox-Singh J Thomas A Conway DJ A large focus of naturally acquired Plasmodium knowlesi infections in human being Lancet 2004 363 1017 1024 10.1016/S0140-6736(04)15836-4 15051281 \nCox-Singh J Davis TM Lee KS Shamsul SS Matusop A Ratnam S Rahman HA Conway DJ Singh B Plasmodium knowlesi in humans is widely distributed and potentially life threatening Clin Infect Dis 2008 46 165 171 10.1086/524888 18171245 \nLee WC Chin PW Lau YL Chin LC Fong MY Yap CJ Supramaniam RR Mahmud R Hyperparasitaemic human Plasmodium knowlesi infection with atypical morphology in peninsular Malaysia Malar J 2013 12 88 10.1186/1475-2875-12-88 23496970 \nBasic Local Alignment Search Tool (BLAST) [http://blast.ncbi.nlm.nih.gov] \nTamura K Dudley J Nei M Kumar S MEGA 4: evolutionary genetics analysis (MEGA) software version 4.0 Mol Biol Evol 2007 24 1596 1599 10.1093/molbev/msm092 17488738 \nLim YA Mahmud R Chew CH Thiruventhiran T Chua KH Plasmodium ovale infection in Malaysia: first imported case Malar J 2010 9 272 10.1186/1475-2875-9-272 20929588 \nTroselj-Vukić B Vuksanović-Mikulicić S Sladoje-Martinović B Milotić I Slavuljica I Unrecognized malaria and its consequences: a case report of severe malaria with acute renal failure Coll Antropol 2013 37 611 613 23941012 \nMiller MJ Marcus DM Cameron DG Latent infections with Plasmodium ovale malaria Canad Med Ass J 1965 92 1241 1247 14296004 \nHøgh B Clinical and parasitological studies on immunity to Plasmodium falciparum malaria in children Scand J Infect Dis Suppl 1996 102 1 53 9060051 \nTanios MA Kogelman L McGovern B Hassoun PM Acute respiratory distress syndrome complicating Plasmodium vivax malaria Crit Care Med 2001 29 665 667 10.1097/00003246-200103000-00037 11373440 \nSarkar S Saha K Das CS Three cases of ARDS: an emerging complication of Plasmodium vivax malaria Lung India 2010 27 154 157 10.4103/0970-2113.68323 20931035 \nTaylor WR Cañon V White NJ Pulmonary manifestations of malaria: recognition and management Treat Respir Med 2006 5 419 428 10.2165/00151829-200605060-00007 17154671 \nAnstey NM Jacups SP Cain T Pearson T Ziesing PJ Fisher DA Currie BJ Marks PJ Maguire GP Pulmonary manifestations of uncomplicated falciparum and vivax malaria: cough, small airways obstruction, impaired gas transfer, and increased pulmonary phagocytic activity J Infect Dis 2002 185 1326 1334 10.1086/339885 12001051 \nPrice L Planche T Rayner C Krishna S Acute respiratory distress syndrome in Plasmodium vivax malaria: case report and review of the literature Trans R Soc Trop Med Hyg 2007 101 655 659 10.1016/j.trstmh.2007.02.014 17433389 \nMartell RW Kallenbach J Zwi S Pulmonary oedema in the falciparum malaria Br Med J 1979 1 1763 1764 380762 \nTaylor WR White NJ Malaria and the lung Clin Chest Med 2002 23 457 468 10.1016/S0272-5231(02)00004-7 12092039 \nRahman AK Sulaiman FN Plasmodium vivax malaria presenting as acute respiratory distress syndrome: a case report Trop Doct 2013 43 83 85 10.1177/0049475513485733 23796679 \nKakar A Bhoi S Prakash V Kakar S Profound thrombocytopenia in Plasmodium vivax malaria Diag Microbiol Infect Dis 1999 35 234 244 \nAnsari S Khoharo HK Abro A Akhund IA Qureshi F Thrombocytopenia in Plasmodium falciparum malaria J Ayub Med Coll Abbottabad 2009 21 145 147 20524493 \nThapa R Biswas B Mallick D Sardar S Modak S Childhood Plasmodium vivax malaria with severe thrombocytopenia and bleeding manifestations J Pediatr Hematol Oncol 2009 31 758 759 10.1097/MPH.0b013e3181b7eb12 19779377 \nLacerda MV Mourão MP Coelho HC Santos JB Thrombocytopenia in malaria: who cares? Mem Inst Oswaldo Cruz 2011 106 Suppl 1 52 63 21881757 \nDavid PH Handunnetti SM Leech JH Gamage P Mendis KN Rosetting: a new cytoadherence property of malaria-infected erythrocytes Am J Trop Med Hyg 1988 38 289 297 3354764 \nHandunnetti SM David PH Perera KL Mendis KN Uninfected erythrocytes form “rosettes” around Plasmodium falciparum infected erythrocytes Am J Trop Med Hyg 1989 40 115 118 2645800 \nUdomsangpetch R Thanikkul K Pukrittayakamee S White NJ Rosette formation by Plasmodium vivax Trans R Soc Trop Med Hyg 1995 89 635 637 10.1016/0035-9203(95)90422-0 8594679 \nAngus BJ Thanikkul K Silamut K White NJ Udomsangpetch R Short report: rosette formation in P. ovale infection Am J Trop Med Hyg 1996 55 560 561 8940990 \nLowe BS Mosobo M Bull PC All four species of human malaria parasites form rosettes Trans R Soc Trop Med Hyg 1998 92 526 10.1016/S0035-9203(98)90901-4 9861369 \nCarvalho BO Lopes SC Mogueira PA Orlandi PP Bargieri DY Blanco YC Mamomi R Leite JA Rodrigues MM Araújo MO Russell B Suwanarusk R Snounou G Rénia L Costa FT On the cytoadhesion of Plasmodium vivax-infected erythrocytes J infect Dis 2010 202 638 647 10.1086/654815 20617923 \nTrampuz A Jereb M Muzlovic I Prabhu RM Clinical review: severe malaria Crit Care 2003 7 315 323 10.1186/cc2183 12930555 \nDas BS Renal failure in malaria J Vector Borne Dis 2008 45 83 97 18592837 \nEiam-Ong S Sitprija V Falciparum malaria and the kidney: a model of inflammation Am J Kidney Dis 1998 32 361 375 10.1053/ajkd.1998.v32.pm9740151 9740151 \nSinniah R Lye W Acute renal failure from myoglobinuria secondary to myositis from severe falciparum malaria Am J Nephrol 2000 20 339 343 10.1159/000013611 10970990 \nSingh B Daneshvar C Human infections and detection of Plasmodium knowlesi Clin Microbiol Rev 2013 26 165 184 10.1128/CMR.00079-12 23554413 \nPrakash J Singh AK Kumar NS Saxena RK Acute renal failure in Plasmodium vivax malaria J Assoc Physicians India 2003 51 265 267 12839348 \nHendrickse RG Adeniyi A Edington GM Glasgow EF White RH Houba V Quartan malarial nephrotic syndrome. Collaborative clinicopathological study in Nigerian children Lancet 1972 1 1143 1149 4113056 \nPatel MP Kute VB Gumber MR Gera DN Shah PR Patel HV Trivedi HL Vanikar AV An unusual case of Plasmodium vivax malaria monoinfection associated with crescentic glomerulonephritis: a need for vigilance Parasitol Res 2013 112 427 430 10.1007/s00436-012-3040-5 22806325 \nGupta A Biyani M Khaira A Vancomycin nephrotoxicity: myths and facts Neth J Med 2011 69 379 383 21978980 \nBhattarai A Ali AS Kachur SP Mártensson A Abbas AK Khatib R Al-mafazy A Ramsan G Rotliant G Gerstenmaier JF Molteni F Abdulla S Montgomery SM Kaneko A Björkman A Impact of artemisinin-based combination therapy and insecticide-treated nets on malaria burden in Znazibar PLoS Med 2007 4 e309 10.1371/journal.pmed.0040309 17988171 \nMombo-Ngoma G Kleine C Basra A Wűrbel H Diop DA Capan M Adegnika AA Kurth F Mordműller B Joanny F Kremsner PG Ramharter M Bélard S Prospective evaluation of artemether-lumefantrine for the treatment of non-falciparum and mixed-species malaria in Gabon Malar J 2012 11 120 10.1186/1475-2875-11-120 22515681 \nRussell B Chalfein F Prasetyorini B Kenangalem E Piera K Suwanarusk R Brockman A Prayoga P Sugiarto P Cheng Q Tjitra E Anstey NM Price RN Determinants of in vitro drug susceptibility testing of Plasmodium vivax Antimicrob Agents Chemother 2008 52 1040 1045 10.1128/AAC.01334-07 18180357 \nSharrock WW Suwanarusk R Lek-Uthai U Edstein MD Kosaisavee V Travers T Jaidee A Sriprawat K Price RN Nosten F Russell B Plasmodium vivax trophozoites insensitive to chloroquine Malar J 2008 7 94 10.1186/1475-2875-7-94 18505560 \nSiswantoro H Russell B Ratcliff A Prasetyorini B Chalfein F Marfurt J Kenangalem E Wuwung M Piera KA Ebsworth EP Anstey NM Tjitra E Price RN In vivo and in vitro efficacy of chloroquine against Plasmodium malariae and P. ovale in Papua, Indonesia Antimicrob Agents Chemother 2011 55 197 202 10.1128/AAC.01122-10 20937779 \nCinquetti G Banal F Rondel C Plancade D de Saint Roman C Adriamanantena D Ragot C Védy C Graffin B Splenic infarction during Plasmodium ovale acute malaria: first case reported Malar J 2010 9 288 10.1186/1475-2875-9-288 20955610\n\n", "fulltext_license": "CC BY", "issn_linking": "1475-2875", "issue": "12()", "journal": "Malaria journal", "keywords": null, "medline_ta": "Malar J", "mesh_terms": "D058186:Acute Kidney Injury; D000962:Antimalarials; D016054:DNA, Protozoan; D017809:Fatal Outcome; D006801:Humans; D008288:Malaria; D008296:Malaysia; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009549:Nigeria; D010802:Phylogeny; D041122:Plasmodium ovale; D012337:RNA, Ribosomal, 18S; D012128:Respiratory Distress Syndrome; D017422:Sequence Analysis, DNA; D014195:Travel", "nlm_unique_id": "101139802", "other_id": null, "pages": "389", "pmc": null, "pmid": "24180319", "pubdate": "2013-11-04", "publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "9740151;20937779;9698266;10970990;4113056;380762;12930555;14296004;21881757;22806325;16410895;20931035;6228898;18084125;23235819;16020691;2645800;11373440;23793668;23496970;15051281;3354764;18180357;10626136;8594679;23554413;9060051;23328641;12001051;23688721;17154671;10530480;19779377;20929588;18505560;23796679;20955610;19635025;8940990;9129203;18592837;17988171;18807374;18171245;18784231;20380562;17488738;9861369;23110165;21978980;17433389;12839348;12092039;20617923;20524493;22515681;23941012", "title": "Acute respiratory distress syndrome and acute renal failure from Plasmodium ovale infection with fatal outcome.", "title_normalized": "acute respiratory distress syndrome and acute renal failure from plasmodium ovale infection with fatal outcome" }

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"Respiratory failure", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Acute respiratory distress syndrome", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Traumatic lung injury", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Lethargy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Haemoptysis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "LAU Y-L, LEE W-C, TAN L-H, KAMARULZAMAN A, SYED OMAR SF, FONG M-Y ET AL. ACUTE RESPIRATORY DISTRESS SYNDROME AND ACUTE RENAL FAILURE FROM PLASMODIUM OVALE INFECTION WITH FATAL OUTCOME. MALARIA JOURNAL 2013;12:389. DOI: 10.1186/1475-2875-12-389.", "literaturereference_normalized": "acute respiratory distress syndrome and acute renal failure from plasmodium ovale infection with fatal outcome", "qualification": "3", "reportercountry": "MY" }, "primarysourcecountry": "MY", "receiptdate": "20171212", "receivedate": "20171212", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14278350, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180321" } ]

{ "abstract": "A 87-year-old man was diagnosed with prostate cancer (cT2aN0M0 Gleason score 4＋4 with initial prostate specific antigen of 23.4 ng/ml). Prostate cancer was treated with combined androgen blockade (goserelin acetate plus flutamide). He was administered goserelin acetate depot injection without any complications as an outpatient. However, 5 hours after he left the hospital, he came back to the hospital, complaining of lower abdominal pain. Abdominal computed tomography revealed a giant subcutaneous hematoma in the lower abdomen. Hemoglobin was 6.9 g/dl and blood pressure was lower than 80 mmHg. He was admitted and given a blood transfusion. Because of pre-disseminated intravascular coagulation score 6, it was hard to antagonize warfarin by Vitamin K (he had taken warfarin because of atrial fibrillation). Arteriography was performed and injury to a branch of the lower epigastric artery was found. Transcatheter arterial embolization was performed at the same time. Injecting goserelin acetate may cause severe arterial injury.", "affiliations": "The Department of Urology, (the) Third Hospital of Jikei University School of Medicine, The Department of Urology, Jikei University School of Medicine.;The Department of Urology, (the) Third Hospital of Jikei University School of Medicine.;The Department of Urology, (the) Third Hospital of Jikei University School of Medicine.;The Department of Urology, (the) Third Hospital of Jikei University School of Medicine.;The Department of Urology, Jikei University School of Medicine.", "authors": "Tashiro|Kojiro|K|;Kimura|Shoji|S|;Naruoka|Takehito|T|;Furuta|Nozomu|N|;Egawa|Shin|S|", "chemical_list": "D018931:Antineoplastic Agents, Hormonal; D017273:Goserelin", "country": "Japan", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0018-1994", "issue": "60(9)", "journal": "Hinyokika kiyo. Acta urologica Japonica", "keywords": null, "medline_ta": "Hinyokika Kiyo", "mesh_terms": "D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal; D017273:Goserelin; D006406:Hematoma; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D011471:Prostatic Neoplasms; D011859:Radiography; D012771:Shock, Hemorrhagic", "nlm_unique_id": "0421145", "other_id": null, "pages": "455-8", "pmc": null, "pmid": "25293802", "pubdate": "2014-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Giant subcutaneous hematoma with hemorrhagic shock induced by goserelin acetate injection for prostate cancer : report of a case.", "title_normalized": "giant subcutaneous hematoma with hemorrhagic shock induced by goserelin acetate injection for prostate cancer report of a case" }

[ { "companynumb": "JP-ASTRAZENECA-2014SE77707", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "FLUTAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSE UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROSTATE CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUTAMIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "GOSERELIN ACETATE" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "IMPLANT", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROSTATE CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3.6", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZOLADEX" } ], "patientagegroup": null, "patientonsetage": "87", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Subcutaneous haematoma", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arterial injury", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Shock haemorrhagic", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TASHIRO K, ET AL.. GIANT SUBCUTANEOUS HEMATOMA WITH HEMORRHAGIC SHOCK INDUCED BY GOSERELIN ACETATE INJECTION FOR PROSTATE CANCER: REPORT OF A CASE.. HINYOKIKA KIYO. 2014; 60(9):455-458.", "literaturereference_normalized": "giant subcutaneous hematoma with hemorrhagic shock induced by goserelin acetate injection for prostate cancer report of a case", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20141017", "receivedate": "20141017", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10524494, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150528" }, { "companynumb": "JP-MYLANLABS-2015M1005599", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "GOSERELIN" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10.8MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROSTATE CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GOSERELIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "040415", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ATRIAL FIBRILLATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Shock haemorrhagic", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Haematoma", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "TASHIRO K, KIMURA S, NARUOKA T, FURUTA N, EGAWA S. GIANT SUBCUTANEOUS HEMATOMA WITH HEMORRHAGIC SHOCK INDUCED BY GOSERELIN ACETATE INJECTION FOR PROSTATE CANCER: REPORT OF A CASE. HINYOKIKA-KIYO 2014; 60(9):455-8.", "literaturereference_normalized": "giant subcutaneous hematoma with hemorrhagic shock induced by goserelin acetate injection for prostate cancer report of a case", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20150223", "receivedate": "20150223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10857966, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150721" } ]

