Datasets:

allenai

/

drug-combo-extraction

like 8

b5116da421faea4246da9634e6a9dfbc

Although MAPK/ERK1/2 kinase inhibitors ( MEKi ) are useful antitumor agents in a clinical setting , including the Food and Drug Administration (FDA)-approved MEK1,2 dual inhibitors cobimetinib and trametinib , there are limitations to their clinical utility , primarily adaptation of the BRAF pathway and ocular toxicities .

Dual inhibition of MEK1/2 and MEK5 suppresses the EMT/migration axis in triple-negative breast cancer through FRA-1 regulation. Triple-negative breast cancer (TNBC) presents a clinical challenge due to the aggressive nature of the disease and a lack of targeted therapies. Constitutive activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway has been linked to chemoresistance and metastatic progression through distinct mechanisms, including activation of epithelial-to-mesenchymal transition (EMT) when cells adopt a motile and invasive phenotype through loss of epithelial markers (CDH1), and acquisition of mesenchymal markers (VIM, CDH2). Although MAPK/ERK1/2 kinase inhibitors ( MEKi ) are useful antitumor agents in a clinical setting , including the Food and Drug Administration (FDA)-approved MEK1,2 dual inhibitors cobimetinib and trametinib , there are limitations to their clinical utility , primarily adaptation of the BRAF pathway and ocular toxicities . The MEK5 (HGNC: MAP2K5) pathway has important roles in metastatic progression of various cancer types, including those of the prostate, colon, bone and breast, and elevated levels of ERK5 expression in breast carcinomas are linked to a worse prognoses in TNBC patients. The purpose of this study is to explore MEK5 regulation of the EMT axis and to evaluate a novel pan-MEK inhibitor on clinically aggressive TNBC cells. Our results show a distinction between the MEK1/2 and MEK5 cascades in maintenance of the mesenchymal phenotype, suggesting that the MEK5 pathway may be necessary and sufficient in EMT regulation while MEK1/2 signaling further sustains the mesenchymal state of TNBC cells. Furthermore, additive effects on MET induction are evident through the inhibition of both MEK1/2 and MEK5. Taken together, these data demonstrate the need for a better understanding of the individual roles of MEK1/2 and MEK5 signaling in breast cancer and provide a rationale for the combined targeting of these pathways to circumvent compensatory signaling and subsequent therapeutic resistance.

https://pubmed.ncbi.nlm.nih.gov/33876843/

65c5329cada8f1320b2c0dfabcf7e776

Suggested evidence linking the association of the drug to the event includes knowing that Panitumumab and Irinotecan can contribute to all other possible causes of cardiac arrest , temporal relationship and pharmacological time plausibility , and recognized association with the product or the class .

A patient with metastatic colon cancer to the liver presenting with cardiac arrest status post receiving combination irinotecan-panitumumab: a case report. panitumumab is a recombinant human Immunoglobulin G antibody. irinotecan is an S-phase cell cycle specific plant alkaloid. Life threatening adverse events occur with panitumumab-chemotherapy combination. A Fifty three years old male with metastatic colon cancer to the liver started panitumumab-irinotecan palliative combination chemotherapy. On cycle two day twenty six the patient presented in the emergency room with cardiac arrest. Suggested evidence linking the association of the drug to the event includes knowing that Panitumumab and Irinotecan can contribute to all other possible causes of cardiac arrest , temporal relationship and pharmacological time plausibility , and recognized association with the product or the class . It is possible that there is a true association linking cardiac arrest to irinotecan-panitumumab combination. The aim of reporting this adverse event is to emphasize the recommendations of the National Comprehensive Cancer Network of discontinuing the use of panitumumab-chemotherapy combination in metastatic colon cancer patients.

https://pubmed.ncbi.nlm.nih.gov/21222364/

4780fc8f0fca92ed3f1c9809bf6f6a95

This study was designed to evaluate the effect of aprotinin on activated versus nonactivated whole blood clotting time using two different on-site methods and to quantify these anticoagulant properties when compared to heparin in a controlled , in vitro environment .

Aprotinin prolongs activated and nonactivated whole blood clotting time and potentiates the effect of heparin in vitro. This study was designed to evaluate the effect of aprotinin on activated versus nonactivated whole blood clotting time using two different on-site methods and to quantify these anticoagulant properties when compared to heparin in a controlled , in vitro environment . Blood specimens were obtained prior to heparin administration from 56 patients undergoing cardiac surgery. Specimens obtained from the first consecutive 20 patients were mixed with either normal saline (NS) or aprotinin (400 kallikrein inhibiting units (KIU)/mL), inserted into Hemochron tubes containing either NS or heparin (0.3 or 0.6 U/mL) and then used to measure celite-activated (celite ACT) and nonactivated whole blood clotting time (WBCT1) using four Hemochron instruments. Accordingly, specimens obtained from the second consecutive 20 patients were mixed with either NS or aprotinin, inserted into Automated Clot Timer cartridges containing either NS or heparin (0.06, 0.13, or 0.25 U/mL) and then used to measure kaolin-activated (kaolin ACT) or nonactivated whole blood clotting times (WBCT2) using four Automated Clot Timer instruments. Specimens obtained from the last 16 patients were mixed with either incrementally larger doses of aprotinin (0, 100, 200, 300, or 400 KIU/mL) or heparin (0, 0.12, 0.24, 0.36, 0.48, or 0.72 U/mL) and were then used for measurement of whole blood clotting time (WBCT2) using six Automated Clot Timer instruments. aprotinin significantly prolonged activated or nonactivated whole blood clotting time and potentiated the prolongation of whole blood clotting time by heparin. The linear relationship between whole blood clotting time and either heparin concentration (WBCT2 = H x 357 + 280, mean adjusted r2 = 0.88) or aprotinin concentration (WBCT2 = A x 0.97 + 300, mean adjusted r2 = 0.94) was variable among patients. On average, 200 KIU/mL of aprotinin prolonged WBCT2 to the same extent as 0.69 +/- 0.28 U/mL of heparin using linear regression models within each patient. aprotinin significantly prolongs activated or nonactivated whole blood clotting time measurements in a dose-dependent manner. Since prolongation of whole blood clotting time by heparin is potentiated by aprotinin in vitro, aprotinin's anticoagulant properties may in part account for the prolonged celite activated clotting time values observed in the presence of aprotinin.

https://pubmed.ncbi.nlm.nih.gov/8638779/

8c3b17fb6111c8666586a609f323991e

Cyclophosphamide , mitoxantrone , fluorouracil versus conventional CMF as adjuvant treatment in node-positive breast cancer patients .

Cyclophosphamide , mitoxantrone , fluorouracil versus conventional CMF as adjuvant treatment in node-positive breast cancer patients . 362 evaluable node-positive patients with stage II breast cancer were randomized, receiving either 6 cycles of conventional CMF or 6 cycles of the combination of cyclophosphamide (500 mg/m2), mitoxantrone (Novantrone 10 mg/m2), and fluorouracil (500 mg/m2; CNF). After a median follow-up of 51 months, 64 (36%) patients relapsed in the CMF group and 60 (33%) in the CNF group (p=0.8276). By Cox multivariate analysis, tumor size, menopausal status and number of involved nodes were retained as independently significant variables. Toxicities were remarkably similar in both groups. It appears that after a median follow-up of 51 months there is no significant difference in relapse-free survival between node-positive patients with breast cancer who received either 6 cycles of the conventional CMF or the CNF combination as adjuvant treatment.

https://pubmed.ncbi.nlm.nih.gov/8604240/

c42e30d67d6e1065eaf786efb226f38a

After the operation , an alternating vincristine , doxorubicin , and cyclophosphamide/ifosfamide and etoposide ( IE ) regimen was given for eight cycles , and the patient survived for 66 mo without progression .

Primitive neuroectodermal tumors of the abdominal wall and vulva in children: Report of two cases and review of the literature. Primitive neuroectodermal tumors are rare, highly malignant small round cell tumors belonging to the Ewing sarcoma family. The purpose of this article is to present clinical manifestation, histology, treatment, and prognosis of two primitive neuroectodermal tumors (PNETs) in extremely rare anatomic locations, the abdominal wall and vulva. ### Case Summary Case 1 was a 66-month-old girl with lesions on the abdominal wall; tumor size was about 3.4 cm × 6.1 cm × 2 cm. The patient underwent radical resection of the tumor. After the operation , an alternating vincristine , doxorubicin , and cyclophosphamide/ifosfamide and etoposide ( IE ) regimen was given for eight cycles , and the patient survived for 66 mo without progression . Case 2 was a 40-month-old girl, with a vulvar lesion; tumor size was about 3.3 cm × 5 cm × 2.5 cm. The tumor was partially resected by surgery. The family left treatment after two cycles of vincristine, pirarubicin, and cyclophosphamide/IE chemotherapy, and the patient died at home six months after surgery. ### conclusion PNET is a rare, fast-growing, highly malignant tumor that requires histologic and molecular analyses for exact diagnosis, and multimodal treatment is required to achieve a good prognosis.

https://pubmed.ncbi.nlm.nih.gov/31750352/

2abe808f1283fbec87893dc71eb3d9d0

A total of 34 patients with androgen-independent prostate cancer received doxorubicin , 30 mg/m(2 ) , every 2 weeks and ketoconazole daily , 400 mg orally every 8 hours .

Biweekly doxorubicin/ketoconazole as second-line treatment in docetaxel-resistant, hormone-refractory prostate cancer. docetaxel is an effective first-line treatment for hormone-refractory prostate cancer. Nevertheless, the prognosis subsequent to progression after first-line therapy is poor and no second-line treatment has been established. ### methods A total of 34 patients with androgen-independent prostate cancer received doxorubicin , 30 mg/m(2 ) , every 2 weeks and ketoconazole daily , 400 mg orally every 8 hours . All patients had been treated with docetaxel and had disease progression within 6 months after completion of first-line treatment. ### results Of the 32 evaluable patients, 13 (43.7%, 95% confidence interval [CI] 26.3% to 62.3%) had a prostate-specific antigen (PSA) response, and 4 (28%, 95% CI 8.4% to 58.1%) of 14 patients with measurable disease had a response to therapy. The median time to progression (TTP) was 3.9 months (95% CI 2.0 to 5.9), and the median overall survival (OS) was 13 months (95% CI 8.7 to 17.3). Toxicity was mild, with only 4 cases of nonhematologic grade 3 or 4 toxicity. The most frequent toxicity was nail changes (33 of 34 patients), which was mainly grade 1 (30 cases). ### conclusions The combination of biweekly doxorubicin and ketoconazole is an effective, well-tolerated, second-line therapy for hormone-refractory prostate cancer.

https://pubmed.ncbi.nlm.nih.gov/18400264/

9ab4556c1196ea2c960f5d09e418cdc3

All 35 patients were treated with the ANLL91 protocol consisting of etoposide , high-dose cytarabine , and anthracyclines .

Superior outcome of infant acute myeloid leukemia with intensive chemotherapy: results of the Japan Infant Leukemia Study Group. This study analyzed data on 35 infants with acute myeloid leukemia (AML) who were treated with intensive chemotherapy between 1995 and 1998 in Japan. The incidence of boys, younger age (< 6 months old), and hyperleukocytosis at onset was high in patients with the M4/M5 subtype (n = 23) in the French-American-British classification, compared with the non-M4/M5 subtype (n = 12). Thirteen (56%) and 16 (70%) patients with the M4/M5 subtype also showed 11q23 translocations and MLL gene rearrangements, respectively, whereas only one patient with the non-M4/M5 subtype had this rearrangement. All 35 patients were treated with the ANLL91 protocol consisting of etoposide , high-dose cytarabine , and anthracyclines . Overall survival and the event-free survival (EFS) rates at 3 years of all patients were 76% (95% confidence interval [CI], 61.3%-90.7%) and 72% (95% CI, 56.4%-87.9%), respectively. EFS showed no significant difference between 2 subgroups divided by age, gender, presence of the MLL gene rearrangements, and white blood cell count at onset; EFS in patients with the M4/M5 subtype tended to be better than those with the non-M4/M5 subtype. Although all 6 patients who underwent allogeneic stem cell transplantation (SCT) have been in complete remission, no benefit of SCT was confirmed. These findings suggest that the intensive chemotherapy with the ANLL91 protocol might have been responsible for the observed good outcome of infant AML, even without SCT. The presence of the MLL gene rearrangements or the age at onset had no impact on the outcome of infant AML.

https://pubmed.ncbi.nlm.nih.gov/11739161/

bcc762ec6c76266e0e6aefaf388b355a

Three first-line drugs are recommended , pegylated interferon alfa-2a , entecavir and tenofovir .

[Interferon-based versus direct antiviral therapy in patients with chronic hepatitis B]. Treatment of chronic hepatitis B is still challenging. Lots of parameters are needed to be considered before and during the therapy. There are several possible endpoints and their durability is very much variable. Patients with HBeAg-positive and HBeAg-negative hepatitis B need treatment. Two different strategies are available. Interferon-based therapy is a limited treatment, which might result in a sustained immune response in about one third of the patients, leading to an induced remission, sometimes years after the end of the treatment. According to the other strategy a continuous, indefinite oral nucleoside/nucleotide analogue (NA) treatment is administered to maintain a remission. However, relapse is rather frequent after the cessation of this therapy. During the long-term NA treatment drug resistance can lead to the loss of antiviral effect. Three first-line drugs are recommended , pegylated interferon alfa-2a , entecavir and tenofovir . If there is no contraindication to interferon, it is worth trying to achieve immune control and an induced remission. In patients, who do not respond to interferon, a sequential NA therapy is indicated.

https://pubmed.ncbi.nlm.nih.gov/21565754/

535a0b7e66c0a1aefa21cf4a5d88c31f

Whereas fluoxetine showed the highest level of specificity , followed by citalopram and fluvoxamine , the effect of paroxetine was nonspecific .

Comparison of the effects of the selective serotonin-reuptake inhibitors fluoxetine, paroxetine, citalopram and fluvoxamine in alcohol-preferring cAA rats. Clinical studies indicate that selective serotonin-reuptake inhibitors (SSRIs) may decrease alcohol intake and craving in particular subgroups of alcoholics. The aim of the present study was to compare the behavioral profile of various SSRIs in alcohol-preferring cAA rats, a genetic model of alcoholism. The effects of acute IP administration of fluoxetine (doses in mg/kg 1-10), citalopram (3-30), fluvoxamine (3-30) and paroxetine (1-10) on ethanol (EtOH) intake and preference, as well as food and total fluid intake, were determined in a 12-h access, water vs. 10% v/v EtOH two-bottle choice paradigm. Each compound reduced EtOH intake [Minimal Effective Doses (MEDs) 5, 10, 30 and 1 mg/kg for fluoxetine, citalopram, fluvoxamine, and paroxetine, respectively]. The degree of selectivity, that is, the extent to which reductions in EtOH intake could be separated from reductions in food and/or total fluid intake varied across the compounds. Thus, whereas EtOH intake was more markedly affected than food intake by fluoxetine, both parameters were equally affected by citalopram, and food intake was more markedly affected than EtOH intake by fluvoxamine and paroxetine. The anti-alcohol effect also differed with respect to specificity, that is, the degree to which effects on EtOH intake coincided with effects on EtOH preference. Whereas fluoxetine showed the highest level of specificity , followed by citalopram and fluvoxamine , the effect of paroxetine was nonspecific . The observed variation in the degree of selectivity and specificity of the anti-alcohol effect of SSRIs suggests that reductions in EtOH intake are not merely a consequence of a general suppressive effect on consummatory behavior. It is hypothesized that differences between the behavioral profiles of these compounds reflect a differential involvement of 5-HT receptor subtypes.

https://pubmed.ncbi.nlm.nih.gov/10231167/

7d7538f51ee43a6cd516678f3e0cc07f

A countercurrent seepage bioreactor immobilized with Phanerochaete chrysosporium was continuously operated under non-sterile conditions to treat a synthetic wastewater spiked with naproxen and carbamazepine ( 1000μg/L each ) for 165days .

Enhanced removal of naproxen and carbamazepine from wastewater using a novel countercurrent seepage bioreactor immobilized with Phanerochaete chrysosporium under non-sterile conditions. A countercurrent seepage bioreactor immobilized with Phanerochaete chrysosporium was continuously operated under non-sterile conditions to treat a synthetic wastewater spiked with naproxen and carbamazepine ( 1000μg/L each ) for 165days . There were no serious bacterial contaminations occurred during the operational period. naproxen was always removed to the undetectable level regardless of the experimental conditions, while the average removal efficiency for carbamazepine, a well-known recalcitrant pharmaceutically active compound, reached around 80%. The excellent removal performance was mainly attributed to the application of countercurrent seepage mode and the cardhouse fabric of the carriers, which provided the high efficiency in the transfer of oxygen and nutrients inside the bioreactor. From the fungal immobilization combined with the temperature adjustment, the fungal activity including the enzyme production was protected as well as the bacterial contamination inside the reactor was suppressed effectively.

https://pubmed.ncbi.nlm.nih.gov/26356119/

a8b7e8418f86bcec5b2f8c04f4141ca3

A phase 1/2 trial of tivozanib in combination with durvalumab is currently underway .

A multicentre phase 1b/2 study of tivozanib in patients with advanced inoperable hepatocellular carcinoma. Hepatocellular carcinoma (HCC) is a major cause of cancer-related death. It is a highly vascular tumour with multiple angiogenic factors, most importantly vascular endothelial growth factor (VEGF), involved in HCC progression. tivozanib is an oral inhibitor of VEGFR-1/2/3 with promising activity against HCC in vivo. ### methods We conducted a phase 1b/2 study of tivozanib in patients with advanced HCC. The safety, dosing, pharmacokinetics, pharmacodynamics, and preliminary antineoplastic efficacy of tivozanib were evaluated. ### results Twenty-seven patients received at least one dose of tivozanib. Using a 3+3 design, the recommended phase 2 dose (RP2D) of tivozanib was determined to be 1 mg per os once daily, 21 days on-7 days off. The median progression-free and overall survival were 24 weeks and 9 months, respectively, for patients treated at RP2D. The overall response rate was 21%. Treatment was well tolerated. A significant decrease in soluble plasma VEGFR-2 was noted, assuring adequate target engagement. ### conclusions Although this study did not proceed to stage 2, there was an early efficacy signal with a very favourable toxicity profile. A phase 1/2 trial of tivozanib in combination with durvalumab is currently underway . ### Trial Registration ClinicalTrials.gov NCT01835223, registered on 15 April 2013.

https://pubmed.ncbi.nlm.nih.gov/32037403/

633a9c1a5d3f0a2ff30edccdc7a7b47d

Health-related quality of life of patients with advanced breast cancer treated with everolimus plus exemestane versus placebo plus exemestane in the phase 3 , randomized , controlled , BOLERO-2 trial .

Health-related quality of life of patients with advanced breast cancer treated with everolimus plus exemestane versus placebo plus exemestane in the phase 3 , randomized , controlled , BOLERO-2 trial . The randomized, controlled BOLERO-2 (Breast Cancer Trials of Oral everolimus) trial demonstrated significantly improved progression-free survival with the use of everolimus plus exemestane (EVE + EXE) versus placebo plus exemestane (PBO + EXE) in patients with advanced breast cancer who developed disease progression after treatment with nonsteroidal aromatase inhibitors. This analysis investigated the treatment effects on health-related quality of life (HRQOL). ### methods Using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) questionnaire, HRQOL was assessed at baseline and every 6 weeks thereafter until disease progression and/or treatment discontinuation. The 30 items in 15 subscales of the QLQ-C30 include global health status wherein higher scores (range, 0-100) indicate better HRQOL. This analysis included a protocol-specified time to definitive deterioration (TDD) analysis at a 5% decrease in HRQOL versus baseline, with no subsequent increase above this threshold. The authors report additional sensitivity analyses using 10-point minimal important difference decreases in the global health status score versus baseline. Treatment arms were compared using the stratified log-rank test and Cox proportional hazards model adjusted for trial stratum (visceral metastases, previous hormone sensitivity), age, sex, race, baseline global health status score and Eastern Cooperative Oncology Group performance status, prognostic risk factors, and treatment history. ### results Baseline global health status scores were found to be similar between treatment groups (64.7 vs 65.3). The median TDD in HRQOL was 8.3 months with EVE + EXE versus 5.8 months with PBO + EXE (hazard ratio, 0.74; P = .0084). At the 10-point minimal important difference, the median TDD with EVE + EXE was 11.7 months versus 8.4 months with PBO + EXE (hazard ratio, 0.80; P = .1017). ### conclusions In patients with advanced breast cancer who develop disease progression after treatment with nonsteroidal aromatase inhibitors, EVE + EXE was associated with a longer TDD in global HRQOL versus PBO + EXE.

https://pubmed.ncbi.nlm.nih.gov/23504821/

865421d64e83a88ada0161460aaf3811

Phase 2 study of irinotecan and paclitaxel in patients with recurrent or refractory small cell lung cancer .

Phase 2 study of irinotecan and paclitaxel in patients with recurrent or refractory small cell lung cancer . Patients with extensive stage small cell lung cancer (SCLC) who develop disease progression with standard cisplatin-based therapy are reported to have a poor overall prognosis. irinotecan and paclitaxel are active as single agents and exhibit preclinical synergy in SCLC cell lines. A phase 2 study was conducted to evaluate this combination in patients with recurrent or refractory SCLC. ### methods Patients with SCLC who progressed with 1 prior chemotherapy regimen and had measurable disease present; an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2; and adequate bone marrow, hepatic, and renal function were included in the study. paclitaxel (at a dose of 75 mg/m(2)) and irinotecan (at a dose of 50 mg/m(2)) were administered intravenously on Days 1 and 8 of each 3-week treatment cycle. Therapy was continued until disease progression or unacceptable toxicity. The target response rate of interest was > or =30%. ### results A total of 55 patients were enrolled, 51 of whom received at least 1 dose of therapy. The majority of the patients had an ECOG PS of 0 or 1 (96%). A median of 3 cycles of treatment was administered, and 15 patients received > or =6 cycles. Seventeen patients experienced toxicity of grade 3 or higher (neutropenia in 8 patients and fatigue in 5 patients). The overall response rate was 21%. The median survival was 25.4 weeks, and the 1-year survival rate was 22%. ### conclusions The regimen of irinotecan and paclitaxel was found to be tolerated well in patients with recurrent or refractory SCLC. Although modest anticancer activity was noted, the efficacy failed to meet the primary endpoint of interest.

https://pubmed.ncbi.nlm.nih.gov/20082454/

8e26b126191a14bcd647bd171f672f4d

Administration of artesunate and artemether at a dose of 400mg/kg to O. viverrini-infected hamsters resulted in worm burden reductions of 77.6 % and 65.5 % , respectively .

Effect of artesunate and artemether against Clonorchis sinensis and Opisthorchis viverrini in rodent models. Food-borne trematodiasis is an emerging public health problem and there is a need to develop novel treatment options. We examined the in vivo efficacy of single oral doses of artesunate and artemether administered to rodents experimentally infected with either Clonorchis sinensis or Opisthorchis viverrini. Rats infected with adult C. sinensis were administered artesunate or artemether at doses of 75, 150 or 300 mg/kg. Hamsters infected with adult O. viverrini were administered artesunate or artemether at doses of 200, 400 or 600 mg/kg. Treatment efficacy was assessed according to reductions in worm burden compared with infected but untreated control animals. Worm burden reductions of 98.6-100% were found in C. sinensis-infected rats after a single dose of artesunate and artemether at 150 mg/kg. Administration of artesunate and artemether at a dose of 400mg/kg to O. viverrini-infected hamsters resulted in worm burden reductions of 77.6 % and 65.5 % , respectively . However, both drugs showed toxic effects when administered to O. viverrini-infected hamsters at a dose > or =400mg/kg. Our study demonstrates that artesunate and artemether possess excellent clonorchicidal activities in vivo. These findings provide a foundation for subsequent clinical trials. More laboratory investigations are warranted to investigate further the opisthorchicidal properties of the artemisinins.

https://pubmed.ncbi.nlm.nih.gov/16973335/

f2744a73ce29996ed3582ac62f9368c6

Whereas no effect on proliferation , cell culture density , or cell cycle was detected , the transfectants were more resistant than the parental cell line to apoptosis induced by chemotherapeutic agents including etoposide , daunorubicin , doxorubicin , cytosine arabinoside , methotrexate and vincristine and also to apoptosis induced by Fas/CD95 cross-linking .

Antiapoptotic effect of ectopic TAL1/SCL expression in a human leukemic T-cell line. Aberrant expression of TAL1 occurs frequently in human T-cell acute lymphoblastic leukemia. The effect of TAL1 expression in the T-cell lymphoid precursor, however, remains unclear. In the current study, we have developed TAL1 stable transfectants in a human immature T-cell lymphoid cell line. Whereas no effect on proliferation , cell culture density , or cell cycle was detected , the transfectants were more resistant than the parental cell line to apoptosis induced by chemotherapeutic agents including etoposide , daunorubicin , doxorubicin , cytosine arabinoside , methotrexate and vincristine and also to apoptosis induced by Fas/CD95 cross-linking . This effect was independent of the cytostatic effects of the drugs. The basic domain-deleted transfectants did not demonstrate altered sensitivity, suggesting that DNA binding was necessary for resistance to apoptosis. The ability to alter the response to a wide range of cell death-inducing stimuli suggests that TAL1 acts at a late stage of the apoptotic cascade. These data therefore provide direct evidence of an antiapoptotic effect of ectopic TAL1 expression in response to cytotoxic agents, thus providing insight into its oncogenic function in T-cell acute lymphoblastic leukemia and a novel experimental model to further investigate the underlying mechanisms. These data also have potential practical significance for cytotoxic therapy of this disorder.

https://pubmed.ncbi.nlm.nih.gov/9635597/

99715e32028be1dcc1747371a19df937

This was a multicenter phase II pilot study of rituximab and modified hyper-fractionated cyclophosphamide , vincristine doxorubicin , dexamethasone ( modified R-hyperCVAD ) administered every 28 days for four to six cycles followed by rituximab maintenance therapy consisting of four weekly doses every 6 months for 2 years .

Maintenance rituximab following induction chemoimmunotherapy may prolong progression-free survival in mantle cell lymphoma: a pilot study from the Wisconsin Oncology Network. There is no standard first line treatment for mantle cell lymphoma. ### Patients And Methods This was a multicenter phase II pilot study of rituximab and modified hyper-fractionated cyclophosphamide , vincristine doxorubicin , dexamethasone ( modified R-hyperCVAD ) administered every 28 days for four to six cycles followed by rituximab maintenance therapy consisting of four weekly doses every 6 months for 2 years . Unlike traditional hyperCVAD regimens, no methotrexate or cytarabine was administered. ### results Of 22 patients, the overall response rate was 77% and the complete response rate was 64%. With a median follow-up time of 37 months in surviving patients, the median PFS was 37 months and the median OS was not reached. The achievement of a molecular remission did not correlate with improved outcome. The major toxicity was expected myelosuppression. Two patients died during induction treatment. There were no major adverse effects during maintenance therapy. ### conclusion In a multicenter trial, modified R-hyperCVAD was tolerable and effective induction therapy for untreated MCL. Maintenance rituximab appeared to prolong PFS without increasing toxicity.

https://pubmed.ncbi.nlm.nih.gov/16766582/

a671a1895cecb359321715c750639925

The first line of treatment is selective serotonin reuptake inhibitors ( dapoxetine , which is the only drug with an official label for this indication , paroxetine , sertraline , fluoxetine , citalopram , escitalopram ) .

[THE FIRST CROATIAN GUIDELINES FOR DIAGNOSIS, TREATMENT AND FOLLOW-UP OF PERSONS WITH PREMATURE EJACULATION]. Premature ejaculation (PE) is a sexual disorder with high prevalence, defined by three characteristics: short intravaginal ejaculation latency time, poor control over delaying ejaculation and personal and/or partner distress. The diagnosis is reached by a thorough and comprehensive history taking, which should include presence/absence of other ­co-morbid conditions (e.g. erectile dysfunction, anxiety), and assessing the type of PE (primary, secondary, variable, subjective). It is important to counsel the patient (and, if possible, the partner) about this condition and treatment options. The first line of treatment is selective serotonin reuptake inhibitors ( dapoxetine , which is the only drug with an official label for this indication , paroxetine , sertraline , fluoxetine , citalopram , escitalopram ) . The first line of treatment also includes psychological/sexological treatment methods, such as behavioural methods (stop-start and squeeze techniques), and new functional sexological treatment. The choice of the method depends on the type of PE and on the patient preference. The second line of treatment are clomipramine and local anaesthetics, and the third line is tramadol.

https://pubmed.ncbi.nlm.nih.gov/30148566/

15cd880937122f95fe839bf853a93050

This trial will close to accrual in September 1995 , and analysis of the trial should provide useful information regarding the potential synergy of doxorubicin and paclitaxel , the degree of cross-resistance between the two compounds , and the relationship between steady-state paclitaxel levels and response to therapy .

Doxorubicin/paclitaxel combination chemotherapy for metastatic breast cancer: the Eastern Cooperative Oncology Group experience. The addition of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to the therapeutic armamentarium for breast cancer has resulted in novel opportunities and challenges for the clinician. In a series of trials that began in 1992, the Eastern Cooperative Oncology Group (ECOG) investigated the role of paclitaxel in combination with doxorubicin for the treatment of patients with advanced breast cancer. The design of the first trial, a limited-institution pilot study, involved alternating doxorubicin and paclitaxel as single agents. The alternating schedule was well tolerated and associated with objective responses in seven of 12 patients entered into the trial. In the second trial, a limited-institution phase I trial, bolus doxorubicin was combined with paclitaxel administered over a 24-hour infusion, with administration of the two drugs separated by 4 hours. While no dose-limiting toxicity was seen at doses of 50 and 150 mg/m2 of doxorubicin and paclitaxel, respectively, dose-limiting mucositis occurred at respective doses of 60 and 175 mg/m2. Mucositis was more common when administration of paclitaxel preceded that of doxorubicin than when doxorubicin preceded paclitaxel. Based on these results, the ECOG initiated a phase III trial comparing single-agent paclitaxel, single-agent doxorubicin, and the combination of paclitaxel and doxorubicin. This study, now an Intergroup trial of ECOG, the Southwest Oncology Group, and the North Central Cancer Treatment Group, is designed to accrue 730 patients. This trial will close to accrual in September 1995 , and analysis of the trial should provide useful information regarding the potential synergy of doxorubicin and paclitaxel , the degree of cross-resistance between the two compounds , and the relationship between steady-state paclitaxel levels and response to therapy . In addition, ECOG is currently conducting a trial designed to confirm the striking activity of cisplatin and paclitaxel seen in the British Columbia trials. Future trials by the group will examine means of combining paclitaxel with other active agents.

https://pubmed.ncbi.nlm.nih.gov/7481854/

b192b6a0aef4cfe50e4130cdcc468ea0

Neither systolic nor diastolic BP during daytime differed between losartan and quinapril treatments , but those during nighttime were lower with losartan treatment than with quinapril treatment .