{ "abstract": "BACKGROUND\nThis is the 27th Annual Report of the American Association of Poison Control Centers' (AAPCC) National Poison Data System (NPDS). As of 1 July 2009, 60 of the nation's 60 US poison centers (PCs) uploaded case data automatically. The upload time was 19.9 [9.7, 58.7] (median [25%, 75%]) minutes, creating a near real-time national exposure and information database and surveillance system.\n\n\nMETHODS\nWe analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Poison center cases with medical outcomes of death were evaluated by a team of 29 medical and clinical toxicologist reviewers using an ordinal scale of 1-6 to determine Relative Contribution to Fatality (RCF) of the exposure to the death.\n\n\nRESULTS\nIn 2009, 4,280,391 calls were captured by NPDS: 2,479,355 closed human exposures, 116,408 animal exposures, 1,677,403 information calls, 6,882 human confirmed nonexposures, and 343 animal confirmed nonexposures. The top 5 substance classes most frequently involved in all human exposures were analgesics (11.7%), cosmetics/personal care products (7.7%), household cleaning substances (7.4%), sedatives/hypnotics/antipsychotics (5.8%), and foreign bodies/toys/miscellaneous (4.3%). Analgesic exposures as a class increased the most rapidly (12,494 calls per year) over the last decade. The top 5 most common exposures in children age 5 or less were cosmetics/personal care products (13.0%), analgesics (9.7%), household cleaning substances (9.3%), foreign bodies/toys/miscellaneous (7.0%), and topical preparations (6.8%). Drug identification requests comprised 63.0% of all information calls. NPDS documented 1,544 human exposures resulting in death with 1,158 human fatalities judged related with an RCF of 1-Undoubtedly responsible, 2-Probably responsible, or 3-Contributory.\n\n\nCONCLUSIONS\nUnintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the US. The near real-time, always current status of NPDS represents a national public health resource to collect and monitor US exposure cases and information calls. The continuing mission of NPDS is to provide a nationwide infrastructure for public health surveillance for all types of exposures, public health event identification, resilience response and situational awareness tracking. NPDS is a model system for the nation and global public health.", "affiliations": "American Association of Poison Control Centers, Alexandria, VA 22314, USA. annualreport@aapcc.org", "authors": "Bronstein|Alvin C|AC|;Spyker|Daniel A|DA|;Cantilena|Louis R|LR|;Green|Jody L|JL|;Rumack|Barry H|BH|;Giffin|Sandra L|SL|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.3109/15563650.2010.543906", "fulltext": null, "fulltext_license": null, "issn_linking": "1556-3650", "issue": "48(10)", "journal": "Clinical toxicology (Philadelphia, Pa.)", "keywords": null, "medline_ta": "Clin Toxicol (Phila)", "mesh_terms": "D000818:Animals; D005260:Female; D006801:Humans; D007256:Information Systems; D008297:Male; D011039:Poison Control Centers; D011041:Poisoning; D013997:Time Factors; D014481:United States", "nlm_unique_id": "101241654", "other_id": null, "pages": "979-1178", "pmc": null, "pmid": "21192756", "pubdate": "2010-12", "publication_types": "D016428:Journal Article", "references": null, "title": "2009 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 27th Annual Report.", "title_normalized": "2009 annual report of the american association of poison control centers national poison data system npds 27th annual report" }

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null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRICHLORMETHIAZIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CITALOPRAM HYDROBROMIDE" }, "drugadditional": "4", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "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": "CITALOPRAM" } ], "patientagegroup": null, "patientonsetage": "40", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Completed suicide", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Cardio-respiratory arrest", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BRONSTEIN AC, SPYKER DA, CANTILENA LR, GREEN JL, RUMACK BH, GIFFIN SL. 2009 Annual Report of the American Association of Poison Control Centers^ National Poison Data System (NPDS): 27th Annual Report. Clinical Toxicology. 2010;48:979-1178", "literaturereference_normalized": "2009 annual report of the american association of poison control centers national poison data system npds 27th annual report", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211203", "receivedate": "20110207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 7802421, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" } ]

{ "abstract": "We report the results of a phase 2 nonrandomized single-arm trial of a combination therapy for relapsed or refractory leukemia. From January 1999 to June 2002, 28 patients with multiple relapsed or refractory acute leukemia received a combination of topotecan, vinorelbine, thiotepa, dexamethasone, and, for patients with an M3 marrow on day 7, gemcitabine. A total of 14 patients had pre-B-ALL (acute lymphoblastic leukemia), three had T-cell leukemia, nine acute myeloblastic leukemia (AML), and two biphenotypic leukemia. In all, 13 patients achieved a significant response (10 complete responses and three partial responses). Among the responders, five had pre-B-ALL, two had T-cell leukemias, five had AML, and one had biphenotypic leukemia. In total, 10 of these patients subsequently underwent hematopoietic stem cell transplantation, and four are alive without disease. One patient died, while in remission, of complications resulting from an episode of sepsis and pneumonia that occurred during topotecan, vinorelbine, thiotepa, dexamethasone, and gemcitabine (TVTG) reinduction. Other toxicities included grade 4 neutropenia in all patients and transient grade 2 hepatotoxicity in 10 patients (36%). In summary, we report that 47% of heavily pretreated pediatric patients with multiply relapsed or refractory leukemia achieved a significant response after therapy on the TVTG protocol. Further studies are warranted to evaluate the role of the TVTG combination in the treatment of leukemia.", "affiliations": "Department of Pediatrics at Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.", "authors": "Kolb|E A|EA|;Steinherz|P G|PG|", "chemical_list": "D003841:Deoxycytidine; D014747:Vinblastine; D019772:Topotecan; D003907:Dexamethasone; D013852:Thiotepa; C056507:gemcitabine; D000077235:Vinorelbine", "country": "England", "delete": false, "doi": "10.1038/sj.leu.2403097", "fulltext": null, "fulltext_license": null, "issn_linking": "0887-6924", "issue": "17(10)", "journal": "Leukemia", "keywords": null, "medline_ta": "Leukemia", "mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D002675:Child, Preschool; D003841:Deoxycytidine; D003907:Dexamethasone; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007938:Leukemia; D008297:Male; D012008:Recurrence; D013852:Thiotepa; D019772:Topotecan; D016896:Treatment Outcome; D014747:Vinblastine; D000077235:Vinorelbine", "nlm_unique_id": "8704895", "other_id": null, "pages": "1967-72", "pmc": null, "pmid": "14513046", "pubdate": "2003-10", "publication_types": "D016430:Clinical Trial; D017427:Clinical Trial, Phase II; D016428:Journal Article", "references": null, "title": "A new multidrug reinduction protocol with topotecan, vinorelbine, thiotepa, dexamethasone, and gemcitabine for relapsed or refractory acute leukemia.", "title_normalized": "a new multidrug reinduction protocol with topotecan vinorelbine thiotepa dexamethasone and gemcitabine for relapsed or refractory acute leukemia" }

[ { "companynumb": "US-PFIZER INC-2018148335", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "GRANULOCYTE COLONY-STIMULATING FACTOR NOS" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 UG/KG, DAILY (5 MCG/KG/DAY SQ, START DAY 7 AND CONTINUE UNTIL ANC}500/UL)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "008", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "G-CSF" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINORELBINE TARTRATE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "076827", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG/M2, CYCLIC (20 MG/M2/DAY I.V. PUSH, ON DAYS 0, 7, 14, 21; 1 CYCLE)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINORELBINE TARTRATE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "GEMCITABINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "078339", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC (10 MG/M2/MIN CONTINUOUS I.V. INFUSION OVER 6 H, TOTAL DOSE 3600 MG/M2/DOSE;ON DAY 7)", "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": "GEMCITABINE HYDROCHLORIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "45 MG/M2, CYCLIC (45 MG/M2/DAY P.O. OR IV DIVIDED TID, ON DAYS 7-4; 1 CYCLE)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "45", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "THIOTEPA" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "15 MG/M2, CYCLIC (15 MG/M2/DAY I.V. OVER 4 H, ON DAY 2; 1 CYCLE)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THIOTEPA." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TOPOTECAN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "200582", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG/M2, CYCLIC(1 MG/M2/DAY AS A CONTINUOUS I.V. INFUSION, ON DAYS 1-5; 1 CYCLE)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPOTECAN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "17", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute respiratory distress syndrome", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KOLB, E.. A NEW MULTIDRUG REINDUCTION PROTOCOL WITH TOPOTECAN, VINORELBINE, THIOTEPA, DEXAMETHASONE, AND GEMCITABINE FOR RELAPSED OR REFRACTORY ACUTE LEUKEMIA. LEUKEMIA. 2003?17 (10):1967-1972", "literaturereference_normalized": "a new multidrug reinduction protocol with topotecan vinorelbine thiotepa dexamethasone and gemcitabine for relapsed or refractory acute leukemia", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180413", "receivedate": "20180413", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14759754, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180711" } ]

{ "abstract": "Cyclosporine is a systemic therapy used for control of severe atopic dermatitis (AD) in children. Although traditionally recommended at a dose of 5 mg/kg/day for 6 months, a longer duration of treatment may be necessary to bring a child with active and severe disease into remission. There are few data on the short- and long-term effectiveness of longer courses of therapy. This was a retrospective chart review of children treated with cyclosporine at a Canadian hospital-affiliated clinic between 2000 and 2013. Fifteen patients with adequate follow-up were identified. Twelve (80%) were male and the mean age at initiation of cyclosporine was 11.2 ± 3.4 years. The mean duration of cyclosporine therapy was 10.9 ± 2.7 months (range 7-15 months) at a starting dose of 2.8 ± 0.6 mg/kg/day. Of 12 patients (80%) who responded to cyclosporine, 5 patients (42%) had relapsed at a follow-up of 22.7 ± 15.0 months. The duration of therapy was longer in patients who did not relapse (17.7 ± 10.7 months) than in those who did (10.2 ± 2.7 months) (p = 0.06). Adverse events led to discontinuation in three patients (20%) and included infection-related complications in two patients and reversible renal toxicity in one. These results suggest that a longer duration of low-dose cyclosporine may help decrease the risk of relapse in patients with severe AD who are resistant to topical therapies.", "affiliations": "Department of Dermatology, University of Toronto, Toronto, Ontario, Canada.", "authors": "Sibbald|Cathryn|C|;Pope|Elena|E|;Ho|Nhung|N|;Weinstein|Miriam|M|", "chemical_list": "D007166:Immunosuppressive Agents; D016572:Cyclosporine", "country": "United States", "delete": false, "doi": "10.1111/pde.12367", "fulltext": null, "fulltext_license": null, "issn_linking": "0736-8046", "issue": "32(1)", "journal": "Pediatric dermatology", "keywords": null, "medline_ta": "Pediatr Dermatol", "mesh_terms": "D000293:Adolescent; D002170:Canada; D002648:Child; D002675:Child, Preschool; D016572:Cyclosporine; D003876:Dermatitis, Atopic; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents; D007223:Infant; D008297:Male; D012008:Recurrence; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome", "nlm_unique_id": "8406799", "other_id": null, "pages": "36-40", "pmc": null, "pmid": "25059452", "pubdate": "2015", "publication_types": "D016428:Journal Article; D016454:Review", "references": null, "title": "Retrospective review of relapse after systemic cyclosporine in children with atopic dermatitis.", "title_normalized": "retrospective review of relapse after systemic cyclosporine in children with atopic dermatitis" }

[ { "companynumb": "CA-APOTEX-2015AP006791", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "065167", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DERMATITIS ATOPIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APO-CYCLOSPORINE ORAL SOLUTION" } ], "patientagegroup": null, "patientonsetage": "1", "patientonsetageunit": "800", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pharyngitis streptococcal", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Respiratory syncytial virus infection", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cellulitis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SIBBALD C, POPE E, HO N, WEINSTEIN M.. RETROSPECTIVE REVIEW OF RELAPSE AFTER SYSTEMIC CYCLOSPORINE IN CHILDREN WITH ATOPIC DERMATITIS.. PEDIATR-DERMATOL. 2015;32(1):36-40.", "literaturereference_normalized": "retrospective review of relapse after systemic cyclosporine in children with atopic dermatitis", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20150219", "receivedate": "20150219", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10833754, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" }, { "companynumb": "CA-APOTEX-2015AP006793", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "065167", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "DERMATITIS ATOPIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APO-CYCLOSPORINE ORAL SOLUTION" } ], "patientagegroup": null, "patientonsetage": "2", "patientonsetageunit": "800", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Eczema herpeticum", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SIBBALD C, POPE E, HO N, WEINSTEIN M.. RETROSPECTIVE REVIEW OF RELAPSE AFTER SYSTEMIC CYCLOSPORINE IN CHILDREN WITH ATOPIC DERMATITIS.. PEDIATR-DERMATOL. 2015;32(1):36-40.", "literaturereference_normalized": "retrospective review of relapse after systemic cyclosporine in children with atopic dermatitis", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20150221", "receivedate": "20150221", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10850115, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" } ]

{ "abstract": "Selinexor is a first-in-class selective inhibitor of nuclear export (SINE) compound with single-agent activity in soft tissue sarcoma (STS). The study's aim was to determine the safety and efficacy of selinexor in combination with doxorubicin in patients with locally advanced/metastatic STS.\n\n\n\nThis phase 1b study used a mTPI design. Patients received selinexor at either 60 or 80 mg weekly PO plus doxorubicin (75 mg/m2 IV q21 days). Patients with clinical benefit (defined as ≥stable disease via RECIST 1.1) after six cycles of combination treatment received maintenance selinexor until disease progression or unacceptable toxicity. Disease assessments were conducted every two cycles. Pharmacokinetic data were collected on the first three patients per dose level.\n\n\n\nTwenty-five patients were enrolled (20 female, ECOG 0/1: 13/12, median age 57 years [range 21-74]). Disease subtypes included leiomyosarcoma (n = 6), malignant peripheral nerve sheath tumour (n = 3) and other sarcomas (n = 16). Three (12%) and 22 (88%) patients were treated at 60 mg and 80 mg of selinexor, respectively. The most common ≥G3 drug-related adverse events (AEs) were haematological, including neutropenia (56%), febrile neutropenia (28%) and anaemia (24%). There were four dose-limiting toxicities (febrile neutropenia (x2), vomiting, fatigue) all at the 80 mg dose level. There was one death secondary to heart failure. Of the 24 evaluable patients, 5 (21%) had a partial response and 15 (63%) had SD as best response. The estimated median progression-free survival (PFS) and overall survival (OS) were 5.5 (95% CI:4.1-5.7) and 10.5 (95% CI:7.5-14) months.\n\n\n\nIn a heterogeneous group of patients with locally advanced/metastatic STS, the combination of selinexor and doxorubicin fulfilled the prespecified boundary for tolerability.", "affiliations": "Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Canada.;Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Canada.;Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Canada.;Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Canada.;Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Canada.;Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Canada.;Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Canada.;Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Canada. Electronic address: albiruni.razak@uhn.ca.", "authors": "Lewin|Jeremy|J|;Malone|Eoghan|E|;Al-Ezzi|Esmail|E|;Fasih|Samir|S|;Pedersen|Pernille|P|;Accardi|Sarah|S|;Gupta|Abha|A|;Abdul Razak|Albiruni|A|", "chemical_list": "D006834:Hydrazines; D014230:Triazoles; C585161:selinexor; D004317:Doxorubicin", "country": "England", "delete": false, "doi": "10.1016/j.ejca.2020.10.032", "fulltext": null, "fulltext_license": null, "issn_linking": "0959-8049", "issue": "144()", "journal": "European journal of cancer (Oxford, England : 1990)", "keywords": "Doxorubicin; Small molecule; Soft tissue sarcoma; XPO-1", "medline_ta": "Eur J Cancer", "mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D004317:Doxorubicin; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006834:Hydrazines; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D065228:Non-Randomized Controlled Trials as Topic; D011379:Prognosis; D012509:Sarcoma; D014018:Tissue Distribution; D014230:Triazoles", "nlm_unique_id": "9005373", "other_id": null, "pages": "360-367", "pmc": null, "pmid": "33418486", "pubdate": "2021-02", "publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "A phase 1b trial of selinexor, a first-in-class selective inhibitor of nuclear export (SINE), in combination with doxorubicin in patients with advanced soft tissue sarcomas (STS).", "title_normalized": "a phase 1b trial of selinexor a first in class selective inhibitor of nuclear export sine in combination with doxorubicin in patients with advanced soft tissue sarcomas sts" }