Effect of losartan on nocturnal blood pressure in patients with stroke: comparison with angiotensin converting enzyme inhibitor. Treatment of nocturnal hypertension has been reported to be beneficial for primary and secondary prevention of stroke. We compared the effects of angiotensin II antagonist (losartan) and angiotensin converting enzyme inhibitor (quinapril) on nocturnal blood pressure (BP) and sympathetic nervous activity in patients with hypertension and stroke. ### methods According to a prospective, randomized, cross-over design, 30 hypertensive patients with a previous history of stroke (25 hemorrhage, 5 infarction) were assigned randomly to receive losartan (50 mg) or quinapril (10 mg) once daily for 4 weeks. The patients were switched to the alternative regimen for an additional 4-week period. In the last week of each treatment, 24-h ambulatory BP monitoring was performed every 30 min, and 24-h urine was collected for the measurement of catecholamine. ### results Neither systolic nor diastolic BP during daytime differed between losartan and quinapril treatments , but those during nighttime were lower with losartan treatment than with quinapril treatment . The nocturnal decreases in systolic and diastolic BP were both greater with losartan treatment than with quinapril treatment (systolic BP: 6.1% +/- 5.9% v 2.5% +/- 6.9%, diastolic BP: 6.4% +/- 6.5% v 3.3% +/- 7.8%, both P <.05). The nocturnal decrease in urinary norepinephrine excretion was greater with losartan treatment than with quinapril treatment (52.8% +/- 9.7% v 42.8% +/- 17.2%, P <.05). ### conclusions losartan enhances the nocturnal decrease in ambulatory BP compared with that of quinapril in patients with a previous history of stroke presumably by way of the suppression of nocturnal sympathetic nervous activity.

https://pubmed.ncbi.nlm.nih.gov/12441222/

1a04ee3c95f14be4b4b3fab51f305686

Ferrochloroquine was 35 times more active than chloroquine ( 35-fold greater against chloroquine-resistant isolates ) , quinine , mefloquine , amodiaquine , cycloguanil and pyrimethamine .

In vitro activities of ferrochloroquine against 55 Senegalese isolates of Plasmodium falciparum in comparison with those of standard antimalarial drugs. The in vitro activities of ferrochloroquine, chloroquine, quinine, mefloquine, halofantrine, amodiaquine, artesunate, atovaquone, cycloguanil and pyrimethamine were evaluated against Plasmodium falciparum isolates from Senegal (Dielmo, Ndiop), using an isotopic micro-drug susceptibility test. The IC50 values for ferrochloroquine ranged from 0.55 to 28.2 nM and the geometric mean IC50 for the 55 isolates was 7.9 nM (95% CI, 6.5-9.7 nM). Ferrochloroquine was 35 times more active than chloroquine ( 35-fold greater against chloroquine-resistant isolates ) , quinine , mefloquine , amodiaquine , cycloguanil and pyrimethamine . Weak positive correlations were observed between the responses to ferrochloroquine and that to chloroquine, quinine, and amodiaquine, but not compulsorily predictive of cross-resistance. There was no significant correlation between the response to ferrochloroquine and that to mefloquine, halofantrine, artesunate, atovaquone, cycloguanil and pyrimethamine. Ferrochloroquine may be an important alternative drug for the treatment of chloroquine-resistant malaria.

https://pubmed.ncbi.nlm.nih.gov/11903989/

a6bbfa01a0f2e4447d4dee91f8973540

26 patients received adjuvant chemotherapy ( carboplatin plus etoposide ) .

Outcomes of adult medulloblastoma treated with a multimodality approach: A tertiary cancer center experience. Adult medulloblastoma (AMB) is a rare central nervous system tumor. We aimed to analyze the treatment outcomes of AMB treated at our institute with surgery followed by craniospinal irradiation (CSI) and adjuvant chemotherapy. ### methods We retrospectively evaluated the treatment charts of 31 patients of AMB treated from 2003-2011. The patient demography, treatment details and survival data were collected in a predesigned proforma. Kaplan Meier method was used to analyze disease free survival (DFS) and the impact of prognostic factors was determined by univariate analysis (log rank test). ### results Male: Female ratio was 21:10. Cerebrospinal fluid dissemination was noted in 16% cases. CSI (36 Gray at 1.8 Gray/fraction to entire neuraxis and 20 Gray at 2 Gray/fraction boost to posterior fossa) was used in all cases. 26 patients received adjuvant chemotherapy ( carboplatin plus etoposide ) . Median follows up was 26.85 months (9.47-119.73 months). The estimated 3 and 5 years DFS was found to be 84.9% and 50.7% respectively. On univariate analysis, tumor located laterally had a trend towards better DFS (HR 3.04; 95%CI 0.722 to 12.812; P = 0.07) compared to midline tumors. Other factors like adjuvant chemotherapy, age, gender, surgical extent had no statistically significant impact on survival. ### conclusion The results of our study (largest series from India) show that the regimen of surgery, adjuvant CSI and chemotherapy is feasible and confers descent survival. AMB patients should be treated with a multimodality approach in a tertiary care centre.

https://pubmed.ncbi.nlm.nih.gov/26981508/

a8cf0a76ea1128997862a247fb4b2943

A concentration-dependent effect of venetoclax on PFS and a prolonged synergistic effect of 6 cycles of concomitant rituximab were identified .

Relationship between venetoclax exposure, rituximab coadministration, and progression-free survival in patients with relapsed or refractory chronic lymphocytic leukemia: demonstration of synergy. venetoclax is indicated at a dosage of 400 mg daily (QD) for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least 1 prior therapy. Ongoing trials are evaluating venetoclax in combination with CD20 targeting monoclonal antibodies, such as rituximab. The objective of this research was to characterize the relationship between venetoclax exposures and progression-free survival (PFS) and to evaluate the effect of rituximab coadministration on PFS in patients with relapsed or refractory (R/R) CLL/small lymphocytic lymphoma (SLL). A total of 323 patients from 3 clinical studies of venetoclax, with and without rituximab coadministration, were pooled for the analyses. A time-variant relative risk survival model was used to relate plasma venetoclax concentrations and rituximab administration to PFS. Demographics and baseline disease characteristics were evaluated for their effect on PFS. A concentration-dependent effect of venetoclax on PFS and a prolonged synergistic effect of 6 cycles of concomitant rituximab were identified . The 17p deletion chromosomal aberration was not identified to affect the PFS of patients treated with venetoclax. A venetoclax dose of 400 mg daily QD was estimated to result in a substantial median PFS of 1.8 years (95% confidence interval [CI], 1.7-2.1), whereas the addition of 6 cycles of rituximab was estimated to increase the median PFS to 3.9 years (95% CI, 2.8-5.6). The analysis demonstrates a concentration-dependent effect of venetoclax on PFS and also a synergistic effect with rituximab. Combining venetoclax with the CD20 targeting monoclonal antibody rituximab in R/R CLL/SLL patients provides substantial synergistic benefit compared with increasing the venetoclax monotherapy dose.

https://pubmed.ncbi.nlm.nih.gov/27982454/

b52fd7bcfc63c0a50d7d339cba68d21e

Carboplatin plus taxanes are non-inferior to epirubicin plus cyclophosphamide followed by taxanes as adjuvant chemotherapy for early triple-negative breast cancer .

Carboplatin plus taxanes are non-inferior to epirubicin plus cyclophosphamide followed by taxanes as adjuvant chemotherapy for early triple-negative breast cancer . Platinum plays an important role in the treatment of triple-negative breast cancer (TNBC) in neoadjuvant and metastatic settings. However, its role in an adjuvant setting remains unclear. ### methods In this non-inferior randomized phase 2 trial, we randomly assigned 308 chemotherapy-naive patients with histologically confirmed TNBC after primary surgery to receive either six cycles of TP (docetaxel: 75 mg/m ### results At a median follow-up of 66.9 months, the 5-year DFS rate was 85.8% in the EC-T arm, and 84.4% in the TP arm (p non-inferiority = 0.034, p log-rank = 0.712). The 5-year overall survival (OS) rate was 94.4% in the EC-T arm and 93.5% in the TP arm (p = 0.770). Patients in the TP arm showed better compliance and experienced significantly lower frequencies of G3/4 neutrocytopenia and G3/4 alopecia, but higher rates of G1-4 thrombocytopenia than those in the EC-T arm. Patients with PD-L1 expressing tumors showed significantly improved DFS and OS. ### conclusions This study indicates that carboplatin plus taxanes could be a feasible adjuvant chemotherapy for patients with early TNBC who are cannot tolerate intensive chemotherapy with anthracycline.

https://pubmed.ncbi.nlm.nih.gov/32394350/

af17cef122c896fa9e25abf3226ef005

Comparative study of ceftriaxone monotherapy versus a combination regimen of cefuroxime plus gentamicin for treatment of serious bacterial infections : the efficacy , safety and effect on fecal flora .

Comparative study of ceftriaxone monotherapy versus a combination regimen of cefuroxime plus gentamicin for treatment of serious bacterial infections : the efficacy , safety and effect on fecal flora . To assess the efficacy of once daily monotherapy relative to standard combination antibiotic therapy for the initial management of patients suspected of serious bacterial infections, we conducted a randomized trial comparing ceftriaxone (Rocephin) with a combination of cefuroxime plus gentamicin. Of 105 patients, 53 were treated with ceftriaxone alone and 52 with the combination; 13 patients were considered not evaluable. 42 of 53 patients given ceftriaxone and 33 of 52 given cefuroxime plus gentamicin responded to treatment (p = 0.07). Three patients given ceftriaxone and 6 who received gentamicin plus cefuroxime died (p = 0.28). Definite bacterial infections were identified in 67 patients; of the evaluable patients with a definite infection 27 of 29 who received ceftriaxone and 21 of 31 who were treated with the combination were cured (p = 0.01). No difference was found in the number of side effects. However, therapy had to be discontinued due to treatment failure, an adverse effect or death in 1 of 33 patients given ceftriaxone and in 11 of 34 given the combination (p = 0.002). ceftriaxone was found to have an impact on the count of E. coli in intestinal microflora. Changes in normal bacterial composition did not lead to the overgrowth with resistant Enterobacteriaceae or Pseudomonas, however, colonization by yeast was observed. Using ceftriaxone reduced the cost of antimicrobial therapy per patient by 107 pounds (US$ 183). Moreover, the total time save per patient due to decreased nursing and drug administration time per day was 40 min.(ABSTRACT TRUNCATED AT 250 WORDS)

https://pubmed.ncbi.nlm.nih.gov/3149929/

53378bb1670658cc548bb5bc1d6ea7a4

A phase 1b , dose escalation study was performed to assess maximum tolerated dose , safety/toxicity , clinical efficacy and explored pharmacodynamic biomarkers of response to entinostat combined with lapatinib with or without trastuzumab .

A phase Ib study of entinostat plus lapatinib with or without trastuzumab in patients with HER2-positive metastatic breast cancer that progressed during trastuzumab treatment. Human epidermal growth factor 2 (HER2) is an effective therapeutic target in breast cancer; however, resistance to anti-HER2 agents such as trastuzumab and lapatinib develops. In a preclinical model, an HDAC inhibitor epigenetically reversed the resistance of cancer cells to trastuzumab and showed synergistic efficacy with lapatinib in inhibiting growth of trastuzumab-resistant HER2-positive (HER2+) breast cancer. ### methods A phase 1b , dose escalation study was performed to assess maximum tolerated dose , safety/toxicity , clinical efficacy and explored pharmacodynamic biomarkers of response to entinostat combined with lapatinib with or without trastuzumab . ### results The combination was safe. The MTD was lapatinib, 1000 mg daily; entinostat, 12 mg every other week; trastuzumab, 8 mg/kg followed by 6 mg/kg every 3 weeks. Adverse events included diarrhoea (89%), neutropenia (31%), and thrombocytopenia (23%). Neutropenia, thrombocytopenia and hypokalaemia were noted. Pharmacodynamic assessment did not yield conclusive results. Among 35 patients with evaluable response, PR was observed in 3 patients and CR in 3 patients, 1 maintained SD for over 6 months. ### discussion This study identified the MTD of the entinostat, lapatinib, and trastuzumab combination that provided acceptable tolerability and anti-tumour activity in heavily pre-treated patients with HER2+ metastatic breast cancer, supporting a confirmatory trial.

https://pubmed.ncbi.nlm.nih.gov/31097774/

32ecc7a7d4e7ce44ea873d52018b5256

Objective and palliative effect of chemotherapy is marked for weekly doxorubicin , prednisone with mitoxantrone and etoposide associated with platin-salts for prostatic carcinoma with neuroendocrine differentiation .

[Study of the hormone-refractory prostate cancer clinical practice in an anti-cancer center]. We have examined 82 patients with hormonoresistant prostate cancer in a retrospective study. Bone and lymph node metastases were observed in 94% and 30% of patients respectively. However, the visceral metastases were frequent: liver (17%), lung (7%), bone marrow (4%), meningitis (4%). PSA is constantly high but 28% of the patients have elevated NSE, which is correlated with lymph node or visceral metastases. ACE is elevated in 27% of cases. Objective and palliative effect of chemotherapy is marked for weekly doxorubicin , prednisone with mitoxantrone and etoposide associated with platin-salts for prostatic carcinoma with neuroendocrine differentiation . This study suggests the presence of different subpopulations of patients with specific evolutive patterns, thus further specific therapy should be evaluated.

https://pubmed.ncbi.nlm.nih.gov/11792613/

3c2b7d83038604e036058333e14ca020

The recommendations derived from the comprehensive assessment of the literature and guidelines are to continue NSAIDs and low dose aspirin , and phosphodiesterase inhibitors ( dipyridamole , cilostazol , Aggrenox ) during interventional techniques .

Assessment of bleeding risk of interventional techniques: a best evidence synthesis of practice patterns and perioperative management of anticoagulant and antithrombotic therapy. Interventional pain management is a specialty that utilizes invasive procedures to diagnose and treat chronic pain. Patients undergoing these treatments may be receiving exogenous anticoagulants and antithrombotics. Even though the risk of major bleeding is very small, the consequences can be catastrophic. However, the role of antithrombotic therapy for primary and secondary prevention of cardiovascular disease to decrease the incidence of acute cerebral and cardiovascular events is also crucial. Overall, there is a paucity of literature on the subject of bleeding risk in interventional pain management along with practice patterns and perioperative management of anticoagulant and anti-thrombotic therapy. ### Study Design Best evidence synthesis. ### objective To critically appraise and synthesize the literature with assessment of the bleeding risk of interventional techniques including practice patterns and perioperative management of anticoagulant and antithrombotic therapy. ### methods The available literature on the bleeding risk of interventional techniques and practice patterns and perioperative management of anticoagulant and antithrombotic therapy was reviewed. Data sources included relevant literature identified through searches of PubMed and EMBASE from 1966 through December 2012 and manual searches of the bibliographies of known primary and review articles. ### results There is good evidence for the risk of thromboembolic phenomenon in patients who discontinue antithrombotic therapy, spontaneous epidural hematomas occur with or without traumatic injury in patients with or without anticoagulant therapy associated with stressors such as chiropractic manipulation, diving, and anatomic abnormalities such as ankylosing spondylitis, and the lack of necessity of discontinuation of nonsteroidal anti-inflammatory drugs (NSAIDs), including low dose aspirin prior to performing interventional techniques. There is fair evidence that excessive bleeding, including epidural hematoma formation may occur with interventional techniques when antithrombotic therapy is continued, the risk of thromboembolic phenomenon is higher than the risk of epidural hematomas with discontinuation of antiplatelet therapy prior to interventional techniques, to continue phosphodiesterase inhibitors (dipyridamole [Persantine], cilostazol [Pletal], and Aggrenox [aspirin and dipyridamole]), and that anatomic conditions such as spondylosis, ankylosing spondylitis and spinal stenosis, and procedures involving the cervical spine; multiple attempts; and large bore needles increase the risk of epidural hematoma; and rapid assessment and surgical or nonsurgical intervention to manage patients with epidural hematoma can avoid permanent neurological complications. There is limited evidence to discontinue antiplatelet therapy with platelet aggregation inhibitors to avoid bleeding and epidural hematomas and/or to continue antiplatelet therapy clopidogrel (Plavix), ticlopidine (Ticlid), or prasugrel (Effient) during interventional techniques to avoid cerebrovascular and cardiovascular thromboembolic fatalities. There is limited evidence in reference to newer antithrombotic agents dabigatran (Pradaxa) and rivaroxaban (Xarelto) to discontinue to avoid bleeding and epidural hematomas during interventional techniques and to continue to avoid cerebrovascular and cardiovascular thromboembolic events. ### recommendations The recommendations derived from the comprehensive assessment of the literature and guidelines are to continue NSAIDs and low dose aspirin , and phosphodiesterase inhibitors ( dipyridamole , cilostazol , Aggrenox ) during interventional techniques . However, the recommendations for discontinuation of antiplatelet therapy with platelet aggregation inhibitors (clopidogrel, ticlopidine, prasugrel) is variable with clinical judgment to continue or discontinue based on the patient's condition, the planned procedure, risk factors, and desires, and the cardiologist's opinion. Low molecular weight heparin (LMWH) or unfractionated heparin may be discontinued 12 hours prior to performing interventional techniques. warfarin should be discontinued or international normalized ratio (INR) be normalized to 1.4 or less for high risk procedures and 2 or less for low risk procedures based on risk factors. It is also recommended to discontinue Pradaxa for 24 hours for paravertebral interventional techniques in 2 to 4 days for epidural interventions in patients with normal renal function and for longer periods of time in patients with renal impairment, and to discontinue rivaroxaban for 24 hours prior to performing interventional techniques. ### limitations The paucity of the literature. ### conclusion Based on the available literature including guidelines, the recommendations in patients with antithrombotic therapy for therapy prior to interventional techniques are provided.

https://pubmed.ncbi.nlm.nih.gov/23615893/

d358239751ac6f0d9f4ac77dc9304e1e

Enhanced growth-inhibiting effects were also observed in HCC cells treated with a combination of sorafenib and silibinin .

Combined treatment with silibinin and either sorafenib or gefitinib enhances their growth-inhibiting effects in hepatocellular carcinoma cells. silibinin, the main component of silymarin, is used as a hepatoprotectant and exhibits anticancer effects against various cancer cells. This study evaluated the effects of a combination of silibinin with either gefitinib or sorafenib on hepatocellular carcinoma (HCC) cells. ### methods Several different human HCC cell lines were used to test the growth-inhibiting effects and cell toxicity of silibinin both alone and in combination with either gefitinib or sorafenib. The cell viability and growth inhibition were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, trypan blue staining, and a colony-forming assay. Furthermore, changes in epidermal growth factor receptor (EGFR)-related signals were evaluated by Western blot analysis. ### results gefitinib, sorafenib, and silibinin individually exhibited dose-dependent antiproliferative effects on HCC cells. Combined treatment with silibinin enhanced the gefitinib-induced growth-inhibiting effects in some HCC cell lines. The combination effect of gefitinib and silibinin was synergistic in the SNU761 cell line, but was only additive in the Huh-BAT cell line. The combination effect may be attributable to inhibition of EGFR-dependent Akt signaling. Enhanced growth-inhibiting effects were also observed in HCC cells treated with a combination of sorafenib and silibinin . ### conclusions Combined treatment with silibinin enhanced the growth-inhibiting effects of both gefitinib and sorafenib. Therefore, the combination of silibinin with either sorafenib or gefitinib could be a useful treatment approach for HCC in the future.

https://pubmed.ncbi.nlm.nih.gov/25834802/

21678481cdac2e4a2d6bb2321f3269d1

The effects of the Acanthopanax obovatus polysaccharide ( AOPS ) as well as its combination with cyclophosphamide ( CY ) or prednisolone on immune responses were investigated in mice .

Immunomodulatory activity of polysaccharide from Acanthopanax obovatus roots. The effects of the Acanthopanax obovatus polysaccharide ( AOPS ) as well as its combination with cyclophosphamide ( CY ) or prednisolone on immune responses were investigated in mice . AOPS (250 mg/kg i.p. x 5) increased the spleen weight and the number of spleen cells, and augmented the phagocytosis of peritoneal macrophages both in normal mice and in immunosuppressed mice. In a haemagglutinin assay AOPS increased the production of specific antibodies and antagonized the suppressive effect of CY. AOPS not only enhanced the degree of in vitro spleen cell-mediated red blood cells (SRBC) hemolysis (quantitative hemolysis of SRBC) but also restored the suppressive effect of CY completely. From these results, AOPS was shown to have an enhancing and a modulating activity on immune responses.

https://pubmed.ncbi.nlm.nih.gov/1775572/

e07cec6f9983820e95f4733a21635993

We did the QuiRedex study to compare early treatment with lenalidomide plus dexamethasone with observation in patients with high-risk smouldering multiple myeloma .

Lenalidomide plus dexamethasone versus observation in patients with high-risk smouldering multiple myeloma (QuiRedex): long-term follow-up of a randomised, controlled, phase 3 trial. The standard of care for smouldering multiple myeloma is observation. We did the QuiRedex study to compare early treatment with lenalidomide plus dexamethasone with observation in patients with high-risk smouldering multiple myeloma . Here we report the long-term follow-up results of the trial. ### methods We did this open-label, randomised, controlled phase 3 study at 19 centres in Spain and three centres in Portugal. Patients aged 18 years or older with high-risk smouldering multiple myeloma were randomly assigned (1:1), via a computerised random number generator, to receive either early treatment with lenalidomide plus dexamethasone or observation, with dynamic balancing to maintain treatment balance within the two groups. Randomisation was stratified by time from diagnosis of smouldering multiple myeloma to study enrolment (≤6 months vs >6 months). Patients in the treatment group received nine 4-week induction cycles (lenalidomide 25 mg per day on days 1-21, plus dexamethasone 20 mg per day on days-1-4 and days 12-15), followed by maintenance therapy (lenalidomide 10 mg per day on days 1-21 of each 28-day cycle) up to 2 years. Group allocation was not masked from study investigators or patients. The primary endpoint was time from randomisation to progression to symptomatic myeloma. The primary analysis was based on the per-protocol population, restricted to patients who fulfilled the protocol in terms of eligibility. Safety assessments were based on the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00480363. ### findings Between Nov 8, 2007, and June 9, 2010, 125 patients were enrolled and underwent randomisation. 119 patients comprised the per-protocol population and were randomly assigned to receive either lenalidomide plus dexamethasone (n=57) or observation (n=62). The cutoff date for this update was June 30, 2015. Median follow-up for surviving patients was 75 months (IQR 67-85). lenalidomide plus dexamethasone continued to provide a benefit on time to progression compared with observation (median time to progression not reached [95% CI 47 months-not reached] vs 23 months [16-31]; hazard ratio [HR] 0·24 [95% CI 0·14-0·41]; p<0·0001). Progression to multiple myeloma occurred in 53 (86%) of 62 patients in the observation group compared with 22 (39%) of 57 patients in the treatment group. At data cutoff, ten (18%) patients had died in the treatment group and 22 (36%) patients had died in the observation group; median overall survival from the time of study entry had not been reached in either group (95% CI 65 months-not reached vs 53 months-not reached; HR 0·43 [95% CI 0·21-0·92], p=0·024). Survival in patients who had received subsequent treatments at the time of progression to active disease did not differ between groups (HR 1·34 [95% CI 0·54-3·30]; p=0·50). The most frequently reported grade 3 adverse events in patients given lenalidomide plus dexamethasone were infection (four [6%]), asthenia (four [6%]), neutropenia (three [5%]), and skin rash (two [3%]); these events all occurred during induction therapy. No grade 4 adverse events occurred, but one (2%) patient in the lenalidomide plus dexamethasone group died from a respiratory infection during induction therapy The frequency of second primary malignancies was higher in patients in the treatment group than in those in the observation group (six [10%] of 62 patients vs one [2%] of 63 patients), but the cumulative risk of development did not differ significantly between the groups (p=0·070). ### interpretation This study is, to our knowledge, the first randomised trial in which early treatment has been assessed in selected patients with high-risk smouldering multiple myeloma. Positive results from ongoing trials would support the use of early treatment for patients with high-risk disease in the near future. ### funding Pethema (Spanish Program for the Treatment of Hematologic Diseases).

https://pubmed.ncbi.nlm.nih.gov/27402145/

1c63535ff27c71fba0866e0d8056bd30

Of the patients , 26 were treated with a chemotherapy regimen known to cause prolonged and sometimes permanent azoospermia ( BEACOPP -- bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine , procarbazine , and prednisolone ) and 26 with a regimen known to have a much milder effect on gonadal function ( ABVD -- doxorubicin , bleomycin , vincristine , and dacarbazine ) .

The impact of systemic chemotherapy on testicular FDG activity in young men with Hodgkin's lymphoma. Based on prior reports suggesting a positive correlation between fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET)/CT and total sperm count and concentration, we sought to identify changes in testicular FDG uptake over the course of chemotherapy in young men with Hodgkin's lymphoma. ### methods Fifty-two patients with a mean age of 24.2 years (range 15.5-44.4) at diagnosis monitored with FDG PET/CT to assess treatment response for Hodgkin's lymphoma were selected for this retrospective analysis under an Institutional Review Board waiver. Of the patients , 26 were treated with a chemotherapy regimen known to cause prolonged and sometimes permanent azoospermia ( BEACOPP -- bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine , procarbazine , and prednisolone ) and 26 with a regimen known to have a much milder effect on gonadal function ( ABVD -- doxorubicin , bleomycin , vincristine , and dacarbazine ) . Each patient underwent one FDG PET/CT before treatment and at least one FDG PET/CT after start of chemotherapy. In all examinations, FDG activity was measured in the testes with different quantification metrics: maximum standardized uptake value (SUVmax), SUVmean, functional volume (FV) and total testicular glycolysis (TTG), and blood pool activity determined (SUVmean). ### results Testicular FDG uptake (SUVmax) was significantly associated with blood pool activity (p < 0.001). Furthermore, testicular FDG uptake metrics incorporating volume (e.g., FV and TTG) were associated with age. There was no significant change in SUVmax, SUVmean, FV, and TTG from the PET/CT at baseline to the PET/CTs over the course of chemotherapy either for patients treated with BEACOPP or for patients treated with ABVD. ### conclusion For patients undergoing chemotherapy for Hodgkin's lymphoma, there is a significant association between testicular FDG uptake and blood pool activity, but no significant changes in FDG uptake over the course of chemotherapy. Therefore, FDG uptake may not be a feasible surrogate marker for fertility monitoring in patients with Hodgkin's lymphoma undergoing chemotherapy.

https://pubmed.ncbi.nlm.nih.gov/23389428/

37fbb54580564543d8ebd2a93b285c7c

Tissue from preclinical models and patients ' biopsies were collected pre-treatment and on Cycle ( C ) 1 , Day ( D ) 9 to characterize the effect of gemcitabine and salirasib on activated Ras protein levels .

Integrated preclinical and clinical development of S-trans, trans-Farnesylthiosalicylic Acid (FTS, Salirasib) in pancreatic cancer. S-trans,trans-Farnesylthiosalicylic Acid (FTS, salirasib) inhibits Ras-dependent cell growth by dislodging all isoforms of Ras, including mutant Ras, from the plasma membrane. This study evaluated the activity, safety, and toxicity of salirasib in preclinical models and patients with metastatic pancreatic adenocarcinoma (PDA). ### Patients And Methods In the preclinical study, salirasib was tested, alone and in combination with gemcitabine, in patient derived xenografts (PDX) of PDA. In the clinical study, treatment-naïve patients with advanced, metastatic PDA were treated with a standard dose schedule of gemcitabine and salirasib 200-800 mg orally (PO) twice daily (bid) for 21 days every 28 days. Tissue from preclinical models and patients ' biopsies were collected pre-treatment and on Cycle ( C ) 1 , Day ( D ) 9 to characterize the effect of gemcitabine and salirasib on activated Ras protein levels . Plasma samples for pharmacokinetics were collected for salirasib administered alone and in combination. ### results salirasib inhibited the growth of 2/14 PDX models of PDA and modulated Ras signaling in these tumors. Nineteen patients were enrolled. No DLTs occurred. Common adverse events included hematologic and gastrointestinal toxicities and fatigue. The median overall survival was 6.2 months and the 1 year survival 37 %. In 2 patients in whom paired tissue biopsies were available, Ras and KRas protein levels were decreased on C1D9. salirasib exposure was not altered by gemcitabine and did not correlate with PD outcomes. ### conclusion The combination of gemcitabine and salirasib appears well-tolerated, with no alteration of salirasib exposure, and exerted clinical and PD activity in PDA.

https://pubmed.ncbi.nlm.nih.gov/22547163/

18e879f7de2bdc1c9e943375a4e184a0

An isocratic liquid chromatographic method with UV detection at 210 nm is described for simultaneous determination of amoxicillin sodium and sulbactam sodium in a new combination formulation .

A liquid chromatographic method for simultaneous determination of amoxicillin sodium and sulbactam sodium in a combination formulation. An isocratic liquid chromatographic method with UV detection at 210 nm is described for simultaneous determination of amoxicillin sodium and sulbactam sodium in a new combination formulation . Chromatographic separation of the two drugs was achieved on a Hypersil C(18) column using a mobile phase consisting of a binary mixture of methanol and 0.01mol/l sodium acetate (5:95, v/v). The commonly used paired-ion aqueous mobile phase for the determination of penicillins was avoided in this study. The developed LC method offers symmetric peak shape, good resolution and reasonable retention time for both drugs. Linearity, accuracy and precision were found to be acceptable over the concentration ranges of 155.3-1553.0microg/ml for amoxicillin sodium and 45.0-450.0microg/ml for sulbactam sodium. The proposed LC method can be used for the quality control of formulated products containing these two drugs.

https://pubmed.ncbi.nlm.nih.gov/15522531/

f8b084512a37315824007183d5246093

The difference in inhibitory potency of parent drugs and metabolites was higher for halofantrine than for mefloquine .