[ { "companynumb": "CA-BAXTER-2021BAX002017", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "SELINEXOR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DL=1 (3 PATIENTS)", "drugenddate": null, "drugenddateformat": null, "drugindication": "LEIOMYOSARCOMA METASTATIC", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SELINEXOR" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "SELINEXOR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DL=2 (22 PATIENTS)", "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": "SELINEXOR" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOXORUBICIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "050718", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": "MAX 6 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "LEIOMYOSARCOMA METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXIL" } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cerebrovascular accident", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac failure", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Endocarditis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LEWIN J, MALONE E, AL?EZZI E, FASIH S, PEDERSEN P, ACCARDI S, GUPTA A, RAZAK A. A PHASE 1B TRIAL OF SELINEXOR, A FIRST?IN?CLASS SELECTIVE INHIBITOR OF NUCLEAR EXPORT (SINE), IN COMBINATION WITH DOXORUBICIN IN PATIENTS WITH ADVANCED SOFT TISSUE SARCOMAS (STS). EUROPEAN JOURNAL OF CANCER. 2021?144:360?367.", "literaturereference_normalized": "a phase 1b trial of selinexor a first in class selective inhibitor of nuclear export sine in combination with doxorubicin in patients with advanced soft tissue sarcomas sts", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20210210", "receivedate": "20210129", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18812204, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210419" }, { "companynumb": "CA-PFIZER INC-2021028866", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOXORUBICIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "050467", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": "330", "drugcumulativedosageunit": "003", "drugdosageform": "POWDER FOR SOLUTION FOR INJECTION", "drugdosagetext": "75 MG/M2, CYCLIC (INTRAVENOUS PUSH ONCE EVERY 21 DAYS FOR SIX CYCLES, CUMULATIVE DOXORUBICIN DOSE OF", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN HCL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "SELINEXOR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "80 MG, WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SELINEXOR" } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiac failure", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "LEWIN, J.. A PHASE 1B TRIAL OF SELINEXOR, A FIRST?IN?CLASS SELECTIVE INHIBITOR OF NUCLEAR EXPORT (SINE), IN COMBINATION WITH DOXORUBICIN IN PATIENTS WITH ADVANCED SOFT TISSUE SARCOMAS (STS). EUROPEAN JOURNAL OF CANCER. 2021?144:360?367", "literaturereference_normalized": "a phase 1b trial of selinexor a first in class selective inhibitor of nuclear export sine in combination with doxorubicin in patients with advanced soft tissue sarcomas sts", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20210121", "receivedate": "20210121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18769202, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210419" } ]

{ "abstract": "Infectious complications in patients with multiple myeloma remain the main cause of mortality because of disease-related immunodeficiency. A mycotic aortic aneurysm caused by Burkhoderia cepacia, which has been recognized as nosocomial pathogen in immunocompromised populations, is very rare and only few cases have been reported in the literature. We describe an unusual case of a ruptured mycotic aneurysm of the descending thoracic aorta with a DeBakey IIIb aortic dissection caused by Burkhoderia cepacia in a patient with active multiple myeloma during chemotherapy with anti-myeloma agents. Successful treatment of this mycotic aneurysm included appropriate antibiotic therapy and replacement of the aortic arch and the descending aorta for the extensive debridement of all infected aortas. This was followed by the wrapping of a prosthetic graft with a well-vascularized tissue flap of the greater omentum and of the latissimus dorsi muscle.", "affiliations": "Department of Cardiovascular Surgery, National Hospital Organization Osaka Minami Medical Center, 2-1, Kidohigashi, Kawachinagano, Osaka, 586-8521, Japan. maru1616@yahoo.co.jp.;Department of Cardiovascular Surgery, National Hospital Organization Osaka Minami Medical Center, 2-1, Kidohigashi, Kawachinagano, Osaka, 586-8521, Japan.", "authors": "Marumoto|Akira|A|;Iwata|Keiji|K|", "chemical_list": "D000970:Antineoplastic Agents", "country": "Japan", "delete": false, "doi": "10.1007/s11748-014-0415-9", "fulltext": null, "fulltext_license": null, "issn_linking": "1863-6705", "issue": "64(3)", "journal": "General thoracic and cardiovascular surgery", "keywords": "Immunocompromised patient; Multiple myeloma; Mycotic aneurysm", "medline_ta": "Gen Thorac Cardiovasc Surg", "mesh_terms": "D000368:Aged; D000784:Aneurysm, Dissecting; D000785:Aneurysm, Infected; D000970:Antineoplastic Agents; D001014:Aortic Aneurysm; D017545:Aortic Aneurysm, Thoracic; D019121:Burkholderia Infections; D016956:Burkholderia cepacia; D005260:Female; D006801:Humans; D021621:Imaging, Three-Dimensional; D008279:Magnetic Resonance Imaging; D009101:Multiple Myeloma; D049268:Positron-Emission Tomography; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "101303952", "other_id": null, "pages": "163-6", "pmc": null, "pmid": "24890088", "pubdate": "2016-03", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "20978578;17905558;22919575;17098542;17976443;21548997;2241378;21674309;16275935;19769539;12042739", "title": "Rupture of an extended mycotic aneurysm of the descending thoracic aorta in a multiple myeloma patient undergoing anti-myeloma therapy.", "title_normalized": "rupture of an extended mycotic aneurysm of the descending thoracic aorta in a multiple myeloma patient undergoing anti myeloma therapy" }

[ { "companynumb": "JP-TAKEDA-2016MPI002780", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BORTEZOMIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021602", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Injection", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VELCADE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISOLONE\\PREDNISOLONE ACETATE\\PREDNISOLONE SODIUM SUCCINATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDONINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "INFECTION PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SULFAMETHOXAZOLE-TRIMETHOPRIM (SMZ)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ACYCLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "INFECTION PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACICLOVIR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ITRACONAZOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "INFECTION PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ITRIZOLE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN" } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Infective aneurysm", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Aortic rupture", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "MARUMOTO A, IWATA K. RUPTURE OF AN EXTENDED MYCOTIC ANEURYSM OF THE DESCENDING THORACIC AORTA IN A MULTIPLE MYELOMA PATIENT UNDERGOING ANTI-MYELOMA THERAPY. GENERAL THORACIC AND CARDIOVASCULAR SURGERY. 2016;64(3):163-166", "literaturereference_normalized": "rupture of an extended mycotic aneurysm of the descending thoracic aorta in a multiple myeloma patient undergoing anti myeloma therapy", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20160412", "receivedate": "20160412", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12258034, "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": "The emergence of resistance to polymyxins in KPC-producing Klebsiella pneumoniae isolates has been a major clinical problem. This study evaluated the molecular mechanisms associated with polymyxin B (PMB) resistance that emerged in a previously PMB-susceptible KPC-2-producing K. pneumoniae during PMB therapy for a bloodstream infection in a neutropenic patient. The first isolate (PMB-susceptible) was obtained while the patient was receiving meropenem and other isolates were recovered from 2 sets of blood cultures in different dates while the patient was receiving PMB therapy (4 of 6 blood cultures bottles yielded isolates with full PMB resistance). The population analysis profile of the first isolate revealed the growth of resistant subpopulations with PFGE profile distinct from the parental isolate but undistinguishable from those obtained in subsequent days under PMB exposure. Resistant subpopulations were obtained from all parental PMB-susceptible and in one PMB-resistant isolate recovered from the patient. The molecular mechanism observed in the hetero-resistant subpopulations (IS1-like in mgrB-promoter region, increased rstB transcription with no mutation and non-identified mechanism) differed from those found in the PMB-resistant isolates, in which no mutation or transcriptional alterations were detected. This study showed that the mechanism of resistance to PMB that emerged during PMB therapy was not related to those observed in subpopulations selected in vitro from PMB-susceptible isolates recovered from the patient. The absence of mutations in the former isolates may be due to adaptive resistance occurred because of sub-optimal PMB levels as well as amikacin and meropenem used in combination.", "affiliations": "Infectious Diseases Service, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil; Department of Internal Medicine, Medical School, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.;Laboratório Alerta, Division of Infectious Diseases, Departament of Internal Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM/UNIFESP), São Paulo, Brazil. Electronic address: raquelgirardello@gmail.com.;Laboratório de Pesquisa em Resistência Bacteriana (LABRESIS), Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Programa de Pós Graduação em Ciências Médicas, Faculdade de Medicina, Porto Alegre, Brazil.;Laboratório de Pesquisa em Resistência Bacteriana (LABRESIS), Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Programa de Pós Graduação em Ciências Médicas, Faculdade de Medicina, Porto Alegre, Brazil.;Infectious Diseases Service, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil.;Laboratório Alerta, Division of Infectious Diseases, Departament of Internal Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM/UNIFESP), São Paulo, Brazil.;Laboratório Alerta, Division of Infectious Diseases, Departament of Internal Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM/UNIFESP), São Paulo, Brazil.", "authors": "Zavascki|Alexandre P|AP|;Girardello|Raquel|R|;Magagnin|Cibele M|CM|;Antochevis|Laura C|LC|;Maciel|Rafael A|RA|;Palmeiro|Jussara K|JK|;Gales|Ana C|AC|", "chemical_list": "D011112:Polymyxin B", "country": "United States", "delete": false, "doi": "10.1016/j.diagmicrobio.2017.10.006", "fulltext": null, "fulltext_license": null, "issn_linking": "0732-8893", "issue": "90(2)", "journal": "Diagnostic microbiology and infectious disease", "keywords": "Colistin; Gram-negative bacilli; Hetero-resistance; Klebsiella pneumoniae carbapenemase; Polymyxins; Resistance; Therapy", "medline_ta": "Diagn Microbiol Infect Dis", "mesh_terms": "D000293:Adolescent; D016470:Bacteremia; D024881:Drug Resistance, Bacterial; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007710:Klebsiella Infections; D007711:Klebsiella pneumoniae; D058889:Molecular Typing; D009503:Neutropenia; D011112:Polymyxin B", "nlm_unique_id": "8305899", "other_id": null, "pages": "134-138", "pmc": null, "pmid": "29150371", "pubdate": "2018-02", "publication_types": "D016428:Journal Article", "references": null, "title": "Emergence of polymyxin B resistance in a polymyxin B-susceptible KPC-producing Klebsiella pneumoniae causing bloodstream infection in a neutropenic patient during polymyxin B therapy.", "title_normalized": "emergence of polymyxin b resistance in a polymyxin b susceptible kpc producing klebsiella pneumoniae causing bloodstream infection in a neutropenic patient during polymyxin b therapy" }

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"drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC THERAPY", "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": null, "activesubstance": { "activesubstancename": "TIGECYCLINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MG LOADING DOSE FOLLOWED BY 100 MG EVERY 12 HOURS", "drugenddate": null, "drugenddateformat": null, "drugindication": "KLEBSIELLA INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIGECYCLINE." }, { "actiondrug": null, "activesubstance": null, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMPHOTERICIN B/AMPHOTERICIN B/LIPOSOME" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CEFEPIME HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFEPIME" }, { "actiondrug": 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"reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ZAVASCKI AP, GIRARDELLO R, MAGAGNIN CM, ANTOCHEVIS LC, MACIEL RA, PALMEIRO JK, ET AL. EMERGENCE OF POLYMYXIN B RESISTANCE IN A POLYMYXIN B-SUSCEPTIBLE KPC-PRODUCING KLEBSIELLA PNEUMONIAE CAUSING BLOODSTREAM INFECTION IN A NEUTROPENIC PATIENT DURING POLYMYXIN B THERAPY. DIAGN MICROBIOL INFECT DIS. 19-OCT-2017.", "literaturereference_normalized": "emergence of polymyxin b resistance in a polymyxin b susceptible kpc producing klebsiella pneumoniae causing bloodstream infection in a neutropenic patient during polymyxin b therapy", "qualification": "3", "reportercountry": "BR" }, "primarysourcecountry": "BR", "receiptdate": "20171202", "receivedate": "20171202", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14245070, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180321" } ]