In vitro effects of racemates, separate enantiomers and major metabolites of mefloquine and halofantrine on metoprolol biotransformation by rat liver microsomes. 1. The effects of the anti-malarial drugs mefloquine and halofantrine and of their major metabolites on metoprolol metabolism by rat liver microsomes have been investigated. 2. The observed Km and Vmax, and the formation kinetics of alpha-hydroxymetoprolol and O-demethylmetoprolol, two major metoprolol metabolites, were in keeping with published data. 3. In vitro, mefloquine competitively inhibited metoprolol biotransformation, whereas halofantrine did so in a mixed fashion. The mefloquine Ki of metoprolol alpha-hydroxylation and O-demethylation were 3.4 and 5.8 microM respectively, whereas those of halofantrine were 0.15 and 0.32 microM respectively. 4. The main metabolites, N-debutylhalofantrine and carboxymefloquine, were 4-10-fold less inhibitory than the parent drugs. The difference in inhibitory potency of parent drugs and metabolites was higher for halofantrine than for mefloquine . The potency order for metoprolol metabolism inhibition was halofantrine >> mefloquine = N-debutylhalofantrine > carboxymefloquine. 5. A preliminary study with anti-malarial enantiomers showed a weak difference, in metoprolol metabolism inhibition between the enantiomers of halofantrine or mefloquine. 6. It is concluded that halofantrine is a potent inhibitor of metoprolol metabolism and that halofantrine metabolites or its enantiomers may have a different inhibitor potency than the parent drug: (1) the inhibition potency of these compounds should be studied in vitro and (2) their in vivo elimination half-life and plasma concentrations should be taken into be account to extrapolate this experimental results to in vivo.

https://pubmed.ncbi.nlm.nih.gov/10426558/

f07923010602dbb6e955ec6a8773218e

In total , 417 patients were included : 312 ( 74·8 % ) received vancomycin and 105 ( 25·2 % ) received daptomycin .

A retrospective analysis of adverse events among patients receiving daptomycin versus vancomycin during outpatient parenteral antimicrobial therapy. Outpatient parenteral antimicrobial therapy (OPAT) is a safe and effective alternative to prolonged inpatient stays for patients requiring long-term intravenous antimicrobials, but antimicrobial-associated adverse events remain a significant challenge. Thus, we sought to measure the association between choice of antimicrobial agent (vancomycin vs daptomycin) and incidence of adverse drug events (ADEs). ### methods Patients receiving OPAT treatment with vancomycin or daptomycin for skin and soft-tissue infections, bone and joint infections, endocarditis, and bacteremia or endovascular infections during the period from July 1, 2013, through September 30, 2016, were included. Demographic and clinical data were abstracted from the medical record. Logistic regression was used to compare ADEs requiring a change in or early discontinuation of therapy, hospital readmission, and emergency room visits between groups. Time from OPAT enrollment to ADE was compared using the log-rank test. ### results In total , 417 patients were included : 312 ( 74·8 % ) received vancomycin and 105 ( 25·2 % ) received daptomycin . After adjusting for age, Charlson comorbidity index, location of OPAT treatment, receipt of combination therapy with either β-lactam or fluoroquinolone, renal function, and availability of safety labs, patients receiving vancomycin had significantly higher incidence of ADEs (adjusted odds ratio [aOR], 3·71; 95% CI, 1·64-8·40). ADEs occurred later in the treatment course for patients treated with daptomycin (P<·01). Rates of readmission and emergency room visits were similar. ### conclusions In the OPAT setting, vancomycin use was associated with higher incidence of ADEs than daptomycin use. This finding is an important policy consideration for programs aiming to optimize outcomes and minimize cost. Careful selection of gram-positive agents for prolonged treatment is necessary to limit toxicity.

https://pubmed.ncbi.nlm.nih.gov/29893658/

d1fdcb21dc3ac637ff1841ff0a3e35ef

The effect of dasatinib , an inhibitor of Src and Abl kinases , on paclitaxel sensitivity was measured in ovarian cancer cells and HEY xenografts .

The role of p27(Kip1) in dasatinib-enhanced paclitaxel cytotoxicity in human ovarian cancer cells. Less than 50% of ovarian cancers respond to paclitaxel. Effective strategies are needed to enhance paclitaxel sensitivity. ### methods A library of silencing RNAs (siRNAs) was used to identify kinases that regulate paclitaxel sensitivity in human ovarian cancer SKOv3 cells. The effect of dasatinib , an inhibitor of Src and Abl kinases , on paclitaxel sensitivity was measured in ovarian cancer cells and HEY xenografts . The roles of p27(Kip1), Bcl-2, and Cdk1 in apoptosis induced by dasatinib and paclitaxel were assessed using a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, siRNA knockdown of gene expression, transfection with Bcl-2 and Cdk1 expression vectors, and flow cytometry. All statistical tests were two-sided. ### results Src family and Abl kinases were identified as modulators of paclitaxel sensitivity in SKOv3 cells. The siRNA knockdown of Src, Fyn, or Abl1 enhanced paclitaxel-mediated growth inhibition in ovarian cancer cells compared with a control siRNA. HEY cells treated with dasatinib plus paclitaxel formed fewer colonies than did cells treated with either agent alone. Treatment of HEY xenograft-bearing mice with dasatinib plus paclitaxel inhibited tumor growth more than treatment with either agent alone (average tumor volume per mouse, dasatinib + paclitaxel vs paclitaxel: 0.28 vs. 0.81 cm3, difference = 0.53 cm3, 95% confidence interval [CI] = 0.44 to 0.62 cm3, P = .014); dasatinib + paclitaxel vs. dasatinib: 0.28 vs. 0.55 cm3, difference = 0.27 cm3, 95% CI = 0.21 to 0.33 cm3, P = .035). Combined treatment induced more TUNEL-positive apoptotic cells than did either agent alone. The siRNA knockdown of p27(Kip1) decreased dasatinib- and paclitaxel-induced apoptosis compared with a negative control siRNA (sub-G1 fraction, control siRNA vs. p27(Kip1) siRNA: 42.5% vs. 20.1%, difference = 22.4%, 95% CI = 20.1% to 24.7%, P = .017). Studies with forced expression and siRNA knockdown of Bcl-2 and Cdk1 suggest that dasatinib-mediated induction of p27(Kip1) enhanced paclitaxel-induced apoptosis by negatively regulating Bcl-2 and Cdk1 expression. ### conclusion Inhibition of Src family and Abl kinases with either siRNAs or dasatinib enhances paclitaxel sensitivity of ovarian cancer cells through p27(Kip1)-mediated suppression of Bcl-2 and Cdk1 expression.

https://pubmed.ncbi.nlm.nih.gov/21813412/

ccb7554fd73847eaa41e1e62f835d6c3

The maximum tolerated dose ( MTD ) was 20 mg/m2/day I.V. bolus for 5 days of fludarabine plus 60 mg/m2/day I.V. of paclitaxel given as a continuous infusion over 72 hours .

Phase I study of fludarabine and paclitaxel for the treatment of low-grade non-Hodgkin's lymphoma. We conducted a phase I clinical trial of a new combination of fludarabine and paclitaxel in which 19 patients with histologically confirmed recurrent low-grade non-Hodgkin's lymphoma (NHL) were treated at five dose levels. fludarabine was administered intravenously by bolus for 5 days and paclitaxel was given by intravenous (I.V.) continuous infusion for 96 or 72 hours starting day 1. Courses were repeated every 4 weeks. Patients whose disease responded received a maximum of six courses. All 19 patients received at least one course and could be evaluated for toxic effects, and 18 patients could be evaluated for response. The maximum tolerated dose ( MTD ) was 20 mg/m2/day I.V. bolus for 5 days of fludarabine plus 60 mg/m2/day I.V. of paclitaxel given as a continuous infusion over 72 hours . The limiting toxic effect was neutropenic fever, which was observed in five of the seven patients treated at the highest dose level. Grade 3 non-hematologic toxic effects of stomatitis (14%), neuropathy (14%), and hypotension (14%) were also observed at the highest dose level. No grade 4 non-hematologic toxic effects or treatment-related deaths occurred. One patient had herpes zoster infection of the skin 1 year after the completion of therapy. The overall response rate was 50%, with the two patients whose disease completely responded remaining disease free at 22 and 17 months. Patients with no prior exposure to either paclitaxel or fludarabine had 62% response rate. We conclude that the combination of fludarabine and paclitaxel appears to have promising activity for the treatment of recurrent low-grade NHL.

https://pubmed.ncbi.nlm.nih.gov/9250790/

042e0b2d00ed9a033094dd9f6010fe84

Further studies are needed to identify predictors of response and toxicity to this approach , as well as the optimal scheduling of ipilimumab with maintenance nivolumab .

Salvage ipilimumab associated with a significant response in sarcomatoid renal cell carcinoma. Metastatic sarcomatoid renal cell carcinoma (sRCC) is an aggressive variant of RCC with generally poor prognosis. Treatment with vascular endothelial growth factor inhibitors or chemotherapy generates only short-lived responses. Recent research has suggested a role for combination checkpoint inhibition as first line treatment for metastatic sRCC. This therapy consists of induction with cytotoxic T-lymphocyte-associated protein 4 inhibitor, ipilimumab, administered with programmed cell death protein 1 (PD-1) inhibitor, nivolumab. After completion of four cycles of combination therapy, single-agent maintenance nivolumab is recommended until progression. Patients who progress on maintenance nivolumab are switched to alternate therapy. Herein, we present a case of a patient with RCC who progressed on maintenance nivolumab who, on retreatment with ipilimumab, demonstrated a significant response In addition, we summarize important findings to support the role of salvage ipilimumab in patients with sRCC. ### Case Presentation A 46-year-old man presented with flank pain and hematuria, the work up of which noted a left kidney mass for which he underwent nephrectomy and was diagnosed with localized sRCC with 60% sarcomatoid differentiation. Within 3 months of nephrectomy, he presented with recurrent flank pain and was diagnosed with recurrence of disease. He was treated with ipilimumab 1 mg/kg and nivolumab 3 mg/kg for four doses and demonstrated a partial response. He was then transitioned to single agent nivolumab maintenance. After 3 months on maintenance therapy, he was noted to have progression of disease. Given prior response to immune check point combination, it was decided to rechallenge the patient with 1 mg/kg ipilimumab. After two doses of ipilimumab and nivolumab combination therapy, the patient was noted to have a partial response. He maintained a response for an additional 9 months and treatment was eventually discontinued due to grade 3 toxicity and progression. ### conclusions This case report demonstrates the utility of retreatment with ipilimumab as a salvage option for patients progressing on maintenance PD-1 inhibitors in metastatic RCC. Further studies are needed to identify predictors of response and toxicity to this approach , as well as the optimal scheduling of ipilimumab with maintenance nivolumab .

https://pubmed.ncbi.nlm.nih.gov/32114501/

1cb0a51408e696ebb1a532c4f5f6f8dd

Efficacy of palonosetron plus aprepitant in preventing chemoradiotherapy-induced nausea and emesis in patients receiving daily low-dose cisplatin-based concurrent chemoradiotherapy for uterine cervical cancer : a phase II study .

Efficacy of palonosetron plus aprepitant in preventing chemoradiotherapy-induced nausea and emesis in patients receiving daily low-dose cisplatin-based concurrent chemoradiotherapy for uterine cervical cancer : a phase II study . Antiemetic recommendations during concurrent chemoradiotherapy (cisplatin-based concurrent chemoradiotherapy (CCRT)) have not been established yet. The aim of this study was to investigate whether the combination of palonosetron plus aprepitant, without routine use of dexamethasone, could alleviate chemoradiotherapy-induced nausea and vomiting (CRINV). ### methods This was a non-randomized, prospective, single-center, open phase II study. Patients with cervical cancer, who were treated with daily low-dose cisplatin (8 mg/m(2)/day) and concurrent radiation (2 Gy/day, 25 fractions, five times a week), were enrolled in this study. All patients received intravenous palonosetron (0.75 mg on day 1 of each week) and oral aprepitant (125 mg on day 1 and 80 mg on days 2 and 3 of each week). The primary endpoint was the percentage of patients with a complete response, defined as no emetic episodes and no use of antiemetic rescue medication during the treatment. ### results Twenty-seven patients (median age, 50 years; range, 33-72 years) were enrolled in this study between June 2013 and April 2014. A total of 13 (48 %) patients showed a complete response to the antiemetic regimen, while 8 patients (30 %) had emetic episodes and 6 patients (22 %) used rescue medication without emetic episodes. No severe adverse effects caused by palonosetron plus aprepitant were observed. ### conclusion The combination of palonosetron plus aprepitant was permissive for the prevention of CRINV. This regimen should be considered for patients in whom dexamethasone is contraindicated or not well tolerated.

https://pubmed.ncbi.nlm.nih.gov/27286875/

809bac232f0bd17c3ad9fcd2ed5be67a

Pre/peri/postmenopausal women with HR+/HER2- MBC were randomized 2:1 to fulvestrant ( 500 mg ) and either palbociclib ( 125 mg/day ; 3 weeks on/1 week off ; n = 347 ) or placebo ( n = 174 ) . Prespecified exploratory analyses compared the efficacy ( data cutoff : October 23 , 2015 ) , safety , and pharmacokinetics ( data cutoff : December 5 , 2014 ) in Japanese women versus the overall population .

Palbociclib in combination with fulvestrant in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: PALOMA-3 subgroup analysis of Japanese patients. In the double-blind, phase 3 PALOMA-3 study, palbociclib-fulvestrant significantly prolonged progression-free survival versus placebo-fulvestrant in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) whose disease had progressed on prior endocrine therapy. The present study evaluated the efficacy, safety, and pharmacokinetics of palbociclib plus fulvestrant in Japanese patients enrolled in PALOMA-3. ### methods Pre/peri/postmenopausal women with HR+/HER2- MBC were randomized 2:1 to fulvestrant ( 500 mg ) and either palbociclib ( 125 mg/day ; 3 weeks on/1 week off ; n = 347 ) or placebo ( n = 174 ) . Prespecified exploratory analyses compared the efficacy ( data cutoff : October 23 , 2015 ) , safety , and pharmacokinetics ( data cutoff : December 5 , 2014 ) in Japanese women versus the overall population . ### results A total of 35 Japanese women were randomized to palbociclib-fulvestrant (n = 27) or placebo-fulvestrant (n = 8). Median progression-free survival was 13.6 months (95% CI, 7.5-not estimable) in the Japanese palbociclib-fulvestrant group and 11.2 months (95% CI, 5.6-not estimable) in the placebo-fulvestrant group. The most common adverse event (AE) in Japanese patients was neutropenia (all grades, 93%); no discontinuations were due to an AE. Geometric mean trough concentration values (within-subject mean steady state) for palbociclib were similar for Japanese Asian (excluding Japanese), and non-Asian patients (84.4 ng/mL, 86.3 ng/mL, and 74.8 ng/mL, respectively). ### Conclusion S The results for the overall population and Japanese patients in PALOMA-3 suggest that palbociclib plus fulvestrant was effective and well tolerated in Japanese patients with HR+/HER2‒ MBC whose disease had progressed on prior endocrine therapy (Pfizer; NCT01942135).

https://pubmed.ncbi.nlm.nih.gov/30392115/

58a8767d39033b741e150619c271a967

was lowest in the propofol + dexmedetomidine group ( all , P < 0.05 ) , and the AUC of pulse oximetry was significantly higher in the propofol + dexmedetomidine and propofol + ketamine groups compared to the other 2 groups ( both , P < 0.05 ) .