{ "abstract": "Neurosarcoidosis, either isolated or as part of systemic sarcoidosis, is an uncommon entity and has diagnostic uncertainty. Treatment for neurosarcoidosis can increase the risk of infections, including fungal infections such as disseminated histoplasmosis. Neurosarcoidosis may further predispose patients to infections of the central nervous system.\nA 54-year-old male with a history of probable neurosarcoidosis on methotrexate and infliximab presented with encephalopathy, hypoxia, and reported fevers. The patient was found to have disseminated histoplasmosis involving the lungs (miliary histoplasmosis), central nervous system (neurohistoplasmosis), and bloodstream. The Histoplasma capsulatum infection was treated with amphotericin and then voriconazole.\nPatients with neurosarcoidosis are suspected to have blood-brain barrier dysfunction. Lumbar puncture should be considered as part of initial investigative studies for infection. Empiric antimicrobial therapy for a patient with neurosarcoidosis on immunosuppressive agents may need to include antifungal agents.", "affiliations": "Department of Emergency Medicine, University of Michigan, Ann Arbor, MI, USA.", "authors": "Bui|Peter V|PV|0000-0001-5398-2501", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1155/2018/3162403", "fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi 10.1155/2018/3162403Case ReportDisseminated Histoplasmosis with Miliary Histoplasmosis, Neurohistoplasmosis, and Histoplasma capsulatum Bacteremia in Probable Neurosarcoidosis http://orcid.org/0000-0001-5398-2501Bui Peter V. buipe@med.umich.eduDepartment of Emergency Medicine, University of Michigan, Ann Arbor, MI, USAAcademic Editor: Masahiro Kohzuki\n\n2018 11 12 2018 2018 316240317 8 2018 26 11 2018 Copyright © 2018 Peter V. Bui.2018This 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.Introduction\n Neurosarcoidosis, either isolated or as part of systemic sarcoidosis, is an uncommon entity and has diagnostic uncertainty. Treatment for neurosarcoidosis can increase the risk of infections, including fungal infections such as disseminated histoplasmosis. Neurosarcoidosis may further predispose patients to infections of the central nervous system. \n\nCase Presentation\n A 54-year-old male with a history of probable neurosarcoidosis on methotrexate and infliximab presented with encephalopathy, hypoxia, and reported fevers. The patient was found to have disseminated histoplasmosis involving the lungs (miliary histoplasmosis), central nervous system (neurohistoplasmosis), and bloodstream. The Histoplasma capsulatum infection was treated with amphotericin and then voriconazole. \n\nDiscussion\n Patients with neurosarcoidosis are suspected to have blood-brain barrier dysfunction. Lumbar puncture should be considered as part of initial investigative studies for infection. Empiric antimicrobial therapy for a patient with neurosarcoidosis on immunosuppressive agents may need to include antifungal agents.\n==== Body\n1. Introduction\nNeurological symptoms occur in approximately 5% of patients with sarcoidosis [1–3]. Because of the complexity involved in diagnosing neurosarcoidosis, particularly isolated neurosarcoidosis, Zajicek et al. proposed criteria for definite, probable, and possible neurosarcoidosis (Table 1) [4].\n\nFor patients with sarcoidosis, risk factors for severe infections, defined as infections leading to hospitalization or death or requiring intravenous antibiotics, included neurologic symptoms, cardiac symptoms, or immunosuppressant use [5]. These infections can include fungal infections, even disseminated histoplasmosis [5–9]. We present the case of a patient diagnosed with probable neurosarcoidosis who subsequently developed disseminated histoplasmosis with miliary histoplasmosis, central nervous system histoplasmosis (neurohistoplasmosis), and Histoplasma capsulatum bacteremia. In our review of the English medical literature, we did not identify any additional cases of extensive multisystem infection with Histoplasma capsulatum in a patient with neurosarcoidosis.\n\n2. Case Presentation\nA 54-year-old male with a history of probable neurosarcoidosis, lymphocytic leptomeningitis, seizures, cirrhosis, and possible ethanol use disorder presented with encephalopathy, hypoxia, and several weeks of reported intermittent fevers. For the treatment of neurosarcoidosis, he was taking mycophenolate 1000 mg orally twice a day and last received an infliximab infusion the month prior to presentation.\n\nApproximately seventeen months prior to presentation, the patient underwent extensive investigation for ataxia, near syncope, and encephalopathy, during which he received empiric treatment for encephalitis with corticosteroids, although herpes simplex virus studies were negative. Magnetic resonance imaging of the brain and spine from the cervical spinal cord to the lumbar spinal cord found leptomeningeal enhancement. Cerebral spinal fluid (CSF) found 24 white blood cells/mm3 (reference range 0–5 cells/mm3) with 83% lymphocytes (reference range 0–60%), 8 red blood cells/mm3 (reference range 0–0 cells/mm3), glucose of 35 mg/dL (reference range 40–70 mg/dL), protein of 247.6 mg/dL (reference range 15–45 mg/dL), and no oligoclonal bands. Biopsies of the brain and meninges found leptomeningeal fibrosis with prominent arachnoid cap cells. Chest imaging and fluorodeoxyglucose-positron emission tomography found nonspecific pulmonary nodules and hilar lymphadenopathy. Additional unremarkable studies included bone marrow biopsies, lung biopsies, and sinus biopsies. No infectious pathogens, including Histoplasma, or neoplastic processes were identified.\n\nEleven months prior to presentation, the patient presented with encephalopathy. He was thought to have lymphocytic leptomeningitis. Serum and CSF angiotensin-converting enzymes (ACE) were normal. CSF studies found 21 white blood cells/mm3 (no reference range) with 91% lymphocytes (no reference range), 1 red blood cell/mm3 (no reference range), glucose of 39 mg/dL (50–70 mg/dL), and protein of 188 mg/dL (15–45 mg/dL). Investigations for infectious pathogens, including serum and CSF fungal studies such as for histoplasmosis, and neoplastic processes were negative. He received intravenous immunoglobulins and corticosteroids for an unclear autoimmune disease. A month later, his neurology providers thought his symptoms and studies were consistent with probable neurosarcoidosis and proceeded with treatment using mycophenolate and infliximab. Six months prior to presentation, he developed keratitis and uveitis.\n\nVital signs at presentation were temperature of 36.4°C, blood pressure of 80 mmHg/52 mmHg, heart rate of 93 beats per minute, respiratory rate of 24 breaths per minute, and oxygen saturation of 91% on 10 liters per minute of supplemental oxygen. Conventional chest radiography (Figure 1) found a diffuse miliary pattern, which was also identified on subsequent computed tomography of the chest. CSF studies found 1 white blood cell/mm3 (no reference range) with 95% lymphocytes (no reference range), 1 red blood cell/mm3 (no reference range), glucose of 28 mg/dL (50–70 mg/dL), and protein of 53 mg/dL (15–45 mg/dL).\n\nThe patient received empiric vancomycin, piperacillin/tazobactam, and amphotericin for possible bacterial and fungal infections. He underwent endotracheal intubation for acute hypoxic respiratory failure and was extubated approximately one week later. Urine, serum, and CSF antigen studies were positive for histoplasmosis and blastomycosis, but the positive studies for blastomycosis were thought to be secondary to cross-reactivity. Respiratory culture obtained via bronchoscopy grew Histoplasma capsulatum. Fungal blood culture grew Histoplasma capsulatum. Bone marrow biopsy, obtained after the administration of antibacterial and antifungal agents, found hemophagocytosis that was thought to be consistent with the diagnosis of disseminated histoplasmosis, although the bone marrow culture had no growth of pathogens. For treatment of disseminated histoplasmosis, he completed a course of amphotericin, was briefly on itraconazole, and was transitioned to voriconazole, on which he was eventually discharged after a month-long hospitalization. Pneumocystis jirovecii polymerase chain reaction study of the bronchoalveolar lavage was positive for which he received a complete course of trimethoprim-sulfamethoxazole, although suspicion for pneumocystis pneumonia was low. The patient's hospital course was complicated by acute kidney injury, aspiration pneumonia, and Pseudomonas aeruginosa pneumonia.\n\n3. Discussion\nThis patient was diagnosed with probable neurosarcoidosis. Evidence of systemic sarcoidosis in this patient included hilar lymphadenopathy and a history of uveitis and keratitis, although these findings do not conform to all the proposed criteria of Zajicek et al. for the diagnosis of neurosarcoidosis [4, 10]. Central nervous system studies suggestive of neurosarcoidosis included leptomeningeal enhancement, elevated proteins in the CSF, and CSF lymphocytic pleocytosis [2, 4, 11]. No oligoclonal bands were found. Serum ACE, which can be elevated in sarcoidosis, was normal. [4] CSF ACE was normal but lacks clinical utility in the diagnosis of neurosarcoidosis [12, 13]. Extensive studies during multiple hospitalizations did not find alternative infectious and neoplastic pathologies to fully account for the patient's symptoms and findings, thereby lending credence to neurosarcoidosis as a diagnosis of exclusion. Additionally, the patient had clinical improvement on methotrexate and infliximab and previously corticosteroids, which are typical treatments for neurosarcoidosis [2, 11, 14].\n\nOur patient developed disseminated histoplasmosis involving the central nervous system, lungs, and bloodstream. Taking methotrexate and infliximab had predisposed him to disseminated histoplasmosis. Furthermore, the blood-brain barrier is thought to be dysfunctional in neurosarcoidosis, a factor which likely contributed to neurohistoplasmosis in our patient [4]. Clinicians should consider fungal studies and empiric antifungal treatment in patients with neurosarcoidosis on immunosuppressants. In a patient with neurosarcoidosis with suspected infection, because of the blood-brain barrier dysfunction, early lumbar puncture may be beneficial to confirm or exclude central nervous system involvement even if another infectious source is identified.\n\nEthical Approval\nCase reports do not require the review and approval of the Institutional Review Board of the University of Michigan. The clinical data and radiographic images presented in this manuscript do not disclose the identity of the patient.\n\nConflicts of Interest\nThe author declares that there are no conflicts of interest. The views expressed in this manuscript do not communicate an official position of the University of Michigan.\n\nFigure 1 Conventional chest radiography obtained at the initial presentation found a diffuse miliary pattern. (a) Posterior-anterior view. (b) Lateral view.\n\nTable 1 Proposed diagnostic criteria for neurosarcoidosis [4].\n\nDefinite\tClinical presentation suggestive of neurosarcoidosis with exclusion of other possible diagnoses and the presence of positive nervous system histology\t\n\n\n\t\nProbable\tClinical syndrome suggestive of neurosarcoidosis with laboratory support for central nervous system inflammation (elevated levels of cerebrospinal fluid protein and/or cells, the presence of oligoclonal bands, and/or magnetic resonance imaging evidence compatible with neurosarcoidosis) and exclusion of alternative diagnoses together with evidence for systemic sarcoidosis (either through positive histology, including Kveim test and/or at least two indirect indicators from gallium scan, chest imaging, and serum angiotensin converting enzyme)\t\n\n\n\t\nPossible\tClinical presentation suggestive of neurosarcoidosis with exclusion of alternative diagnoses where the above criteria are not met\n==== Refs\n1 Baughman R. P. Teirstein A. S. Judson M. A. Clinical characteristics of patients in a case control study of sarcoidosis American Journal of Respiratory and Critical Care Medicine 2001 164 10 1885 1889 10.1164/ajrccm.164.10.2104046 2-s2.0-0035891579 11734441 \n2 Fritz D. van de Beek D. Brouwer M. C. Clinical features, treatment and outcome in neurosarcoidosis: systematic review and meta-analysis BMC Neurology 2016 16 1 p. 220 10.1186/s12883-016-0741-x 2-s2.0-84995459638 \n3 Stern B. J. Krumholz A. Johns C. Scott P. Nissim J. Sarcoidosis and its neurological manifestations Archives of Neurology 1985 42 9 909 917 10.1001/archneur.1985.04060080095022 2-s2.0-0021889161 3896208 \n4 Zajicek J. P. Scolding N. J. Foster O. Central nervous system sarcoidosisdiagnosis and management QJM 1999 92 2 103 117 10.1093/qjmed/92.2.103 10209662 \n5 Duréault A. Chapelon C. Biard L. Severe infections in sarcoidosis Medicine 2017 96 49 e8846 10.1097/md.0000000000008846 2-s2.0-85038641350 \n6 Badesha P. S. Saklayen M. G. Hillman N. Diffuse Histoplasmosis in a patient with sarcoidosis Postgraduate Medical Journal 1997 73 856 101 103 10.1136/pgmj.73.856.101 2-s2.0-0031044407 9122085 \n7 Baughman R. P. Lower E. E. Fungal infections as a complication of therapy for sarcoidosis QJM: An International Journal of Medicine 2005 98 6 451 456 10.1093/qjmed/hci073 2-s2.0-20444430052 15879444 \n8 Israel H. L. DeLamater E. Sones M. Willis W. D. Mirmelstein A. An investigation of the relationship of chronic disseminated histoplasmosis and sarcoidosis Bulletin of the New York Academy of Medicine 1951 27 6 403 404 14839394 \n9 Tebib J. G. Piens M. A. Guillaux M. Colomb D. Garin J. P. Tete R. Sarcoidosis possibly predisposing to disseminated histoplasmosis Thorax 1988 43 1 73 74 10.1136/thx.43.1.73 2-s2.0-0023874714 3353879 \n10 Koczman J. J. Rouleau J. Gaunt M. Kardon R. H. Wall M. Lee A. G. Neuro-ophthalmic sarcoidosis: the University of Iowa experience Seminars in Ophthalmology 2009 23 3 157 168 10.1080/08820530802007382 2-s2.0-42449146661 \n11 Cação G. Branco A. Meireles M. Neurosarcoidosis according to Zajicek and Scolding criteria: 15 probable and definite cases, their treatment and outcomes Journal of the Neurological Sciences 2017 379 84 88 10.1016/j.jns.2017.05.055 2-s2.0-85020035213 28716286 \n12 Bridel C. Courvoisier D. S. Vuilleumier N. Lalive P. H. Cerebrospinal fluid angiotensin-converting enzyme for diagnosis of neurosarcoidosis Journal of Neuroimmunology 2015 285 1 3 10.1016/j.jneuroim.2015.05.020 2-s2.0-84943256646 26198911 \n13 Khoury J. Wellik K. E. Demaerschalk B. M. Wingerchuk D. M. Cerebrospinal fluid angiotensin-converting enzyme for diagnosis of central nervous system sarcoidosis Neurologist 2009 15 2 108 111 10.1097/nrl.0b013e31819bcf84 2-s2.0-63449131224 19276791 \n14 Wegener S. Linnebank M. Martin R. Valavanis A. Weller M. Clinically isolated neurosarcoidosis: a recommended diagnostic path European Neurology 2014 73 1-2 71 77 10.1159/000366199 2-s2.0-84927911315 25401278\n\n", "fulltext_license": "CC BY", "issn_linking": null, "issue": "2018()", "journal": "Case reports in medicine", "keywords": null, "medline_ta": "Case Rep Med", "mesh_terms": null, "nlm_unique_id": "101512910", "other_id": null, "pages": "3162403", "pmc": null, "pmid": "30651732", "pubdate": "2018", "publication_types": "D002363:Case Reports", "references": "10209662;11734441;14839394;15879444;18432542;19276791;25401278;26198911;27846819;28716286;29245251;3353879;3896208;9122085", "title": "Disseminated Histoplasmosis with Miliary Histoplasmosis, Neurohistoplasmosis, and Histoplasma capsulatum Bacteremia in Probable Neurosarcoidosis.", "title_normalized": "disseminated histoplasmosis with miliary histoplasmosis neurohistoplasmosis and histoplasma capsulatum bacteremia in probable neurosarcoidosis" }

[ { "companynumb": "US-SAMSUNG BIOEPIS-SB-2019-00745", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUROSARCOIDOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INFLIXIMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUROSARCOIDOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUROSARCOIDOSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE" } ], "patientagegroup": null, "patientonsetage": "54", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Histoplasmosis disseminated", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia pseudomonal", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumocystis jirovecii pneumonia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia aspiration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BUI P. DISSEMINATED HISTOPLASMOSIS WITH MILIARY HISTOPLASMOSIS, NEUROHISTOPLASMOSIS, AND HISTOPLASMA CAPSULATUM BACTEREMIA IN PROBABLE NEUROSARCOIDOSIS. 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DISSEMINATED HISTOPLASMOSIS WITH MILIARY HISTOPLASMOSIS, NEUROHISTOPLASMOSIS, AND HISTOPLASMA CAPSULATUM BACTEREMIA IN PROBABLE NEUROSARCOIDOSIS. CASE REPORTS IN MEDICINE 2018?10.1155/2018/3162403.", "literaturereference_normalized": "disseminated histoplasmosis with miliary histoplasmosis neurohistoplasmosis and histoplasma capsulatum bacteremia in probable neurosarcoidosis", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190201", "receivedate": "20190201", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15901328, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "US-ACCORD-104289", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "065416", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MG ORALLY TWICE A DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUROSARCOIDOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUROSARCOIDOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUROSARCOIDOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INFLIXIMAB" } ], "patientagegroup": null, "patientonsetage": "54", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pneumonia pseudomonal", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumocystis jirovecii infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia aspiration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Histoplasmosis disseminated", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BUI PV. DISSEMINATED HISTOPLASMOSIS WITH MILIARY HISTOPLASMOSIS, NEUROHISTOPLASMOSIS, AND HISTOPLASMA CAPSULATUM BACTEREMIA IN PROBABLE NEUROSARCOIDOSIS. CASE REP MED. 2018 DEC 11?2018:3162403.", "literaturereference_normalized": "disseminated histoplasmosis with miliary histoplasmosis neurohistoplasmosis and histoplasma capsulatum bacteremia in probable neurosarcoidosis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190201", "receivedate": "20190201", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15898696, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "US-MEDAC PHARMA, INC.-2062232", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "205776", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUROSARCOIDOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "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": "INFLIXIMAB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": "048", "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": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." } ], "patientagegroup": null, "patientonsetage": "54", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Histoplasmosis disseminated", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BUI PV. DISSEMINATED HISTOPLASMOSIS WITH MILIARY HISTOPLASMOSIS, NEUROHISTOPLASMOSIS, AND HISTOPLASMA CAPSULATUM BACTEREMIA IN PROBABLE NEUROSARCOIDOSIS. CASE REP MED. 2018?2018:3162403. PUBLISHED 2018 DEC 11. DOI:10.1155/2018/3162403", "literaturereference_normalized": "disseminated histoplasmosis with miliary histoplasmosis neurohistoplasmosis and histoplasma capsulatum bacteremia in probable neurosarcoidosis", "qualification": "1", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": null, "receiptdate": "20190206", "receivedate": "20190206", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 15929279, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20190417" } ]

{ "abstract": "Although few recent studies have reported efficacy and safety data among patients with multiple sclerosis (MS) switching between immunotherapies, data on the mechanism of rebound activity postwithdrawal of fingolimod in patients with MS is scarce. A 36-year-old woman developed severe reactivation of her disease within 7 weeks of fingolimod's withdrawal despite the absence of breakthrough disease during the 8-week natalizumab washout period previously. The clinical presentation and radiological features were described indicating the diagnostic challenge given the potential risk of developing progressive multifocal leucoencephalopathy. The severe reactivation postwithdrawal of fingolimod could be due to the immune reconstitution inflammatory syndrome (IRIS) given the abrupt rise in lymphocyte count. Patients who discontinued fingolimod might be at risk of developing IRIS resulting in disease reactivation in the washout period.", "affiliations": "Division of Neurology, Department of Medicine, Amiri Hospital, Kuwait City, Kuwait Neurology Clinic, Dasman Diabetes Institute, Kuwait City, Kuwait.;Division of Neurology, Department of Medicine, Amiri Hospital, Kuwait City, Kuwait.;Division of Neurology, Department of Medicine, Amiri Hospital, Kuwait City, Kuwait.;Division of Neurology, Department of Medicine, Amiri Hospital, Kuwait City, Kuwait Neurology Clinic, Dasman Diabetes Institute, Kuwait City, Kuwait.", "authors": "Alroughani|R|R|http://orcid.org/0000-0001-5436-5804;Almulla|A|A|;Lamdhade|S|S|;Thussu|A|A|", "chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D007166:Immunosuppressive Agents; D000069442:Natalizumab; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine", "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": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D004334:Drug Administration Schedule; D005260:Female; D000068876:Fingolimod Hydrochloride; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome; D007166:Immunosuppressive Agents; D009103:Multiple Sclerosis; D000069442:Natalizumab; D011409:Propylene Glycols; D012008:Recurrence; D013110:Sphingosine", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "25320259", "pubdate": "2014-10-15", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "20937940;23915113;21499099;20661928;23161460;21832229;21628899;20697980;20298967;18987352;22054236;24610329;21625938;21431380;24566807;16634029;22332194;21543733;22829326;24136456;24124371;23493158", "title": "Multiple sclerosis reactivation postfingolimod cessation: is it IRIS?", "title_normalized": "multiple sclerosis reactivation postfingolimod cessation is it iris" }

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"drugindication": "MULTIPLE SCLEROSIS", "drugintervaldosagedefinition": "802", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "20110124", "drugstartdateformat": "102", "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TYSABRI" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DALFAMPRIDINE" }, "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, 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"drugtreatmentdurationunit": null, "medicinalproduct": "METHYL PREDNISOLONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RISPERIDONE" }, "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": "2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERDAL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MEMANTINE 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": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EBIXA" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FINGOLIMOD HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "201401", "drugenddateformat": "610", "drugindication": "MULTIPLE SCLEROSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "201306", "drugstartdateformat": "610", "drugstructuredosagenumb": "0", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GILENYA" } ], "patientagegroup": "5", "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Multiple sclerosis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Coma", "reactionmeddraversionpt": "18.0", "reactionoutcome": "3" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20140422" } }, "primarysource": { "literaturereference": "ALROUGHANI R, ALMULLA A, LAMDHADE S, THUSSU A. MULTIPLE SCLEROSIS REACTIVATION POSTFINGOLIMOD CESSATION: IS IT IRIS? BMJ CASE REP. 2014 OCT 15;2014. PII: BCR2014206314. DOI: 10.1136/BCR-2014-206314.", "literaturereference_normalized": "multiple sclerosis reactivation postfingolimod cessation is it iris", "qualification": "1", "reportercountry": "KW" }, "primarysourcecountry": "KW", "receiptdate": "20141107", "receivedate": "20140523", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10190664, "safetyreportversion": 5, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150528" } ]

{ "abstract": "Flecainide pill-in-the-pocket therapy is a pharmacologic treatment option for patients with infrequent episodes of symptomatic atrial fibrillation. We report a case of wide complex tachycardia due to atrial flutter with 1:1 atrioventricular conduction in a patient who took pill-in-the-pocket flecainide without concomitant atrioventricular nodalblockade.", "affiliations": "Northwestern University Feinberg School of Medicine, Chicago, IL. Electronic address: jordan.gavin@northwestern.edu.;Northwestern University Feinberg School of Medicine, Chicago, IL.;Northwestern University Feinberg School of Medicine, Chicago, IL.", "authors": "Gavin|Jordan L|JL|;Peigh|Graham S|GS|;Kim|Susan S|SS|", "chemical_list": "D000889:Anti-Arrhythmia Agents; D005424:Flecainide", "country": "Netherlands", "delete": false, "doi": "10.1016/j.ejim.2020.09.014", "fulltext": null, "fulltext_license": null, "issn_linking": "0953-6205", "issue": "81()", "journal": "European journal of internal medicine", "keywords": "atrial fibrillation; electrocardiogram; flecainide", "medline_ta": "Eur J Intern Med", "mesh_terms": "D000889:Anti-Arrhythmia Agents; D001281:Atrial Fibrillation; D001282:Atrial Flutter; D004562:Electrocardiography; D005424:Flecainide; D006801:Humans; D013610:Tachycardia", "nlm_unique_id": "9003220", "other_id": null, "pages": "89-90", "pmc": null, "pmid": "32980218", "pubdate": "2020-11", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Paroxysmal Atrial Fibrillation on Flecainide Therapy.", "title_normalized": "paroxysmal atrial fibrillation on flecainide therapy" }

[ { "companynumb": "US-APOTEX-2020AP020745", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "FLECAINIDE ACETATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "079164", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "200 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "ATRIAL FIBRILLATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLECAINIDE ACETATE." } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Atrial flutter", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GAVIN JL, PEIGH GS, KIM SS. PAROXYSMAL ATRIAL FIBRILLATION ON FLECAINIDE THERAPY. EUROPEAN JOURNAL OF INTERNAL MEDICINE. 2020?1?2", "literaturereference_normalized": "paroxysmal atrial fibrillation on flecainide therapy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210729", "receivedate": "20210729", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19625072, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20211014" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-265871", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLECAINIDE ACETATE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "76421", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MILLIGRAM, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PALPITATIONS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLECAINIDE ACETATE." } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Atrial fibrillation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "GAVIN JL, PEIGH GS, KIM SS. PAROXYSMAL ATRIAL FIBRILLATION ON FLECAINIDE THERAPY. EUR J INTERN MED. 2020?SEP 24:NO PAGINATION", "literaturereference_normalized": "paroxysmal atrial fibrillation on flecainide therapy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201102", "receivedate": "20201102", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18449795, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210114" } ]

{ "abstract": "OBJECTIVE\nTo determine the clinicopathological characteristics of nonsteroidal anti-inflammatory drug (NSAID)-induced acute hepato-nephrotoxicity among Chinese patients.\n\n\nMETHODS\nWe conducted a retrospective chart review of patients using the International Classification of Diseases, Ninth Revision diagnosis code for acute kidney injury (AKI) (584.5 or 584.9) and for acute liver injury (ALI) (570.0 or 573.3) from January 2004 to December 2013. Medical records were reviewed to confirm the diagnosis of AKI and ALI and to quantify NSAID administration.\n\n\nRESULTS\nSeven of 59 patients (11.8%) were identified with acute hepato-nephrotoxicity induced by NSAIDs. Five patients (71.4%) received over the recommended NSAIDs dose. Compared with NSAIDs-associated mere AKI, the risk factors of NSAIDs-induced acute hepato-nephrotoxicity are age older than 60 years (57.1%), a high prevalence of alcohol use (71.4%) and positive hepatitis B virus (HBV) markers (85.7%). Compared with NSAIDs-associated mere ALI, the risk factors of NSAIDs-induced acute hepato-nephrotoxicity are age older than 60 years (57.1%), increased extracellular volume depletion (71.4%), and renin-angiotensin-aldosterone system (RAAS) inhibitor combined use (57.1%). Acute interstitial nephritis and acute tubulointerstitial disease were apparent in three out of six (42.9%) kidney biopsy patients, respectively. Acute hepatitis was found in four out of six (66.7%) liver biopsy patients. Overall complete recovery occurred in four patients within a mean of 118.25 ± 55.42 d.\n\n\nCONCLUSIONS\nThe injury typically occurred after an overdose of NSAIDs. The risk factors include age older than 60 years, alcohol use, positive HBV markers, extracellular volume depletion and RAAS inhibitor combined use.", "affiliations": "Ya-Li Cao, Wen-Ge Li, Yan-Fang Yang, Hong-Mei Gao, Department of Nephrology, China-Japan Friendship Hospital, Beijing 100029, China.;Ya-Li Cao, Wen-Ge Li, Yan-Fang Yang, Hong-Mei Gao, Department of Nephrology, China-Japan Friendship Hospital, Beijing 100029, China.;Ya-Li Cao, Wen-Ge Li, Yan-Fang Yang, Hong-Mei Gao, Department of Nephrology, China-Japan Friendship Hospital, Beijing 100029, China.;Ya-Li Cao, Wen-Ge Li, Yan-Fang Yang, Hong-Mei Gao, Department of Nephrology, China-Japan Friendship Hospital, Beijing 100029, China.;Ya-Li Cao, Wen-Ge Li, Yan-Fang Yang, Hong-Mei Gao, Department of Nephrology, China-Japan Friendship Hospital, Beijing 100029, China.;Ya-Li Cao, Wen-Ge Li, Yan-Fang Yang, Hong-Mei Gao, Department of Nephrology, China-Japan Friendship Hospital, Beijing 100029, China.;Ya-Li Cao, Wen-Ge Li, Yan-Fang Yang, Hong-Mei Gao, Department of Nephrology, China-Japan Friendship Hospital, Beijing 100029, China.", "authors": "Cao|Ya-Li|YL|;Tian|Zhi-Gang|ZG|;Wang|Fang|F|;Li|Wen-Ge|WG|;Cheng|Dan-Ying|DY|;Yang|Yan-Fang|YF|;Gao|Hong-Mei|HM|", "chemical_list": "D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000894:Anti-Inflammatory Agents, Non-Steroidal", "country": "United States", "delete": false, "doi": "10.3748/wjg.v20.i38.13956", "fulltext": null, "fulltext_license": null, "issn_linking": "1007-9327", "issue": "20(38)", "journal": "World journal of gastroenterology", "keywords": "Acute hepatitis; Acute interstitial nephritis; Cholestasis; Hepato-nephrotoxicity; Nonsteroidal anti-inflammatory drug", "medline_ta": "World J Gastroenterol", "mesh_terms": "D058186:Acute Kidney Injury; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000428:Alcohol Drinking; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000894:Anti-Inflammatory Agents, Non-Steroidal; D044466:Asians; D001706:Biopsy; D056486:Chemical and Drug Induced Liver Injury; D002675:Child, Preschool; D002681:China; D005260:Female; D006509:Hepatitis B; D006801:Humans; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D012189:Retrospective Studies; D012307:Risk Factors; D016896:Treatment Outcome; D055815:Young Adult", "nlm_unique_id": "100883448", "other_id": null, "pages": "13956-65", "pmc": null, "pmid": "25320533", "pubdate": "2014-10-14", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "19475693;21070361;19174782;2254635;20374223;20486732;11473672;19183124;11423768;2183665;21128314;23510965;18325075;10772593;18382197;22213561;9690198;15199199;22288307;15298630;15556053;19834119;23394211;12812012;10672143;18196471;12755960;17967156;16083708;20394749;10225536;16496329;21473713", "title": "Characteristics and clinical outcome of nonsteroidal anti-inflammatory drug-induced acute hepato-nephrotoxicity among Chinese patients.", "title_normalized": "characteristics and clinical outcome of nonsteroidal anti inflammatory drug induced acute hepato nephrotoxicity among chinese patients" }