Efficacy and Tolerability of Sufentanil, Dexmedetomidine, or Ketamine Added to Propofol-based Sedation for Gastrointestinal Endoscopy in Elderly Patients: A Prospective, Randomized, Controlled Trial. To investigate the optimal agent combined with propofol for sedation in elderly patients undergoing gastrointestinal endoscopy. ### methods A total of 120 elderly patients scheduled for gastrointestinal endoscopy under propofol-based sedation were randomly allocated to receive propofol + saline (control group), propofol + sufentanil 0.1 μg/kg, propofol + dexmedetomidine 0.4 μg/kg, or propofol + ketamine 0.4 mg/kg. Mean arterial pressure, heart rate, pulse oximetry, pressure of end-tidal carbon dioxide, respiratory rate, and Ramsay sedation scale score were recorded. Induction time, procedure time, recovery time, propofol dose, and adverse events were also recorded. ### findings During the sedation procedure, the AUC of HR was lowest in the propofol + dexmedetomidine group ( all , P < 0.05 ) , and the AUC of pulse oximetry was significantly higher in the propofol + dexmedetomidine and propofol + ketamine groups compared to the other 2 groups ( both , P < 0.05 ) . The propofol + dexmedetomidine group had the highest prevalences of hypotension and bradycardia, and the control group experienced the largest number of hypoxia episodes (all, P < 0.05). The control group consumed the highest dose of propofol, while the propofol + ketamine group needed the lowest dose (all, P < 0.05). ### implications The combination of propofol + ketamine 0.4 mg/kg maintained hemodynamic and respiratory stability, as evidenced by less hypotension, bradycardia, and hypoxia events, in elderly patients undergoing gastrointestinal endoscopy. China clinical trial registration (chictr.org.cn) ID: ChiCTR-INR-17013710.

https://pubmed.ncbi.nlm.nih.gov/31345559/

0bd777658d84790649190009cef1cce2

Ethosuximide primarily acts by blocking T-type voltage-gated calcium channels in thalamic neurones while topiramate and zonisamide have multiple mechanisms of action .

Properties of antiepileptic drugs in the treatment of idiopathic generalized epilepsies. Although valproate is considered to be the drug of first choice for the treatment of idiopathic generalized epilepsies (IGEs), other antiepileptic drugs (AEDs), both old (ethosuximide, clobazam, and clonazepam) and new (lamotrigine, levetiracetam, topiramate, and zonisamide) are also available. These AEDs do not appear to have a common mechanism of action in that both inhibitory gamma-aminobutyric acid (GABA; e.g., clobazam, clonazepam, and valproate) and excitatory glutamate (e.g., lamotrigine and topiramate) mechanisms are involved. Ethosuximide primarily acts by blocking T-type voltage-gated calcium channels in thalamic neurones while topiramate and zonisamide have multiple mechanisms of action . In contrast, levetiracetam is unique in that it may act via a specific binding site in the brain. In terms of their pharmacokinetic characteristics, all eight AEDs are rapidly absorbed after oral ingestion with peak blood concentration being achieved within 1-4 hours. Bioavailability is 100% with the exception clonazepam (90%) and topiramate (81-95%). Plasma protein binding is variable with valproate (90%), clobazam (85%) and clonazepam (86%) showing substantial binding, lamotrigine (55%) and zonisamide (50%) intermediate binding, and levetiracetam (0%), ethosuximide (0%) and topiramate (10%) being minimally bound. However, the binding by zonisamide is complicated by its binding to erythrocytes as well as albumin. All AEDs, with the exception of lamotrigine and levetiracetam, undergo elimination as a result of extensive metabolism by hepatic cytochrome P450 enzymes, which are highly amenable to induction and inhibition by other drugs and therefore susceptible to pharmacokinetic interactions. lamotrigine metabolism is via hepatic glucuronidation, a process that is also susceptible to induction and inhibition by concurrent drugs. levetiracetam is minimally metabolized (by hydrolysis in blood), is excreted predominantly unchanged in urine, and to date has not been associated with any clinically significant pharmacokinetic interactions. Using a semiquantitative pharmacokinetic rating system, based on 16 pharmacokinetic characteristics, a direct comparison between AEDs is possible. Thus valproic acid, regarded as the drug of first choice in the treatment of IGEs, rates lowest with respect to favorable pharmacokinetic characteristics, mostly because of its nonlinear pharmacokinetics, extensive hepatic metabolism, and its high propensity to interact both with other AEDs and non-AEDs. levetiracetam rates highest with topiramate in second place.

https://pubmed.ncbi.nlm.nih.gov/16302888/

3ce316a06e76c599b5da16e5786d3991

Patients aged 15 to 60 years , presenting with newly diagnosed acute myeloid leukemia ( AML ) were randomized to receive either high-dose cytarabine , 3 g/m2 12 hourly on days 1 , 3 , 5 , and 7 for 8 doses , daunorubicin 50 mg/m2 days 1 to 3 , etoposide 75 mg/m2 days 1 to 7 , ( HIDAC-3 - 7 ) or standard dose cytarabine 100 mg/m2 continuous intravenous infusion for 7 days with daunorubicin and etoposide at the same dose and schedule as above ( 7 - 3 - 7 ) .

A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. High-dose cytarabine (ara-c) may overcome cytarabine resistance in leukemic blasts. It has been used as a successful salvage and in postremission therapy but not as initial induction treatment. Patients aged 15 to 60 years , presenting with newly diagnosed acute myeloid leukemia ( AML ) were randomized to receive either high-dose cytarabine , 3 g/m2 12 hourly on days 1 , 3 , 5 , and 7 for 8 doses , daunorubicin 50 mg/m2 days 1 to 3 , etoposide 75 mg/m2 days 1 to 7 , ( HIDAC-3 - 7 ) or standard dose cytarabine 100 mg/m2 continuous intravenous infusion for 7 days with daunorubicin and etoposide at the same dose and schedule as above ( 7 - 3 - 7 ) . Patients could receive a second or third induction course if complete remission (CR) was not achieved. All patients received the same postinduction consolidation therapy (5-2-5) for 2 courses. Eligible patients had no prior chemotherapy or myelodysplastic disease. Patients have been followed for a median of 4.5 years. Of 301 patients treated, complete response (CR) was achieved in 71% with HIDAC-3-7 and 74% with 7-3-7. For patients in CR, the estimated median remission duration was 45 months with HIDAC-3-7 and 12 months with 7-3-7 (P = .0005 univariate analysis, P = .0004 multivariate analysis). The estimated percentage of patients relapse free 5 years after achieving a CR was 49% on HIDAC-3-7 and 24% on 7-3-7. Patients in CR tended to survive longer with HIDAC-3-7 but there were no overall survival differences between the two arms. HIDAC-3-7 was associated with significantly more toxicity in induction with more leukopenia, thrombocytopenia, nausea, and vomiting and eye toxicity (all P < .001) but a similar incidence of severe central nervous system and cerebellar toxicity compared to 7-3-7. The consolidation treatment was the same in both arms but caused significantly more leukopenia and thrombocytopenia in patients previously treated with HIDAC-3-7 induction (P < .0001). We conclude that a dose-effect exists for cytarabine in AML and that HIDAC-3-7 prolongs remission duration and disease-free survival and is tolerable when used as initial induction therapy in patients with de novo AML.

https://pubmed.ncbi.nlm.nih.gov/8634416/

fe01e044f02622902299f2dc04336c22

Therefore , if a combination regimen is necessary to control CMV in a patient , foscarnet and ganciclovir should be used first .

Combination antiviral therapy for cytomegalovirus disease in patients with AIDS. Currently, combination therapy with ganciclovir and foscarnet should be reserved for patients with disease progression while receiving monotherapy or for those who are unresponsive to either agent alone. Although cidofovir and ganciclovir were shown to have synergistic activity against human CMV in vitro, there have been no in vivo studies to confirm this activity. Therefore , if a combination regimen is necessary to control CMV in a patient , foscarnet and ganciclovir should be used first . There are several advantages of the combination therapy regimen. For instance, lower doses of the individual agents can be used with superior efficacy to monotherapy and similar toxicities. Also, for neurologic CMV involvement, the combination therapy may be superior to monotherapy because of the variable CSF penetration of either drug alone. In addition, combined therapy may be beneficial in treating and/or preventing drug-resistant strains of CMV. Even though combination therapy has evidence of superior efficacy compared with monotherapy in the treatment of CMV, several issues must be considered. First, combination therapy has longer administration times because of the infusion of multiple drugs, which may be an inconvenience. Also, even though the toxic effects are similar with both combined therapy and monotherapy, the adverse effects associated with combination therapy may be less well tolerated and may negatively affect the patient's quality of life. Finally, combination therapy is more expensive than monotherapy with ganciclovir or foscarnet alone. Patients should be evaluated with these issues in mind before combination therapy is initiated.

https://pubmed.ncbi.nlm.nih.gov/9296250/

af03c3fd5445015f03271eeae6b1445d

A Phase Ib/II Study of Afatinib in Combination with Nimotuzumab in Non-Small Cell Lung Cancer Patients with Acquired Resistance to Gefitinib or Erlotinib .

A Phase Ib/II Study of Afatinib in Combination with Nimotuzumab in Non-Small Cell Lung Cancer Patients with Acquired Resistance to Gefitinib or Erlotinib . In this phase Ib/II study, we aimed to assess the safety and efficacy of afatinib plus nimotuzumab (N) in advanced non-small cell lung cancer (NSCLC) patients with acquired resistance to gefitinib or erlotinib. ### Experimental Design In phase Ib stage, patients received afatinib (40 mg or 30 mg once daily) plus nimotuzumab (100 mg or 200 mg once weekly) for 28-day cycles to determine the recommended phase II dose (RPIID). The safety and efficacy of RPIID dose was evaluated in phase II stage. ### results In total, 50 patients were enrolled (13 to phase Ib and 37 to phase II). In the first dose-finding cohort (afatinib 40 mg plus nimotuzumab 100 mg), one patient experienced dose-limiting toxicity (DLT) of grade 3 diarrhea and in the subsequent cohort (afatinib 40 mg plus nimotuzumab 200 mg), two DLTs (grade 3 diarrhea and grade 3 neutropenia) occurred in 2 of 6 patients. Accordingly, RPIID was determined as afatinib 40 mg plus nimotuzumab 100 mg. In 44 patients treated with RPIID, 7 (16%) patients had grade 3 toxicities; skin rash (7%), diarrhea (5%), acne (2%), and fatigue (2%). The overall response rate was 23% and the median duration of response was 4.3 months (range, 0.7-16.2 months). The median progression-free survival and overall survival were 4.0 months [95% confidence interval (CI), 2.3-5.7 months] and 11.7 months (95% CI, 9.4-14.0 months), respectively. ### conclusions Combination treatment of afatinib and nimotuzumab demonstrated an acceptable safety profile and encouraging antitumor activity in advanced NSCLC patients with acquired resistance to gefitinib or erlotinib. Larger phase III trial is warranted to confirm its efficacy and safety. Clin Cancer Res; 22(9); 2139-45. ©2015 AACR.

https://pubmed.ncbi.nlm.nih.gov/26667485/

190ab2480d9e1091cc333569085fc69f

RESULTS In first-line treatment , compared with sunitinib , improvement of one-year CPFS for the nivolumab plus ipilimumab group after living for 0.5 and 0.75 years were 14 % ( from 53.0 % to 67.0 % ) and 16 % ( from 57.0 % to 73.0 % ) higher than the one-year PFS of 6.5 % ( from 42.9 % to 49.4 % ) , with similar results for one-year COS following first-line treatment .

Conditional Survival in Patients with Advanced Renal Cell Carcinoma Treated with Nivolumab. BACKGROUND nivolumab is approved for the treatment of advanced renal cell carcinoma (RCC). However, traditional overall survival (OS) or progression-free survival (PFS) do not reflect patient prognosis after initial management. Therefore, this study aimed to evaluate conditional overall survival (COS) and conditional progression-free survival (CPFS) in patients with advanced RCC treated with nivolumab. MATERIAL AND METHODS There were 847 patients with advanced RCC treated with first-line nivolumab plus ipilimumab (n=425) and sunitinib (n=422), and 821 patients were treated with second-line nivolumab (n=410) and everolimus (n=411). Primary endpoints were COS and CPFS. Individual patient data of PFS and OS were digitally reconstructed from two large randomized controlled trials (CheckMate 025 and CheckMate 214). RESULTS In first-line treatment , compared with sunitinib , improvement of one-year CPFS for the nivolumab plus ipilimumab group after living for 0.5 and 0.75 years were 14 % ( from 53.0 % to 67.0 % ) and 16 % ( from 57.0 % to 73.0 % ) higher than the one-year PFS of 6.5 % ( from 42.9 % to 49.4 % ) , with similar results for one-year COS following first-line treatment . For second-line treatment, compared with everolimus, the improvement of one-year CPFS for the nivolumab group after living for 0.5 and 0.75 years were 19% (from 25.0% to 44.0%) and 19% (from 27.0% to 46.0%) and significantly higher than the one-year PFS of 4.5% (from 18.5% to 23.0%). CONCLUSIONS Survival benefit for patients with advanced RCC from nivolumab (plus ipilimumab) compared with sunitinib was more evident from conditional survival (CS) analysis of first-line treatment.

https://pubmed.ncbi.nlm.nih.gov/31469816/

a9871c42260965ad80e7f1e460de10fe

Two model drugs , omeprazole and verapamil , were used to test the integrated model .

A versatile, compartmentalised gut-on-a-chip system for pharmacological and toxicological analyses. A novel, integrated, in vitro gastrointestinal (GI) system is presented to study oral bioavailability parameters of small molecules. Three compartments were combined into one hyphenated, flow-through set-up. In the first compartment, a compound was exposed dynamically to enzymatic digestion in three consecutive microreactors, mimicking the processes of the mouth, stomach, and intestine. The resulting solution (chyme) continued to the second compartment, a flow-through barrier model of the intestinal epithelium allowing absorption of the compound and metabolites thereof. The composition of the effluents from the barrier model were analysed either offline by electrospray-ionisation-mass spectrometry (ESI-MS), or online in the final compartment using chip-based ESI-MS. Two model drugs , omeprazole and verapamil , were used to test the integrated model . omeprazole was shown to be broken down upon treatment with gastric acid, but reached the cell barrier unharmed when introduced to the system in a manner emulating an enteric-coated formulation. In contrast, verapamil was unaffected by digestion. Finally, a reduced uptake of verapamil was observed when verapamil was introduced to the system dissolved in apple juice, a simple food matrix. It is envisaged that this integrated, compartmentalised GI system has potential for enabling future research in the fields of pharmacology, toxicology, and nutrition.

https://pubmed.ncbi.nlm.nih.gov/33649376/

7b07311a9256b5756499cbd58b924bca

This study analysed 126 patients with relapsed , advanced stage follicular lymphoma who received BEAM ( BCNU [ carmustine ] , cytarabine , etoposide , melphalan)-alemtuzumab allogeneic HSCT ( BEAM-allo ) ( n = 44 ) or BEAM-autologous HSCT ( BEAM-auto ) ( n = 82 ) .

Outcome of BEAM-autologous and BEAM-alemtuzumab allogeneic transplantation in relapsed advanced stage follicular lymphoma. The role of haematopoietic stem cell transplantation (HSCT) in relapsed follicular lymphoma remains controversial. This study analysed 126 patients with relapsed , advanced stage follicular lymphoma who received BEAM ( BCNU [ carmustine ] , cytarabine , etoposide , melphalan)-alemtuzumab allogeneic HSCT ( BEAM-allo ) ( n = 44 ) or BEAM-autologous HSCT ( BEAM-auto ) ( n = 82 ) . The BEAM-allo group had a younger median age (48 years vs. 56 years, P < 0.001) but received a higher median number of therapies pretransplant (P = 0.015) compared with the BEAM-auto group. There was a higher non-relapse mortality (NRM) in the BEAM-allo group compared with the BEAM-auto group at 1 year (20% vs. 2%, P = 0.001). Older age and heavily pretreated patients were associated with a higher NRM and poorer survival in the BEAM-allo group. There was, however, a significantly lower relapse rate (20% vs. 43%, P = 0.01) at 3 years with BEAM-alemtuzumab, with no relapses after 2 years, compared with a continued pattern of relapse in the autologous group. No difference in overall survival (OS) (P = 0.99) or disease-free survival (DFS) (P = 0.90) was identified at 3 years, whereas a plateau in OS and DFS with crossing of the survival curves in favour of BEAM-allo group was observed. Furthermore, the ability to re-induce remissions with donor leucocytes provides additional benefit in favour of allogeneic HSCT.

https://pubmed.ncbi.nlm.nih.gov/18318762/

db97dfb3cf6a40983ab012c41fb37b15

Apixaban and rivaroxaban were evaluated in phase III trials for prevention of recurrent ischaemia in ACS patients , most of whom were also receiving dual antiplatelet therapy with aspirin and clopidogrel .

Oral anticoagulants in coronary heart disease (Section IV). Position paper of the ESC Working Group on Thrombosis - Task Force on Anticoagulants in Heart Disease. Until recently, vitamin K antagonists (VKAs) were the only available oral anticoagulants evaluated for long-term treatment of patients with coronary heart disease (CHD), particularly after an acute coronary syndrome (ACS). Despite efficacy in this setting, VKAs are rarely used because they are cumbersome to administer. Instead, the more readily manageable antiplatelet agents are the mainstay of prevention in ACS patients. This situation has the potential to change with the introduction of non-VKA oral anticoagulants (NOACs), which are easier to administer than VKAs because they can be given in fixed doses without routine coagulation monitoring. The NOACs include dabigatran, which inhibits thrombin, and apixaban, rivaroxaban and edoxaban, which inhibit factor Xa. Apixaban and rivaroxaban were evaluated in phase III trials for prevention of recurrent ischaemia in ACS patients , most of whom were also receiving dual antiplatelet therapy with aspirin and clopidogrel . Although at the doses tested rivaroxaban was effective and apixaban was not, both agents increased major bleeding. The role for the NOACs in ACS management, although promising, is therefore complicated, because it is uncertain how they compare with newer antiplatelet agents, such as prasugrel, ticagrelor or vorapaxar, and because their safety in combination with these other drugs is unknown. Ongoing studies are also now evaluating the use of NOACs in non-valvular atrial fibrillation patients, where their role is established, with coexistent ACS or coronary stenting. Focusing on CHD, we review the results of clinical trials with the NOACs and provide a perspective on their future incorporation into clinical practice.

https://pubmed.ncbi.nlm.nih.gov/26952877/

2b166d1bac8f4c6d0718ee9b3736bf26

Systemic and local effects of lidocaine or mepivacaine when used for intravenous regional anaesthesia of the distal limb in standing sedated horses .

Systemic and local effects of lidocaine or mepivacaine when used for intravenous regional anaesthesia of the distal limb in standing sedated horses . Local anaesthetics are being combined clinically with amikacin in intravenous regional limb perfusion (IVRLP), with limited knowledge on the analgesia provided and its onset and duration of action after tourniquet application and release. ### objective To evaluate the systemic clinical effect, limb withdrawal to nociceptive stimulation, and plasma and synovial fluid concentrations after IVRLP with lidocaine or mepivacaine in standing sedated horses. ### Study Design Prospective, controlled, randomised, cross-over study. ### methods Six healthy adult horses were sedated and received IVRLP with lidocaine, mepivacaine or saline (negative control), or perineural anaesthesia of the medial and lateral palmar and palmar metacarpal nerves (positive control) in one forelimb with a 3-week washout period between trials. Electrical and mechanical stimuli were used to test nociceptive threshold of the limb before and after IVRLP/perineural anaesthesia. For lidocaine and mepivacaine trials, blood was collected from the jugular vein and synovial fluid from the radiocarpal joint before, during and out to 24 hours after IVRLP. Drug concentrations were measured using high-performance liquid chromatography. ### results Nociceptive thresholds for lidocaine, mepivacaine and perineural anaesthesia trials were significantly increased compared with saline and baseline values at 10, 20 and 30 minutes, with no differences between anaesthetic trials. During this time, horses had lower heart rates than IVRLP with saline. After tourniquet release at 30 minutes, nociceptive thresholds for lidocaine and mepivacaine trials gradually returned to baselines, whereas perineural anaesthesia trial remained unchanged out to an hour. Plasma lidocaine and mepivacaine concentrations were ≤50 ng/mL while the tourniquet was in place, significantly increasing 10 minutes after tourniquet release. Maximal lidocaine and mepivacaine concentrations in synovial fluid were reached 25 minutes after IVRLP injection. ### Main Limitations amikacin was not included in the perfusate. ### conclusion Similar to perineural anaesthesia, IVRLP with lidocaine or mepivacaine provides anti-nociception to the distal limb in standing sedated horses while a tourniquet is applied with concentrations remaining below toxic levels in plasma and synovial fluid.

https://pubmed.ncbi.nlm.nih.gov/31972065/

a65f5670ed4d904725cedd2fd71cae69

These 18 TMP-resistant E. coli were also resistant to ampicillin ( 44 % ) , azithromycin ( 11 % ) , chloramphenicol ( 39 % ) , ciprofloxacin ( 11 % ) , doxycycline ( 89 % ) , erythromycin ( 100 % ) , furazolidone ( 72 % ) , levofloxacin ( 17 % ) , trimethoprim-sulfamethoxazole ( 89 % ) and trovafloxacin ( 17 % ) .

Emergence of trimethoprim-resistant Escherichia coli in healthy persons in the absence of prophylactic or therapeutic antibiotics during travel to Guadalajara, Mexico. Thirty-nine healthy US students without diarrheal disease and who had not received prophylactic or therapeutic antibiotics were monitored for emergence of trimethoprim-resistant gram-negative fecal flora for a 3-week period after arrival in Guadalajara, Mexico. During this time period, most students showed no change in total fecal gram-negative bacteria (p > 0.05) but showed an increasing level of trimethoprim (TMP) resistance (p < 0.01) among fecal coliforms. Escherichia coli was the TMP-resistant organism isolated in 18 of 39 (46%) healthy students. These 18 TMP-resistant E. coli were also resistant to ampicillin ( 44 % ) , azithromycin ( 11 % ) , chloramphenicol ( 39 % ) , ciprofloxacin ( 11 % ) , doxycycline ( 89 % ) , erythromycin ( 100 % ) , furazolidone ( 72 % ) , levofloxacin ( 17 % ) , trimethoprim-sulfamethoxazole ( 89 % ) and trovafloxacin ( 17 % ) . In the absence of prophylactic and therapeutic antibiotics, increased acquisition of TMP-resistant gram-negative fecal flora in this developing country is probably due to poor sanitary conditions and the recurrent and heavy exposure to antimicrobial-resistant indigenous flora as a result of contaminated food and drink.

https://pubmed.ncbi.nlm.nih.gov/11760159/

433151d677929e57b93ffac5089d0b96

Furthermore , VPA significantly increased chemosensitivity to fludarabine , flavopiridol , bortezomib , thalidomide and lenalidomide .

Antileukemic activity of valproic acid in chronic lymphocytic leukemia B cells defined by microarray analysis. Epigenetic code modifications by histone deacetylase inhibitors have recently been proposed as potential new therapies for hematological malignancies. Chronic lymphocytic leukemia (CLL) remains incurable despite the introduction of new treatments. CLL B cells are characterized by an apoptosis defect rather than excessive proliferation, but proliferation centers have been found in organs such as the bone marrow and lymph nodes. In this study, we analyzed gene expression modifications in CLL B cells after treatment with valproic acid (VPA), a well-tolerated anti-epileptic drug with HDAC inhibitory activity. CLL B cells obtained from 14 patients were treated in vitro with a concentration of 1 mM VPA for 4 h. VPA effects on gene expression were thereafter studied using Affymetrix technology, and some identified genes were validated by real-time PCR and western blot. We observed that VPA induced apoptosis by downregulating several anti-apoptotic genes and by upregulating pro-apoptotic genes. Furthermore , VPA significantly increased chemosensitivity to fludarabine , flavopiridol , bortezomib , thalidomide and lenalidomide . VPA inhibited the proliferation of CpG/IL2-stimulated CLL B cells and modulated many cell cycle messenger RNAs. In conclusion, exposure of CLL B cells to VPA induced apoptosis, potentiated chemotherapeutic agent effects and inhibited proliferation. These data strongly suggest the use of VPA in CLL treatment, particularly in combination with antileukemia agents.

https://pubmed.ncbi.nlm.nih.gov/19710697/

4d85c68f8f355389e68b163f110214ab

Use of the tumor-infiltrating CD8 to FOXP3 lymphocyte ratio in predicting treatment responses to combination therapy with pertuzumab , trastuzumab , and docetaxel for advanced HER2-positive breast cancer .

Use of the tumor-infiltrating CD8 to FOXP3 lymphocyte ratio in predicting treatment responses to combination therapy with pertuzumab , trastuzumab , and docetaxel for advanced HER2-positive breast cancer . The trastuzumab, pertuzumab, and docetaxel (TPD) regimen is strongly recommended as a treatment option for first-line therapy for advanced human epidermal growth factor receptor (HER) 2-positive breast cancer. Monitoring the host microenvironments in cancer plays a significant role in predicting prognoses and curative effects. It is important to clarify the role of immune related gene expression in tumor-infiltrating lymphocytes in the tumor microenvironment. In this study, we evaluated the impact of chemotherapy with a TPD regimen, on immune micro environments in HER2-positive breast cancer using immune related proteins as indicators. ### methods The subjects consisted of 30 patients who received the TPD regimen. The expression levels of estrogen receptor, progesterone receptor, Ki67, CD8, forkhead box protein (FOXP) 3, programmed death (PD) 1, programmed death ligand (PD-L) 1, CD163, phosphatase and tensin homolog and lymphocyte activation gene 3 were evaluated in biopsy specimens, by immunostaining. ### results CD8 ### conclusions This study shows with the TPD regimen, a high CFR leads to a high ORR and long PFS in HER2-positive breast cancer. CFR, therefore, may be one of the important prognostic factors for this disease.

https://pubmed.ncbi.nlm.nih.gov/29615076/

a6693732092e0544b1d827509c89c425

The clinical symptoms were relieved after combination of doxycycline , rifampicin , levofloxacin and amikacin for 6 weeks , only one patient with bone destruction needed orthopedic surgery .

[Diagnosis and treatment of seven patients with brucellosis in non-pastoral areas]. To explore how to diagnose and treat brucellosis accurately and timely in patients with fever of unkown origin in non-pastoral areas. The epidemiological history, clinical symptoms, complete blood counts, procalcitonin and treatment efficacy of 7 patients with brucellosis were analyzed retrospectively. Some characteristic manifestations should be differentiated from tuberculosis. The clinical symptoms were relieved after combination of doxycycline , rifampicin , levofloxacin and amikacin for 6 weeks , only one patient with bone destruction needed orthopedic surgery . The overall response rate was 6/7. No relapse occurred during half year follow-up.

https://pubmed.ncbi.nlm.nih.gov/31365982/

16b2c7d23f8c877898632000b4557b53

Validated LC-MS/MS method for the simultaneous determination of enalapril maleate , nitrendipine , hydrochlorothiazide , and their major metabolites in human plasma .

Validated LC-MS/MS method for the simultaneous determination of enalapril maleate , nitrendipine , hydrochlorothiazide , and their major metabolites in human plasma . Hypertension is a major risk factor for atherosclerosis and ischemic heart disease. Most hypertensive patients need a combination of antihypertensive agents to achieve therapeutic goals. A rapid, sensitive, and selective liquid chromatography-tandem mass spectrometric method was developed and validated for simultaneous determination of enalapril maleate (ENA) and its major metabolite enalaprilat (ENAT), nitrendipine (NIT) and its major metabolite dehydronitrendipine (DNIT), and hydrochlorothiazide (HCT) in human plasma using felodipine as an internal standard (IS). The drugs were extracted from plasma using one-step protein precipitation. Chromatographic separation was performed on a Symmetry C

https://pubmed.ncbi.nlm.nih.gov/32706446/

35b9071f8063de81491292ca8f730a8c

Four years after surgery , she experienced a recurrence of breast cancer in the thoracic wall , and was treated with exemestane , toremifene , and fulvestrant for 1 year and 5 months .

[An Elderly Patient with Metastatic Breast Cancer Who Developed Severe Adverse Events such as Stomatitis and Interstitial Pneumonia after Everolimus plus Exemestane Treatment]. An 80-year-old woman was diagnosed with right breast cancer with clinical Stage IIIA 6 years previously. She underwent mastectomy and axillary lymph node dissection. The pathological diagnosis was invasive micropapillary carcinoma with lymph node involvement. Immunohistochemically, the tumor was positive for estrogen receptor and progesterone receptor, and negative for HER2. Postoperatively, the patient was treated with adjuvant chemotherapy consisting of cyclophosphamide, epirubicin, 5-fluorouracil, and paclitaxel, followed by endocrine therapy with letrozole. Four years after surgery , she experienced a recurrence of breast cancer in the thoracic wall , and was treated with exemestane , toremifene , and fulvestrant for 1 year and 5 months . However, she developed carcinomatous pleurisy and was treated with eribulin. This last treatment was ineffective. Subsequently, she received combination therapy with everolimus and exemestane. Although the pleural effusion reduced markedly after 5 weeks, stomatitis, diarrhea, melena, and interstitial pneumonia occurred as adverse events. The symptoms improved after drug discontinuation and steroid therapy. The combination therapy with everolimus and exemestane is a prospective therapy for hormone-resistant recurrent breast cancer, but the management of adverse events is very important.

https://pubmed.ncbi.nlm.nih.gov/27306814/

8b2f7e675c635b8226a3a0e2b639ba5b

Long-term efficacy of doxazosin plus atenolol in the management of severe and sustained arterial hypertension and reversibility of the cardiac damage induced by chronic cathecolamine excess .

Long-term efficacy of doxazosin plus atenolol in the management of severe and sustained arterial hypertension and reversibility of the cardiac damage induced by chronic cathecolamine excess . Herein we report on a young girl with recurrent, functioning paraganglioma of the organ of Zuckerkandl and severe and sustained arterial hypertension (systolic pressure >200, diastolic pressure >120 mmHg); with evidence of cardiac damage induced by chronic cathecolamine excess. She promptly and steadily improved after the institution of doxazosin (6 mg/day) plus atenolol (50 mg bid) treatment. This case demonstrates that a correct therapeutic strategy in the long-term management of patients with inoperable catecholamine-producing neuroendocrine tumors (pheochromocytomas and paragangliomas) can maintain arterial pressure in the normal range and reverse the cardiac damage induced by chronic cathecolamine excess.

https://pubmed.ncbi.nlm.nih.gov/15636433/

c03f66304e0843a28ace324a46a466ac

To evaluate the use of low-molecular-weight heparin ( LMWH ) in combination with low-dose aspirin ( LDA ) for the treatment of antiphospholipid antibody (APA)-associated recurrent pregnancy loss and to compare the results with the use of unfractionated heparin ( UFH ) plus LDA .