[ { "companynumb": "CN-BAYER-2014-188223", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "NIMESULIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.1 G X 2 PILLS", "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": "NIMESULIDE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ASPIRIN LYSINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021317", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.5 G X 2 PILLS", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "032", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LYSINE ACETYLSALICYLATE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CEFOXITIN\\CEFOXITIN 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": "CEFOXITIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FOSINOPRIL" }, "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": "FOSINOPRIL" } ], "patientagegroup": "6", "patientonsetage": "71", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nephropathy toxic", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CAO YL, TIAN ZG, WANG F, LI WG, CHENG DY, YANG YF ET AL.. CHARACTERISTICS AND CLINICAL OUTCOME OF NONSTEROIDAL ANTI-INFLAMMATORY DRUG-INDUCED ACUTE HEPATO-NEPHROTOXICITY AMONG CHINESE PATIENTS. WORLD JOURNAL OF GASTROENTEROLOGY. 2014;20 (38):13956-13965", "literaturereference_normalized": "characteristics and clinical outcome of nonsteroidal anti inflammatory drug induced acute hepato nephrotoxicity among chinese patients", "qualification": "1", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20141230", "receivedate": "20141230", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 10683464, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150529" }, { "companynumb": "CN-MYLANLABS-2014M1013857", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": "35", "drugcumulativedosageunit": "032", "drugdosageform": null, "drugdosagetext": "0.1, INTERMITTENT", "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": "PARACETAMOL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PIROXICAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "074102", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG/DAY", "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": "PIROXICAM." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Nephropathy toxic", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tubulointerstitial nephritis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cholestasis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hepatotoxicity", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CAO Y-L, TIAN Z-G, WANG F, LI W-G, CHENG D-Y, YANG Y-F, ET AL. CHARACTERISTICS AND CLINICAL OUTCOME OF NONSTEROIDAL ANTI-INFLAMMATORY DRUG-INDUCED ACUTE HEPATO-NEPHROTOXICITY AMONG CHINESE PATIENTS. WORLD-J-GASTROENTEROL 2014; 20(38) 13956-13965", "literaturereference_normalized": "characteristics and clinical outcome of nonsteroidal anti inflammatory drug induced acute hepato nephrotoxicity among chinese patients", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20141215", "receivedate": "20141215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10652888, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150529" }, { "companynumb": "CN-MYLANLABS-2014M1013856", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "INDOMETHACIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "018858", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": "2", "drugcumulativedosageunit": "032", "drugdosageform": null, "drugdosagetext": "75MG", "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": "INDOMETACIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BENAZEPRIL\\BENAZEPRIL HYDROCHLORIDE" }, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BENAZEPRIL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CEFACLOR" }, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFACLOR." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatotoxicity", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hepatitis acute", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nephropathy toxic", "reactionmeddraversionpt": "18.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Tubulointerstitial nephritis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "IgA nephropathy", "reactionmeddraversionpt": "18.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "CAO Y-L, TIAN Z-G, WANG F, LI W-G, CHENG D-Y, YANG Y-F, ET AL. CHARACTERISTICS AND CLINICAL OUTCOME OF NONSTEROIDAL ANTI-INFLAMMATORY DRUG-INDUCED ACUTE HEPATO-NEPHROTOXICITY AMONG CHINESE PATIENTS. WORLD-J-GASTROENTEROL 2014; 20(38) 13956-13965", "literaturereference_normalized": "characteristics and clinical outcome of nonsteroidal anti inflammatory drug induced acute hepato nephrotoxicity among chinese patients", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20141215", "receivedate": "20141215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10652898, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150529" }, { "companynumb": "PHHY2014CN160852", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PIROXICAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PIROXICAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.1 OT, 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": "PARACETAMOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HERBALS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MENSTRUAL CYCLE MANAGEMENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HERBAL EXTRACT NOS" } ], "patientagegroup": null, "patientonsetage": "37", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Tubulointerstitial nephritis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cholestasis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CAO Y-L, TIAN Z-G, WANG F, LI W-G, CHENG D-Y, YANG Y-F, ET AL.. CHARACTERISTICS AND CLINICAL OUTCOME OF NONSTEROIDAL ANTI-INFLAMMATORY DRUG-INDUCED ACUTE HEPATO-NEPHROTOXICITY AMONG CHINESE PATIENTS.. WORLD JOURNAL OF GASTROENTEROLOGY. 2014;20(38):13956-65", "literaturereference_normalized": "characteristics and clinical outcome of nonsteroidal anti inflammatory drug induced acute hepato nephrotoxicity among chinese patients", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20141210", "receivedate": "20141210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10644578, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150529" }, { "companynumb": "CN-PFIZER INC-2014329926", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "018989", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.3 G X 5 PILLS, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".3", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MEROPENEM" }, "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": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MEROPENEM." }, { "actiondrug": null, "activesubstance": null, "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": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NORFLOXACIN BACCIDAL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RIFAMPIN" }, "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": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "INDOMETHACIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "75 MG X 10 PILLS, INTERMITTENT FOR 1 MO", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INDOMETHACIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CEFOPERAZONE" }, "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": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFOPERAZONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FLUCONAZOLE" }, "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": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIFLUCAN" } ], "patientagegroup": null, "patientonsetage": "17", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis cholestatic", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nephropathy toxic", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatotoxicity", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CAO, Y.. CHARACTERISTICS AND CLINICAL OUTCOME OF NONSTEROIDAL ANTI-INFLAMMATORY DRUG-INDUCED ACUTE HEPATO-NEPHROTOXICITY AMONG CHINESE PATIENTS.. WORLD JOURNAL OF GASTROENTEROLOGY. 2014;20 (38):13956-13965", "literaturereference_normalized": "characteristics and clinical outcome of nonsteroidal anti inflammatory drug induced acute hepato nephrotoxicity among chinese patients", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20141209", "receivedate": "20141209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 10640276, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150529" }, { "companynumb": "CN-PFIZER INC-2014329898", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ERYTHROMYCIN" }, "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": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ERYTHROMYCIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TELMISARTAN" }, "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": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TELMISARTAN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "018989", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.3 G FOR 2 DAYS, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".3", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.5 G X 5 PILLS, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TYLENOL" } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nephropathy toxic", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CAO, Y.. CHARACTERISTICS AND CLINICAL OUTCOME OF NONSTEROIDAL ANTI-INFLAMMATORY DRUG-INDUCED ACUTE HEPATO-NEPHROTOXICITY AMONG CHINESE PATIENTS.. WORLD JOURNAL OF GASTROENTEROLOGY. 2014;20 (38):13956-13965", "literaturereference_normalized": "characteristics and clinical outcome of nonsteroidal anti inflammatory drug induced acute hepato nephrotoxicity among chinese patients", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20141208", "receivedate": "20141208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 10637769, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150529" }, { "companynumb": "CN-MYLANLABS-2014M1013854", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ERYTHROMYCIN" }, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ERYTHROMYCIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "070045", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.3G", "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": "IBUPROFEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TELMISARTAN" }, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TELMISARTAN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": "5", "drugcumulativedosageunit": "032", "drugdosageform": null, "drugdosagetext": "0.5G", "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": "PARACETAMOL" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis acute", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tubulointerstitial nephritis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nephropathy toxic", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hepatotoxicity", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CAO Y-L, TIAN Z-G, WANG F, LI W-G, CHENG D-Y, YANG Y-F, ET AL. CHARACTERISTICS AND CLINICAL OUTCOME OF NONSTEROIDAL ANTI-INFLAMMATORY DRUG-INDUCED ACUTE HEPATO-NEPHROTOXICITY AMONG CHINESE PATIENTS. WORLD-J-GASTROENTEROL 2014; 20(38) 13956-13965", "literaturereference_normalized": "characteristics and clinical outcome of nonsteroidal anti inflammatory drug induced acute hepato nephrotoxicity among chinese patients", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20141215", "receivedate": "20141215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10652892, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150529" }, { "companynumb": "CN-VISTAPHARM, INC.-VER202103-001024", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PIROXICAM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG/DAY", "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": "PIROXICAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN\\HYDROCODONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "200343", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.1 X 35 PILLS INTERMITTENT FOR 3 MONTHS", "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": "HYDROCODONE AND ACETAMINOPHEN" } ], "patientagegroup": "5", "patientonsetage": "37", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Tubulointerstitial nephritis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hepatitis cholestatic", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nephropathy toxic", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "LI W, CAO Y, TIAN Z, WANG F, CHENG D, YANG Y. CHARACTERISTICS AND CLINICAL OUTCOME OF NONSTEROIDAL ANTI?INFLAMMATORY DRUG?INDUCED ACUTE HEPATO?NEPHROTOXICITY AMONG CHINESE PATIENTS. WORLD I GASTROENTEROL. 2014 OCT 14?20(38):13956?65.", "literaturereference_normalized": "characteristics and clinical outcome of nonsteroidal anti inflammatory drug induced acute hepato nephrotoxicity among chinese patients", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "CN", "receiptdate": "20210331", "receivedate": "20210331", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19076055, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210420" }, { "companynumb": "PHHY2014CN160866", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "NORFLOXACIN" }, "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": "NORFLOXACIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HERBALS" }, "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": "HERBAL NOS" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CEFOPERAZONE" }, "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": "CEFOPERAZONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 DF, 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": "5", "drugstructuredosageunit": "032", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "INDOMETHACIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "070673", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 DF, 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": "10", "drugstructuredosageunit": "032", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INDOMETHACIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MEROPENEM" }, "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": "MEROPENEM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "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": "RIFAMPICIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUCONAZOLE" }, "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": "DIFLUCAN" } ], "patientagegroup": null, "patientonsetage": "17", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatitis cholestatic", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nephropathy toxic", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CAO Y-L, TIAN Z-G, WANG F, LI W-G, CHENG D-Y, YANG Y-F, ET AL.. CHARACTERISTICS AND CLINICAL OUTCOME OF NONSTEROIDAL ANTI-INFLAMMATORY DRUG-INDUCED ACUTE HEPATO-NEPHROTOXICITY AMONG CHINESE PATIENTS.. WORLD JOURNAL OF GASTROENTEROLOGY. 2014;20(38):13956-65", "literaturereference_normalized": "characteristics and clinical outcome of nonsteroidal anti inflammatory drug induced acute hepato nephrotoxicity among chinese patients", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20141210", "receivedate": "20141210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10643085, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150529" }, { "companynumb": "PHHY2014CN160758", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DICLOFENAC" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "074376", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 DF, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "032", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DICLOFENAC" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HERBALS" }, "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": "HERBAL NOS" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CELECOXIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CELECOXIB." } ], "patientagegroup": null, "patientonsetage": "69", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Renal tubular acidosis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tubulointerstitial nephritis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatitis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CAO Y-L, TIAN Z-G, WANG F, LI W-G, CHENG D-Y, YANG Y-F, ET AL.. CHARACTERISTICS AND CLINICAL OUTCOME OF NONSTEROIDAL ANTI-INFLAMMATORY DRUG-INDUCED ACUTE HEPATO-NEPHROTOXICITY AMONG CHINESE PATIENTS.. WORLD JOURNAL OF GASTROENTEROLOGY. 2014;20(38):13956-65", "literaturereference_normalized": "characteristics and clinical outcome of nonsteroidal anti inflammatory drug induced acute hepato nephrotoxicity among chinese patients", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20141210", "receivedate": "20141210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10642571, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150529" }, { "companynumb": "CN-APOTEX-2014AP006125", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": null, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RHIZOMA CIBOTII" }, { "actiondrug": "5", "activesubstance": null, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RADIX AUCKLANDIAE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DICLOFENAC SODIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "077600", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, QD", "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": "1", "drugstructuredosageunit": "032", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DICLOFENAC SODIUM." }, { "actiondrug": "5", "activesubstance": null, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, 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}, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CELECOXIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG, QD", "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": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CELECOXIB." }, { "actiondrug": "5", "activesubstance": null, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, 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"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": "RADIX DIPSACI" } ], "patientagegroup": null, "patientonsetage": "69", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Nephropathy toxic", "reactionmeddraversionpt": "18.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Hepatotoxicity", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hepatitis acute", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tubulointerstitial nephritis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "CAO Y-L, TIAN Z-G, WANG F, LI W-G, CHENG D-Y, YANG Y-F, ET AL.. CHARACTERISTICS AND CLINICAL OUTCOME OF NONSTEROIDAL ANTI-INFLAMMATORY DRUG-INDUCED ACUTE HEPATO-NEPHROTOXICITY AMONG CHINESE PATIENTS.. WORLD-J-GASTROENTEROL. 2014;20(38):13956-13965", "literaturereference_normalized": "characteristics and clinical outcome of nonsteroidal anti inflammatory drug induced acute hepato nephrotoxicity among chinese patients", "qualification": "1", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20141215", "receivedate": "20141215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10652561, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150529" }, { "companynumb": "PHHY2014CN158325", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TELMISARTAN" }, "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": "TELMISARTAN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "70733", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.3 G, 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": ".3", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 DF, 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": "5", "drugstructuredosageunit": "032", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TYLENOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ERYTHROMYCIN" }, "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": "ERYTHROMYCIN." } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Tubulointerstitial nephritis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatitis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CAO Y-L, TIAN Z-G, WANG F, LI W-G, CHENG D-Y, YANG Y-F, ET AL.. CHARACTERISTICS AND CLINICAL OUTCOME OF NONSTEROIDAL ANTI-INFLAMMATORY DRUG-INDUCED ACUTE HEPATO-NEPHROTOXICITY AMONG CHINESE PATIENTS.. WORLD JOURNAL OF GASTROENTEROLOGY. 2014;20(38):13956-65", "literaturereference_normalized": "characteristics and clinical outcome of nonsteroidal anti inflammatory drug induced acute hepato nephrotoxicity among chinese patients", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20141210", "receivedate": "20141210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10642691, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150529" }, { "companynumb": "CN-JNJFOC-20141215444", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "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": "TYLENOL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TELMISARTAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "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": "TELMISARTAN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ERYTHROMYCIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "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": "ERYTHROMYCIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "019872", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": "5 PILLS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANALGESIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TYLENOL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "FOR 2 DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANALGESIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".3", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN." } ], "patientagegroup": "5", "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis acute", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tubulointerstitial nephritis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CAO Y, TIAN Z, WANG F, LI W, CHENG D, YANG Y, ET AL. CHARACTERISTICS AND CLINICAL OUTCOME OF NONSTEROIDAL ANTI-INFLAMMATORY DRUG-INDUCED ACUTE HEPATO-NEPHROTOXICITY AMONG CHINESE PATIENTS . WORLD JOURNAL OF GASTROENTEROLOGY 14-OCT-2014;20(38):13956-13965.", "literaturereference_normalized": "characteristics and clinical outcome of nonsteroidal anti inflammatory drug induced acute hepato nephrotoxicity among chinese patients", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20141231", "receivedate": "20141231", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10684903, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150529" } ]

{ "abstract": "OBJECTIVE\nTo use data from a large multicenter trial to assess the role and significance of chest radiograph (CXR) in the initial evaluation of acute stroke.\n\n\nMETHODS\nPredefined clinical characteristics of patients who had recorded data on CXR examination during the initial evaluation were collected. We compared features of patients who had a CXR done before IV thrombolytics with those who did not. Rates of adverse cardiopulmonary events, intubation, and in-hospital mortality were also compared. Logistic regression analysis was performed to evaluate for the association of CXR performance with door-to-needle time ≥60 minutes.\n\n\nRESULTS\nIn a cohort of 615 patients, 243 had CXR done before IV thrombolytics. Patients with CXR before treatment had significantly higher admission neurologic deficit, initial respiratory rates, and door-to-needle time than those with CXR after treatment. The rates of cardiopulmonary adverse events in the first 24 hours of admission, endotracheal intubation in the first 7 hours, and in-hospital mortality were not different between the 2 groups. Patients with CXR done before treatment had longer mean door-to-needle times than those without pretreatment radiography (75.8 vs 58.3 minutes, p = 0.0001). Performance of CXR was independently associated with door-to-needle time ≥60 minutes (odds ratio 2.78, 95% confidence interval 1.97-3.92; p = 0.00001).\n\n\nCONCLUSIONS\nPerformance of CXR prior to IV thrombolytics prolongs door-to-needle time in acute ischemic stroke patients. CXR before treatment should be reserved for situations wherein acute cardiopulmonary conditions would otherwise preclude the administration of IV thrombolytics or substantially influence management.", "affiliations": "From the Department of Neurology (H.S.), Wayne State University School of Medicine, Detroit, MI; Department of Neurology (B.S.), Warren Alpert Medial School, Brown University; Comprehensive Stroke Center (B.S.), Rhode Island Hospital, Providence; Department of Neurology (A.S., V.M., R.B.), School of Medicine, University of Texas Health Science Center, San Antonio; and Department of Clinical Neurological Sciences (M.R.A.), Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.;From the Department of Neurology (H.S.), Wayne State University School of Medicine, Detroit, MI; Department of Neurology (B.S.), Warren Alpert Medial School, Brown University; Comprehensive Stroke Center (B.S.), Rhode Island Hospital, Providence; Department of Neurology (A.S., V.M., R.B.), School of Medicine, University of Texas Health Science Center, San Antonio; and Department of Clinical Neurological Sciences (M.R.A.), Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.;From the Department of Neurology (H.S.), Wayne State University School of Medicine, Detroit, MI; Department of Neurology (B.S.), Warren Alpert Medial School, Brown University; Comprehensive Stroke Center (B.S.), Rhode Island Hospital, Providence; Department of Neurology (A.S., V.M., R.B.), School of Medicine, University of Texas Health Science Center, San Antonio; and Department of Clinical Neurological Sciences (M.R.A.), Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.;From the Department of Neurology (H.S.), Wayne State University School of Medicine, Detroit, MI; Department of Neurology (B.S.), Warren Alpert Medial School, Brown University; Comprehensive Stroke Center (B.S.), Rhode Island Hospital, Providence; Department of Neurology (A.S., V.M., R.B.), School of Medicine, University of Texas Health Science Center, San Antonio; and Department of Clinical Neurological Sciences (M.R.A.), Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.;From the Department of Neurology (H.S.), Wayne State University School of Medicine, Detroit, MI; Department of Neurology (B.S.), Warren Alpert Medial School, Brown University; Comprehensive Stroke Center (B.S.), Rhode Island Hospital, Providence; Department of Neurology (A.S., V.M., R.B.), School of Medicine, University of Texas Health Science Center, San Antonio; and Department of Clinical Neurological Sciences (M.R.A.), Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.;From the Department of Neurology (H.S.), Wayne State University School of Medicine, Detroit, MI; Department of Neurology (B.S.), Warren Alpert Medial School, Brown University; Comprehensive Stroke Center (B.S.), Rhode Island Hospital, Providence; Department of Neurology (A.S., V.M., R.B.), School of Medicine, University of Texas Health Science Center, San Antonio; and Department of Clinical Neurological Sciences (M.R.A.), Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. Behrouz@uthscsa.edu.", "authors": "Saber|Hamidreza|H|;Silver|Brian|B|;Santillan|Alejandro|A|;Azarpazhooh|Mahmoud R|MR|;Misra|Vivek|V|;Behrouz|Réza|R|", "chemical_list": "D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator", "country": "United States", "delete": false, "doi": "10.1212/WNL.0000000000002964", "fulltext": null, "fulltext_license": null, "issn_linking": "0028-3878", "issue": "87(8)", "journal": "Neurology", "keywords": null, "medline_ta": "Neurology", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D008297:Male; D008875:Middle Aged; D010043:Outcome and Process Assessment, Health Care; D013902:Radiography, Thoracic; D020521:Stroke; D013997:Time Factors; D010959:Tissue Plasminogen Activator; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "0401060", "other_id": null, "pages": "782-5", "pmc": null, "pmid": "27412145", "pubdate": "2016-08-23", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial", "references": null, "title": "Role of emergent chest radiography in evaluation of hyperacute stroke.", "title_normalized": "role of emergent chest radiography in evaluation of hyperacute stroke" }

[ { "companynumb": "US-ROCHE-1836100", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALTEPLASE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "103172", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ISCHAEMIC STROKE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALTEPLASE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute myocardial infarction", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SABER H, SILVER B, SANTILLAN A, AZARPAZHOOH M, MISRA V, BEHROUZ R. ROLE OF EMERGENT CHEST RADIOGRAPHY IN EVALUATION OF HYPERACUTE STROKE. NEUROLOGY 2016 AUG 23;87 (8):782-785.", "literaturereference_normalized": "role of emergent chest radiography in evaluation of hyperacute stroke", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20161124", "receivedate": "20160929", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12791298, "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\nEncephalopathy with continuous spike-wave during sleep (CSWS) is a particularly difficult-to-treat childhood epileptic syndrome. This study sought to present the EEG improvement and clinical efficacy of topiramate (TPM), a broad spectrum antiepileptic drug (AED), in a series of 21 children with CSWS encephalopathy.\n\n\nMETHODS\nWe retrospectively reviewed the EEG results and clinical data of children with CSWS followed-up in our institution and treated with TPM. Sleep EEGs were performed 0-3 months prior to TPM introduction and then at 3 and 12 months. The exclusion criteria were (1) introduction of another AED and (2) withdrawal of a potentially aggravating AED during the first 3 months of treatment. In addition to spike index (SI), the severity of EEG abnormalities was rated using an original scale that also considered the spatial extent of interictal epileptiform discharges.\n\n\nRESULTS\n21 patients were included (18 males, 4-14y, three symptomatic cases). At 3 months, sleep EEG was improved in 14 and normalized in four (TPM doses: 2-5.5 mg/kg/day). Among these 18 patients, 16 manifested cognitive or behavioural improvement. In a subgroup of seven patients with frequent seizures, five became seizure-free and one had over 75% decrease in seizure frequency. At the one-year follow-up, 20 children were still on TPM and 10 exhibited persistent EEG improvement without any other AED being introduced, most of them with clinical benefits.\n\n\nCONCLUSIONS\nTPM can decrease EEG abnormalities in epileptic encephalopathy with CSWS, achieving clinical improvement in the majority of patients. However, relapse may occur in the long-term in nearly half of cases. Otherwise, TPM has proven particularly useful in reducing seizure frequency in refractory cases.", "affiliations": "William Lennox Neurological Hospital, Reference Center for Refractory Epilepsy, Université Catholique de Louvain, Ottignies, Belgium. Electronic address: pascal.vrielynck@cnwl.be.;William Lennox Neurological Hospital, Reference Center for Refractory Epilepsy, Université Catholique de Louvain, Ottignies, Belgium.;William Lennox Neurological Hospital, Reference Center for Refractory Epilepsy, Université Catholique de Louvain, Ottignies, Belgium.;William Lennox Neurological Hospital, Reference Center for Refractory Epilepsy, Université Catholique de Louvain, Ottignies, Belgium.;William Lennox Neurological Hospital, Reference Center for Refractory Epilepsy, Université Catholique de Louvain, Ottignies, Belgium.;William Lennox Neurological Hospital, Reference Center for Refractory Epilepsy, Université Catholique de Louvain, Ottignies, Belgium.;William Lennox Neurological Hospital, Reference Center for Refractory Epilepsy, Université Catholique de Louvain, Ottignies, Belgium.", "authors": "Vrielynck|P|P|;Marique|P|P|;Ghariani|S|S|;Lienard|F|F|;de Borchgrave|V|V|;van Rijckevorsel|K|K|;Bonnier|C|C|", "chemical_list": "D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose", "country": "England", "delete": false, "doi": "10.1016/j.ejpn.2016.08.015", "fulltext": null, "fulltext_license": null, "issn_linking": "1090-3798", "issue": "21(2)", "journal": "European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society", "keywords": "CSWS; Childhood; ESES; Epilepsy; Topiramate", "medline_ta": "Eur J Paediatr Neurol", "mesh_terms": "D000293:Adolescent; D000927:Anticonvulsants; D002648:Child; D002675:Child, Preschool; D004569:Electroencephalography; D005260:Female; D005632:Fructose; D006801:Humans; D008297:Male; D012008:Recurrence; D012189:Retrospective Studies; D012890:Sleep; D013036:Spasms, Infantile; D000077236:Topiramate", "nlm_unique_id": "9715169", "other_id": null, "pages": "305-311", "pmc": null, "pmid": "27641809", "pubdate": "2017-03", "publication_types": "D016428:Journal Article", "references": null, "title": "Topiramate in childhood epileptic encephalopathy with continuous spike-waves during sleep: A retrospective study of 21 cases.", "title_normalized": "topiramate in childhood epileptic encephalopathy with continuous spike waves during sleep a retrospective study of 21 cases" }

[ { "companynumb": "BE-JNJFOC-20170219893", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "020505", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EPILEPTIC ENCEPHALOPATHY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." } ], "patientagegroup": "3", "patientonsetage": "7", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Electroencephalogram abnormal", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cognitive disorder", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VRIELYNCK P, MARIQUE P, GHARIANI S, LIENARD F, DE BORCHGRAVE V, VAN RIJCKEVORSEL K, ET AL. TOPIRAMATE IN CHILDHOOD EPILEPTIC ENCEPHALOPATHY WITH CONTINUOUS SPIKE-WAVES DURING SLEEP: A RETROSPECTIVE STUDY OF 21 CASES. EUROPEAN JOURNAL OF PAEDIATRIC NEUROLOGY 2017;21 (2):305-311.", "literaturereference_normalized": "topiramate in childhood epileptic encephalopathy with continuous spike waves during sleep a retrospective study of 21 cases", "qualification": "3", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20170224", "receivedate": "20170224", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13269811, "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" } ]

{ "abstract": "Following cerebral arteriovenous malformation (AVM) surgery, severe brain edema and hemorrhage may be caused by postoperative normal perfusion pressure breakthrough (NPPB). Sedation is necessary for this population. It is a challenge for the anesthesiologist to maintain hemodynamic stability without interfering with the neurological assessment. In Japan, propofol is contraindicated for pregnant patients. Dexmedetomidine is a versatile drug in anesthesia practice and may be useful for this situation. There is no report using dexmedetomidine for the purpose of NPPB control in pregnant patients. We describe the postoperative management with dexmedetomidine for a pregnant patient who underwent cerebral AVM nidus removal.\nA 32-year-old patient presented with headache at the 16th week of gestation. Neuroimaging revealed an intraventricular hemorrhage and an AVM at the right anterior horn of the lateral ventricle which caused bleeding. A multidisciplinary team discussion was done, and then a craniotomy for AVM nidus removal was performed under general anesthesia. Preanesthetic aspiration prophylaxis and rapid sequence induction were added to our conventional anesthetic management. Hypotension occurred after anesthetic induction but the patient recovered by volume resuscitation and vasopressors. Anesthesia was maintained with 50% O2 in air and sevoflurane. The AVM was completely removed, and no perioperative complications occurred. Postoperative sedation with dexmedetomidine was used to prevent breakthrough hyperperfusion and cerebral edema.\nDexmedetomidine infusion was used for postoperative sedation without causing any side effects, and it can be an alternative for sedation, especially when propofol is contraindicated.", "affiliations": "1Department of Anesthesiology, School of Medicine, Tokyo Women's Medical University, 8-1 Kawada-cho Shinjuku-ku, Tokyo, 1628666 Japan.;1Department of Anesthesiology, School of Medicine, Tokyo Women's Medical University, 8-1 Kawada-cho Shinjuku-ku, Tokyo, 1628666 Japan.;1Department of Anesthesiology, School of Medicine, Tokyo Women's Medical University, 8-1 Kawada-cho Shinjuku-ku, Tokyo, 1628666 Japan.;3Department of Neurosurgery, School of Medicine, Tokyo Women's Medical University, 8-1 Kawada-cho Shinjuku-ku, Tokyo, 1628666 Japan.;1Department of Anesthesiology, School of Medicine, Tokyo Women's Medical University, 8-1 Kawada-cho Shinjuku-ku, Tokyo, 1628666 Japan.;1Department of Anesthesiology, School of Medicine, Tokyo Women's Medical University, 8-1 Kawada-cho Shinjuku-ku, Tokyo, 1628666 Japan.", "authors": "Kitsiripant|Chanatthee|C|0000-0003-1504-9336;Kamata|Kotoe|K|;Kanamori|Rie|R|;Yamaguchi|Koji|K|;Ozaki|Makoto|M|;Nomura|Minoru|M|", "chemical_list": null, "country": "Germany", "delete": false, "doi": "10.1186/s40981-017-0085-6", "fulltext": "\n==== Front\nJA Clin RepJA Clin RepJA Clinical Reports2363-9024Springer Berlin Heidelberg Berlin/Heidelberg 294570618510.1186/s40981-017-0085-6Case ReportPostoperative management with dexmedetomidine in a pregnant patient who underwent AVM nidus removal: a case report http://orcid.org/0000-0003-1504-9336Kitsiripant Chanatthee +81-3-3353-8111chanat_k@hotmail.com 12Kamata Kotoe macaroon@nifty.com 1Kanamori Rie kukku1102@gmail.com 1Yamaguchi Koji kyamaguchi2007@yahoo.co.jp 3Ozaki Makoto mozaki@anes.twmu.ac.jp 1Nomura Minoru mnomura@anes.twmu.ac.jp 11 0000 0001 0720 6587grid.410818.4Department of Anesthesiology, School of Medicine, Tokyo Women’s Medical University, 8-1 Kawada-cho Shinjuku-ku, Tokyo, 1628666 Japan 2 0000 0004 0470 1162grid.7130.5Department of Anesthesiology, Faculty of Medicine, Prince of Songkla University, 15 Karnjanavanich Road, Hat Yai, Songkhla 90110 Thailand 3 0000 0001 0720 6587grid.410818.4Department of Neurosurgery, School of Medicine, Tokyo Women’s Medical University, 8-1 Kawada-cho Shinjuku-ku, Tokyo, 1628666 Japan 24 4 2017 24 4 2017 12 2017 3 1730 11 2016 8 4 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.Background\nFollowing cerebral arteriovenous malformation (AVM) surgery, severe brain edema and hemorrhage may be caused by postoperative normal perfusion pressure breakthrough (NPPB). Sedation is necessary for this population. It is a challenge for the anesthesiologist to maintain hemodynamic stability without interfering with the neurological assessment. In Japan, propofol is contraindicated for pregnant patients. Dexmedetomidine is a versatile drug in anesthesia practice and may be useful for this situation. There is no report using dexmedetomidine for the purpose of NPPB control in pregnant patients. We describe the postoperative management with dexmedetomidine for a pregnant patient who underwent cerebral AVM nidus removal.\n\nCase presentation\nA 32-year-old patient presented with headache at the 16th week of gestation. Neuroimaging revealed an intraventricular hemorrhage and an AVM at the right anterior horn of the lateral ventricle which caused bleeding. A multidisciplinary team discussion was done, and then a craniotomy for AVM nidus removal was performed under general anesthesia. Preanesthetic aspiration prophylaxis and rapid sequence induction were added to our conventional anesthetic management. Hypotension occurred after anesthetic induction but the patient recovered by volume resuscitation and vasopressors. Anesthesia was maintained with 50% O2 in air and sevoflurane. The AVM was completely removed, and no perioperative complications occurred. Postoperative sedation with dexmedetomidine was used to prevent breakthrough hyperperfusion and cerebral edema.\n\nConclusions\nDexmedetomidine infusion was used for postoperative sedation without causing any side effects, and it can be an alternative for sedation, especially when propofol is contraindicated.\n\nKeywords\nIntracranial arteriovenous malformationPregnancyNormal perfusion pressure breakthroughDexmedetomidineissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nNeurosurgical intervention during pregnancy is still a challenge due to the strict surgical indications and maternal-fetal effects of anesthetic drugs. Arteriovenous malformation (AVM) accounts for about 50% of subarachnoid hemorrhage in pregnant women [1]. It has been considered that hormonal changes to the arterial wall and increased cardiac output are related to the increased risk of AVM rupture, especially in the second and the third trimester. The risk of rebleeding is 25% during the same pregnancy compared with 3–6% risk during the first year in nonpregnant women [2]. Neurosurgical resection represents the definitive treatment because it eliminates rebleeding [2–4]. In addition, after excision of an AVM, normal perfusion pressure breakthrough (NPPB) impairs autoregulation which causes severe neurological damage and should be prevented by postoperative sedation. There are many medication options for sedation such as propofol, benzodiazepines, or dexmedetomidine. However, the maternal use of propofol is prohibited in Japan. Dexmedetomidine is a versatile agent in anesthesia practice and can be used as an alternative in this circumstance. It induces conscious sedation/analgesia while preserving respiratory and cardiovascular functions with cerebral hemodynamic stabilizing properties. Nowadays, the existing literature on the use of dexmedetomidine in obstetric patients for neurosurgery is limited. The purpose of this report is to describe our experience in postoperative management with dexmedetomidine for a pregnant patient who underwent cerebral AVM nidus removal.\n\nCase presentation\nA 32-year-old secundigravida presented with constant headache and complained of disorientation in her day-to-day life at 16 weeks of gestation. Because her headache was not controlled with 400 mg of acetaminophen, she visited a nearby hospital at week 17 of gestation. She was conscious and alert. She was not hypertensive; her heart rate (HR) was 83 beats/min and her blood pressure (BP) was 103/50 mmHg. Obstetric ultrasonography showed a single viable fetus without any fetal compromise. Computed tomography (CT) and magnetic resonance imaging revealed intraventricular hemorrhage, but there was no evidence of increased intracranial pressure. Three-dimensional contrast-enhanced computed tomography angiography showed a 1.5 cm AVM nidus fed from a branch of the right Heubner’s artery and intraventricular venous drainage. At week 18 of gestation, she was referred to our institution for further treatment. Her AVM was classified as grade 2 in the Spetzler-Martin grading system. After a preoperative multidisciplinary conference including neurosurgeons, obstetricians, and anesthesiologists, AVM nidus removal was planned at week 21 of gestational age under general anesthesia.\n\nThe patient was premedicated with famotidine 20 mg intravenously. Standard cardiorespiratory monitoring, invasive BP, and bispectral index (BIS) monitoring were adopted. Left uterine displacement was done, and the fetal heart rate (FHR) was reassured before the induction of anesthesia. After preoxygenation, rapid sequence induction with cricoid pressure was performed with fentanyl 150 mcg, thiopental 250 mg, and rocuronium 50 mg. Intubation was successfully done on the first attempt with a McGRATH™ MAC video laryngoscope. Maternal BP decreased to 83 mmHg after the anesthetic induction, but it subsequently recovered with volume resuscitation and vasopressors that included ephedrine 4 mg and two boluses of phenylephrine 0.05 mg. Anesthesia was maintained with 50% oxygen in air, sevoflurane, and remifentanil 0.3–0.5 mcg/kg/min. End-tidal concentration of sevoflurane was titrated according to the depth of anesthesia. During the operation, the systolic BP was maintained in the range of 90–120 mmHg, HR of 82–86 beats/min, peripheral oxygen saturation of 99–100%, an end-tidal CO2 of 33–40 mmHg, and BIS value of 40–60. The AVM was completely and successfully removed. Estimated blood loss was 50 mL, and 850 mL of bicarbonate Ringer’s solution and 1000 mL of hydroxyethyl starch were infused. The total duration of the surgery and anesthesia was 186 and 259 min, respectively. FHR monitoring confirmed fetal viability at the end of anesthesia. In consequence, dexmedetomidine 1 mcg/kg was administered over 10 min as a loading dose then followed by a maintenance infusion of 0.7 mcg/kg/h. After the dexmedetomidine infusion was initiated, her vital signs were stable without hypotension or bradycardia. Complete resection of the AVM without intraventricular hemorrhage and cerebral ischemia were confirmed by postoperative CT. In the intensive care unit (ICU), she was awake while the maintenance infusion rate of dexmedetomidine was 0.35 mcg/kg/h. One hour after surgery, the patient recovered fully awake without neurological deficit. Dexmedetomidine infusion was then stopped, and extubation was performed. The total dexmedetomidine dose used was 99.5 mcg, and the duration of infusion was 2 h. Multimodal analgesia of intravenous fentanyl and acetaminophen was effective to control postcraniotomy headache without postoperative nausea and vomiting. Her analgesic requirement was reduced, and her postoperative pain score was 0. She was discharged from the ICU on postoperative day 1 and went home on postoperative day 10. There were no obstetric complications, and the pregnancy proceeded uneventfully.\n\nDiscussion\nAfter an excision of a high-flow AVM, there is the potential risk for postoperative neurological complications due to NPPB which leads to hyperemia, cerebral edema, and intracranial hemorrhage without evidence of residual AVM [5]. Patients at risk for NPPB may benefit from blood pressure control and sedation. The challenge for the anesthesiologist is to select a technique that minimizes perioperative hemodynamic instability, provides analgesia, and diminishes the risk of postoperative complications. Our case report showed that intraoperative loading of dexmedetomidine provided smooth transition from intraoperative to postoperative patient care. It contributed to a smooth recovery without cardiovascular instability and had the advantage of postoperative neurological assessment due to conscious sedation.\n\nIn postoperative sedation of obstetric patients, no sedative drug has been reported as the drug of choice due to a lack of adequate or well-controlled studies. Propofol may be associated with lower initial Apgar scores at the time of cesarean section and may cause mild metabolic acidosis during a long neurosurgical procedure in pregnant patients. Moreover, in several countries, including Japan, propofol is stated by the manufacturer to be contraindicated during pregnancy [3, 6]. Benzodiazepines present the risk of congenital malformations, and central nervous system abnormalities, respiratory depression, floppy infant syndrome, and potential neonatal withdrawal [7, 8].\n\nDexmedetomidine is a highly selective alpha-2 adrenergic agonist which is a useful agent because it provides anxiolytic and sympatholytic effects, analgesia, and conscious sedation without respiratory depression. The existing literature reports on dexmedetomidine use in pregnant patients who underwent neurosurgery are limited. Recently, Handlogten and colleagues revealed that dexmedetomidine infusion allowed adequate sedation for an awake neurosurgical procedure in a pregnant patient without causing any adverse effects [9]. For pregnant patients, several studies mentioned that dexmedetomidine was used safely in many interventions such as sedation during noninvasive ventilation [10], as an alternative for maintenance of general anesthesia [9, 11], blunt hemodynamic response to intubation, and maintained hemodynamic stability without neonatal respiratory depression during cesarean section under general anesthesia [12, 13]. However, it can cross the placenta to the fetus [12, 14]. Dexmedetomidine use is recommended only if the benefit is clearly needed and the benefits overcome the risks to the fetus. In neurosurgery, dexmedetomidine decreases cerebral blood flow that could be the result of a decrease in cerebral metabolic activity [15, 16]. The Acute Neurosurgical ICU Sedation Trial reported that sedation with dexmedetomidine improved the cognitive score compared with propofol [17]. For postoperative care, a meta-analysis by Jin and colleagues found that continuous infusion of dexmedetomidine had the advantage of preventing postoperative nausea and vomiting and could reduce potential adverse events such as bradycardia and hypotension [18]. Su and colleagues studied the opioid-sparing effect of perioperative dexmedetomidine plus sufentanil infusion during neurosurgery and reported that dexmedetomidine (0.02 mcg/kg/h) plus sufentanil (0.02 mcg/kg/h) could reduce postoperative opioid consumption and improve pain scores [19]. Besides, dexmedetomidine was associated with a notably lower incidence of postoperative delirium [20, 21].\n\nConclusions\nDexmedetomidine is considered a multipurpose agent for pregnant patients who undergo neurosurgery. It is a sedative agent with minimal effects on respiratory function, maintains hemodynamic stability and cerebral protection with analgesic effects, and also decreases the risk of postoperative complications. Because propofol is prohibited for maternal use in Japan, our case showed that dexmedetomidine is an alternative to propofol for sedation in the obstetric population.\n\nAbbreviations\nAVMArteriovenous malformation\n\nBISBispectral index\n\nBPBlood pressure\n\nCTComputed tomography\n\nFHRFetal heart rate\n\nICUIntensive care unit\n\nNPPBNormal perfusion pressure breakthrough\n\nAcknowledgements\nThe authors would like to thank Mr. Glenn Shingledecker for editing the English manuscript.\n\nFunding\nNone.\n\nAvailability of data and materials\nNot applicable.\n\nAuthors’ contributions\nCK drafted the manuscript. KK, RK, KY, MO and MN supervised the manuscript drafting. All authors read and approved the final manuscript.\n\nAuthors’ information\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nConsent for publication of images was not applicable.\n\nEthics approval and consent to participate\nNot applicable.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Le LT Wendling A Anesthetic management for cesarean section in a patient with rupture of a cerebellar arteriovenous malformation J Clin Anesth 2009 21 143 8 10.1016/j.jclinane.2008.07.003 19329022 \n2. Wang LP Paech MJ Neuroanesthesia for the pregnant woman Anesth Analg 2008 107 193 200 10.1213/ane.0b013e31816c8888 18635488 \n3. Sinha PK Neema PK Rathod RC Anesthesia and intracranial arteriovenous malformation Neurol India 2004 52 163 70 15269462 \n4. Guerrero-Domínguez R Rubio-Romero R López-Herrera-Rodríguez D Federero F Jiménez I Anaesthetic management for craniotomy in a pregnant patient with rupture of a cerebral arterio-venous malformation: case report Colomb J Anesthesiol 2015 43 57 60 \n5. O’Connor TE Fargen KM Mocco J Normal perfusion pressure breakthrough following AVM resection: a case report and review of the literature Open J Mod Neurosurg 2013 3 66 71 10.4236/ojmn.2013.34015 \n6. Kochs EF Himmelseher S Pregnancy and neurosurgery Eur Soc Anaesthesiol 2011 07RC1 1 14 \n7. Reitman E Flood P Anaesthetic considerations for non-obstetric surgery during pregnancy Br J Anaesth 2011 107 suppl 1 i72 8 10.1093/bja/aer343 22156272 \n8. Riker RR Shehabi Y Bokesch PM Ceraso D Wisemandle W Koura F Whitten P Margolis BD Byrne DW Ely EW Rocha MG SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study group Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial JAMA 2009 301 489 99 10.1001/jama.2009.56 19188334 \n9. Handlogten KS Sharpe EE Brost BC Parney IF Pasternak JJ Dexmedetomidine and mannitol for awake craniotomy in a pregnant patient Anesth Analg 2015 120 1099 103 10.1213/ANE.0000000000000710 25899274 \n10. Duan M Lee J Bittner EA Dexmedetomidine for sedation in the parturient with respiratory failure requiring noninvasive ventilation Respir Care 2012 57 1967 9 10.4187/respcare.01733 22709960 \n11. Souza KM Anzoategui LC Pedroso WC Gemperli WA Dexmedetomidine in general anesthesia for surgical treatment of cerebral aneurysm in pregnant patient with specific hypertensive disease of pregnancy: case report Rev Bras Anestesiol 2005 55 212 6 19471825 \n12. Yu M Han C Jiang X Wu X Yu L Ding Z Effect and placental transfer of dexmedetomidine during caesarean section under general anaesthesia Basic Clin Pharmacol Toxicol 2015 117 204 8 10.1111/bcpt.12389 25652672 \n13. Cui Z, Olutoye OA, Zamora IJ, Ruano R, Olutoye OO, Chow Ds. Pharmacokinetics and placental transfer of dexmedetomidine in the pregnant ewe-fetus model. Poster session presented at: the 2013 ACCP Annual meeting; 2013 October 13-16; Albuquerque, NM, USA. (1710471).\n14. Li C Li Y Wang K Kong X Comparative evaluation of remifentanil and dexmedetomidine in general anesthesia for cesarean delivery Med Sci Monit 2015 21 3806 13 10.12659/MSM.895209 26638888 \n15. Wang X Ji J Fen L Wang A Effects of dexmedetomidine on cerebral blood flow in critically ill patients with or without traumatic brain injury: a prospective controlled trial Brain Inj 2013 27 1617 22 10.3109/02699052.2013.831130 24102571 \n16. Prielipp RC Wall MH Tobin JR Groban L Cannon MA Fahey FH Gage HD Stump DA James RL Bennett J Butterworth J Dexmedetomidine-induced sedation in volunteers decreases regional and global cerebral blood flow Anesth Analg 2002 95 1052 9 12351293 \n17. Mirski MA Lewin JJ 3rd Ledroux S Cognitive improvement during continuous sedation in critically ill, awake and responsive patients: the Acute Neurological ICU Sedation Trial (ANIST) Intensive Care Med 2010 36 9 1505 13 10.1007/s00134-010-1874-9 20376430 \n18. Jin S Liang DD Chen C Zhang M Wang J Dexmedetomidine prevent postoperative nausea and vomiting on patients during general anesthesia: a PRISMA-compliant meta-analysis of randomized controlled trials Medicine (Baltimore) 2017 96 e5770 10.1097/MD.0000000000005770 28072722 \n19. Su S Ren C Zhang H Liu Z Zhang Z The opioid-sparing effect of perioperative dexmedetomidine plus sufentanil infusion during neurosurgery: a retrospective study Front Pharmacol 2016 7 407 10.3389/fphar.2016.00407 27833559 \n20. Su X Meng ZT Wu XH Cui F Li HL Wang DX Zhu X Zhu SN Maze M Ma D Dexmedetomidine for prevention of delirium in elderly patients after non-cardiac surgery: a randomized, double-blind, placebo-controlled trial Lancet 2016 388 1893 902 10.1016/S0140-6736(16)30580-3 27542303 \n21. Maldonado JR Wysong A Van der Starre PJA Block T Miller C Reitz BA Dexmedetomidine and reduction of postoperative delirium after cardiac surgery Psychosomatics 2009 50 206 17 10.1176/appi.psy.50.3.206 19567759\n\n", "fulltext_license": "CC BY", "issn_linking": "2363-9024", "issue": "3(1)", "journal": "JA clinical reports", "keywords": "Dexmedetomidine; Intracranial arteriovenous malformation; Normal perfusion pressure breakthrough; Pregnancy", "medline_ta": "JA Clin Rep", "mesh_terms": null, "nlm_unique_id": "101682121", "other_id": null, "pages": "17", "pmc": null, "pmid": "29457061", "pubdate": "2017", "publication_types": "D016428:Journal Article", "references": "20376430;19329022;15269462;22709960;27833559;24102571;25652672;19188334;25899274;12351293;26638888;22156272;19471825;18635488;27542303;28072722;19567759", "title": "Postoperative management with dexmedetomidine in a pregnant patient who underwent AVM nidus removal: a case report.", "title_normalized": "postoperative management with dexmedetomidine in a pregnant patient who underwent avm nidus removal a case report" }

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"patientagegroup": null, "patientonsetage": "32", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KITSIRIPANT C, KAMATA K, KANAMORI R, YAMAGUCHI K, OZAKI M, NOMURA M. POSTOPERATIVE MANAGEMENT WITH DEXMEDETOMIDINE IN A PREGNANT PATIENT WHO UNDERWENT AVM NIDUS REMOVAL: A CASE REPORT. JA CLIN REP. 2017;3(17):4 PAGES", "literaturereference_normalized": "postoperative management with dexmedetomidine in a pregnant patient who underwent avm nidus removal a case report", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20171222", "receivedate": "20170525", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13580793, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180320" } ]

{ "abstract": "Bevacizumab (Avastin) is a recombinant humanized monoclonal antibody used for the management of various solid malignancies including colorectal, lung, brain, renal, and ovarian cancers as well as age-related macular degeneration of the eye. It is a vascular endothelial growth factor inhibitor which exhibits its action by blocking the growth of blood vessels in cancerous tissue. Common side effects include hypertension, fatigue, headaches, and increased risk of infections. Atypical hemolytic uremic syndrome is a serious side effect associated with bevacizumab due to its anti-angiogenic effect. It encompasses the clinical triad of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure, without any association with Shiga toxins. Eculizumab is a terminal complement inhibitor used in the treatment of atypical hemolytic uremic syndrome. Herein, we present three cases of bevacizumab-induced atypical hemolytic syndrome treated successfully with eculizumab.", "affiliations": "1 Department of Internal Medicine, MedStar Washington Hospital Center, Washington, DC, USA.;2 Department of Hematology and Oncology, Loyola University Medical Center, Maywood, IL, USA.;1 Department of Internal Medicine, MedStar Washington Hospital Center, Washington, DC, USA.;1 Department of Internal Medicine, MedStar Washington Hospital Center, Washington, DC, USA.;3 Division of Hematology and Oncology, Department of Internal Medicine, MedStar Washington Hospital Center, Washington, DC, USA.", "authors": "Vakiti|Anusha|A|;Singh|Daulath|D|https://orcid.org/0000-0002-0346-8501;Pilla|Ravi|R|;Alhaj-Moustafa|Muhamad|M|https://orcid.org/0000-0001-8582-1219;Fitzpatrick|Kelly W|KW|", "chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; C481642:eculizumab", "country": "England", "delete": false, "doi": "10.1177/1078155218774895", "fulltext": null, "fulltext_license": null, "issn_linking": "1078-1552", "issue": "25(4)", "journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners", "keywords": "Bevacizumab; atypical hemolytic uremic syndrome; complement; eculizumab; thrombotic microangiopathy", "medline_ta": "J Oncol Pharm Pract", "mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D065766:Atypical Hemolytic Uremic Syndrome; D000068258:Bevacizumab; D005260:Female; D006801:Humans; D008875:Middle Aged; D042461:Vascular Endothelial Growth Factor A", "nlm_unique_id": "9511372", "other_id": null, "pages": "1011-1015", "pmc": null, "pmid": "29768958", "pubdate": "2019-06", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Bevacizumab-induced atypical hemolytic uremic syndrome and treatment with eculizumab.", "title_normalized": "bevacizumab induced atypical hemolytic uremic syndrome and treatment with eculizumab" }

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