Antiphospholipid antibodies associated with recurrent pregnancy loss: prospective, multicenter, controlled pilot study comparing treatment with low-molecular-weight heparin versus unfractionated heparin. To evaluate the use of low-molecular-weight heparin ( LMWH ) in combination with low-dose aspirin ( LDA ) for the treatment of antiphospholipid antibody (APA)-associated recurrent pregnancy loss and to compare the results with the use of unfractionated heparin ( UFH ) plus LDA . ### design Prospective, controlled, multicenter pilot study. ### setting Two academically based reproductive health centers. ### Patient S Patients with three or more pregnancy losses and positive APA. ### Intervention S Patients were treated with LMWH and LDA (n = 25) or UFH and LDA (n = 25). ### Main Outcome Measure S Fetal outcome and maternal complications from treatments were compared between the two treatment groups. ### Result S Of the 25 patients in the LMWH group, 21 (84%) delivered a viable infant and 4 (16%) miscarried. Of the 25 patients in the UFH group, 20 (80%) delivered a viable infant and 5 (20%) miscarried. These differences were not statistically significant. No major bleeding episodes occurred during pregnancy or at the time of delivery. No cases of deep venous thrombosis, thrombocytopenia, pre-eclampsia, gestational diabetes, or bone fractures were noted in either of the two groups. ### Conclusion S In this pilot study, the use of LDA in combination with LMWH during pregnancy for the prevention of recurrent pregnancy loss in women with antiphospholipid syndrome seems to be as safe as UFH plus LDA. Large, randomized trials will be required to determine differences in outcome with LMWH and LDA compared with treatment with UFH combined with LDA in this group of patients.

https://pubmed.ncbi.nlm.nih.gov/15749498/

e8d4b3349c6eea6a256541a6d78a9023

Therefore , the pain scores were significantly higher in the neostigmine group than the other two groups ( p = 0.02 ) , but no significant difference was found between the two groups that received dexmedetomidine and a combination of dexmedetomidine + neostigmine .

Addition of dexmedetomidine and neostigmine to 1.5 % lidocaine and triamcinolone for epidural block to reduce the duration of analgesia in patients suffering from chronic low back pain. Lower back pain is one of the leading causes of disability in the world. The aim of this study was to evaluate the effect of supplementation of dexmedetomidine and neostigmine with lidocaine 1.5% and triamcinolone for epidural block in increasing the duration of analgesia among patients suffering from chronic low back pain. In this double-blind, randomized clinical trial, 33 patients with chronic low back pain were included in three groups of 11 patients for epidural blockage. triamcinolone (40 mg/ml) was added to lidocaine 1.5% solution (2 cc/segment) for all three groups. In group N, neostigmine was used at a dose of 1 mg (mg), followed by group D (dexmedetomidine 35 μg [0.5 μg/kg]), and grou [ND (neostigmine 0.5 mg, and 35 μg dexmedetomidine, all of which were added to the triamcinolone and lidocaine solution in each group. Medications were injected into the epidural space using an interlaminar approach. Subsequently, scores of pain and duration of analgesia were recorded in questionnaires and analysed using SPSS version 23. One month after the injections, pain scores recorded in the N group were 7.6±1.4, followed by 5.88±1.2 in group D and 5.42 ±1.1 in group ND. Therefore , the pain scores were significantly higher in the neostigmine group than the other two groups ( p = 0.02 ) , but no significant difference was found between the two groups that received dexmedetomidine and a combination of dexmedetomidine + neostigmine . Three months after the injections, there was a significant difference in pain scores between the two groups (P = 0.01). Both neostigmine and dexmedetomidine were capable of reducing the pain of patients with chronic low back pain after epidural block. However, neostigmine's impact is lower compared to dexmedetomidine. The combination of the two drugs also reduced the pain scores of the patients after the intervention.

https://pubmed.ncbi.nlm.nih.gov/31666828/

8bfbe9c7d915500340b3aea9a8db333e

[ Two cases of complete response to combination chemotherapy of gemcitabine and docetaxel for recurrent ovarian cancer ] .

[ Two cases of complete response to combination chemotherapy of gemcitabine and docetaxel for recurrent ovarian cancer ] . The established standard treatment for advanced ovarian cancer is carboplatin and paclitaxel. However, more than 70% of patients have recurrent disease. The standard therapy for recurrent ovarian cancer has not been confirmed. It was reported that docetaxel had a 30-40% of response rate in patients with recurrent ovarian cancer, and that gemcitabine had a 13-22% response rate. The combination chemotherapy of gemcitabine and docetaxel is also applied to non-small cell lung cancer. We use a regimen of 800 mg/m2 of gemcitabine on day 1 and day 8 in combination with 70 mg/m2 of docetaxel on day 8 with a 3-week interval. We treated 2 patients with recurrent ovarian cancer who responded completely to combination chemotherapy with gemcitabine and docetaxel.

https://pubmed.ncbi.nlm.nih.gov/12557720/

dab3736d683a7224d59c55170994934b

Hormonal changes in postmenopausal women with breast cancer treated with trilostane and dexamethasone .

Hormonal changes in postmenopausal women with breast cancer treated with trilostane and dexamethasone . Postmenopausal women with metastatic breast cancer were treated with trilostane, initially 240 mg daily increasing after 3 days to 480 mg daily and after a further three days to 960 mg daily. After 3 days at this dose dexamethasone 1 mg daily was added and this combination was continued until disease progression occurred. Partial remission was seen in 26% and stabilization of previously progressive disease in a further 13% of the first twenty-three patients studied. During therapy with trilostane alone significant increases in DHEAS, androstenedione, 17-hydroxypregnenolone, progesterone, testosterone and oestradiol were seen. A significant fall in oestrone concentration occurred at the same time. After dexamethasone was added the elevated steroid concentrations fell back to the baseline while oestrone remained depressed below this and testosterone was also significantly lowered. No change was seen in cortisol or ACTH concentration while patients were on trilostane alone but cortisol levels were undetectable after dexamethasone was added though, in most patients, ACTH remained detectable. There was no change in the ratio of delta 5:delta 4 steroids at any stage of therapy but a highly significant increase in the androstenedione: oestrone ratio was seen. We conclude that in long-term use in vivo it is difficult to demonstrate that trilostane inhibits 3 beta-hydroxysteroid dehydrogenase but it may produce inhibition of aromatase.

https://pubmed.ncbi.nlm.nih.gov/4064349/

ae1b9bc6b0bae9ca6b9cc05a23b32ab5

After surgical insertion of a catheter in the hepatic artery , patients were treated with oxaliplatin 100 mg/m(2 ) HAI combined with FU + leucovorin IV according to the LV5FU2 protocol .

Hepatic arterial oxaliplatin infusion plus intravenous chemotherapy in colorectal cancer with inoperable hepatic metastases: a trial of the gastrointestinal group of the Federation Nationale des Centres de Lutte Contre le Cancer. Isolated hepatic metastases of colorectal cancer constitute a frequent and serious therapeutic problem that has led to the evaluation of hepatic arterial infusion (HAI) of different drugs. oxaliplatin combined with fluorouracil (FU) and leucovorin is effective in the treatment of colorectal cancer. In this context, a phase II study was conducted to evaluate concomitant administration of oxaliplatin by HAI and intravenous (IV) FU plus leucovorin according to the LV5FU2 protocol (leucovorin 200 mg/m(2), FU 400 mg/m(2) IV bolus, FU 600 mg/m(2) 22-hour continuous infusion on days 1 and 2 every 2 weeks). ### Patients And Methods Patients had metastatic colorectal cancer that was restricted to the liver and inoperable. The patients were not to have previously received oxaliplatin. After surgical insertion of a catheter in the hepatic artery , patients were treated with oxaliplatin 100 mg/m(2 ) HAI combined with FU + leucovorin IV according to the LV5FU2 protocol . Treatment was continued until disease progression or toxicity. Response was evaluated every 2 months. ### results Twenty-eight patients were included, and 26 patients were treated. Two hundred courses of therapy were administered, and the median number of courses received was eight courses (range, zero to 20 courses). The most frequent toxicity consisted of neutropenia. The main toxicity related to HAI was pain. The intent-to-treat objective response rate was 64% (95% CI, 44% to 81%; 18 of 28 patients). With a median follow-up of 23 months, the median overall and disease-free survival times were 27 and 27 months, respectively. ### conclusion The combination of oxaliplatin HAI and FU + leucovorin according to the LV5FU2 protocol is feasible and effective in patients presenting with isolated hepatic metastases of colorectal cancer.

https://pubmed.ncbi.nlm.nih.gov/16009952/

eae2d307ad1816139a7a952f27d111a2

Furthermore methysergide ( 10 mg/kg i.p . ) , but not muscimol ( 2 mg/kg i.p . ) elicited jumping behavior when combined with clonidine ( 0.5 mg/kg i.p . ) , TRH ( 20 mg/kg i.p . ) , haloperidol ( 4 mg/kg i.p . ) or atropine ( 5 mg/kg i.p . ) .

Neuronal mechanisms involved in drug-induced jumping behavior in mice. Previously we have found that lithium chloride (250 mg/kg i.p.) plus haloperidol (4 mg/kg i.p.), or apomorphine (0.25 mg/kg i.p.) plus thyrotropin releasing hormone (TRH, 20 mg/kg i.p.), elicited a jumping behavior which involves dopaminergic and cholinergic inhibition, and noradrenergic activation. Pretreatment with antiserotonergic agents such as methysergide (5 and 10 mg/kg i.p.) and cyproheptadine (5 mg/kg i.p.) enhanced the jumping behavior induced by these drugs. 5-Methoxy-N,N-dimethyltryptamine (5-MDMT, 5 mg/kg i.p.), a serotonergic receptor agonist, inhibited the jumping behavior. Muscimol, a GABA receptor agonist, at 2 mg/kg, potentiated jumping. GABA receptor antagonists such as bicuculline (4 mg/kg i.p.) and picrotoxin (0.2 and 1 mg/kg i.p.) depressed jumping. An antihistamine agent, diphenhydramine (5 mg/kg i.p.), also potentiated the jumping behavior. Furthermore methysergide ( 10 mg/kg i.p . ) , but not muscimol ( 2 mg/kg i.p . ) elicited jumping behavior when combined with clonidine ( 0.5 mg/kg i.p . ) , TRH ( 20 mg/kg i.p . ) , haloperidol ( 4 mg/kg i.p . ) or atropine ( 5 mg/kg i.p . ) . These results suggest that in addition to dopaminergic, cholinergic and noradrenergic mechanisms, serotonergic inhibition may be directly contributing to the initiation of jumping behavior, whereas GABAergic activation appears to be a modulating factor in this behavior.

https://pubmed.ncbi.nlm.nih.gov/2992995/

f69bd6ea16caddaaa4ec412cadbda9fc

Then , doxorubicin with or without flavopiridol was injected .

Synergistic anti-tumor efficacy of doxorubicin and flavopiridol in an in vivo hepatocellular carcinoma model. A previous study showed that flavopiridol increased doxorubicin sensitivity in hypoxic hepatocellular carcinoma (HCC) cells by increasing apoptosis through suppressing hypoxia-inducible N-myc downstream-regulated gene-1 (NDRG1) expression. However, this has not been investigated in an in vivo HCC model. Therefore, we aimed to elucidate whether the combination of doxorubicin and flavopiridol has a synergistic anti-tumor effect in an in vivo HCC model. ### methods An HCC mouse model was established by implanting C3H/He mouse with MH134 cells. Then , doxorubicin with or without flavopiridol was injected . The anti-tumor efficacy was assessed by evaluating tumor volumes, and the underlying mechanism was investigated by quantifying apoptotic cells, the Ki-67 proliferation index, and microvessel densities (MVDs). Immunohistochemistry of NDRG1 was performed to determine the underlying mechanism. ### results Tumor growth was significantly suppressed in the doxorubicin + flavopiridol combination group compared to the other three groups. The percentage of apoptotic cells was significantly higher, and Ki-67-positive proliferating cells were significantly lower in the combination group compared to the other groups; however, MVDs were not significantly different across the groups. Increased apoptosis by flavopiridol occurred by suppressing hypoxia-inducible NDRG1 expression. ### conclusions These results show that a combination of doxorubicin and flavopiridol has a synergistic anti-tumor effect in an in vivo HCC model. This synergistic effect of combination therapy was attributed to increased apoptosis and decreased proliferation of tumor cells rather than decreased angiogenesis. These findings suggest that flavopiridol might be an effective adjuvant therapy to doxorubicin-resistant HCC cells by inducing apoptosis through suppression of NDRG1 expression.

https://pubmed.ncbi.nlm.nih.gov/25989942/

c5102e62153a779d0d7e6bb781df4865

Subjects were treated in two cycles , 3 months apart , in which they received bicalutamide 150 mg daily days 1 - 28 and tremelimumab on day 29 .

Phase I trial of tremelimumab in combination with short-term androgen deprivation in patients with PSA-recurrent prostate cancer. CTLA-4 blockade has demonstrated antitumor efficacy in human clinical trials. The antitumor mechanism is presumably mediated in part by the expansion of tumor-specific T cells. Androgen deprivation, the cornerstone of treatment for patients with metastatic prostate cancer, has been shown to elicit prostate tissue apoptosis and lymphocytic inflammation. We hypothesized that treatment with androgen deprivation, followed by an anti-CTLA-4 antibody, could augment a tumor-specific immune response elicited by androgen deprivation. We report here the results of a phase I trial evaluating a humanized monoclonal antibody targeting CTLA-4, CP-675,206 (tremelimumab), in combination with androgen deprivation using an antiandrogen. Eligible patients were those with PSA-recurrent prostate cancer after primary surgery and/or radiation therapy, not previously treated with androgen deprivation, and without radiographic evidence of metastatic disease. Subjects were treated in two cycles , 3 months apart , in which they received bicalutamide 150 mg daily days 1 - 28 and tremelimumab on day 29 . The primary endpoint of the trial was safety. Secondary endpoints included measures of PSA kinetics and identification of a maximum tolerated dose. Eleven patients were enrolled and completed at least 1 year of follow-up. Dose-limiting toxicities included grade 3 diarrhea and skin rash. No favorable changes in PSA doubling time were observed in a period shortly after completing treatment; however, three patients experienced a prolongation in PSA doubling time detectable several months after completing treatment. The identification of delayed, prolonged favorable changes in serum PSA suggests that future studies could explore this combination in studies evaluating time to disease progression.

https://pubmed.ncbi.nlm.nih.gov/22210552/

85404bd608e6bd5211c9821f0c43e636

In the search better tumoral response in the treatment of epithelial ovarian cancer new drugs have surged that promise good results , including docetaxel , topotecan and gemcitabine ,

[Chemotherapy in germinal and epithelial ovarian cancer]. Generically, ovarian cancer represents a group of tumors with diverse biological and clinical behavior. Thus, germinal cells ovarian tumors, in the vast majority of patients are successfully treated utilizing traditional based on cisplatin chemotherapy. Epithelial ovarian cancer, that accounts for 90% of these cases, although sensitive to chemotherapy has not shown satisfactory results. In the search better tumoral response in the treatment of epithelial ovarian cancer new drugs have surged that promise good results , including docetaxel , topotecan and gemcitabine , both as single agents, or in combination with other therapies utilizing monoclonal antibodies.

https://pubmed.ncbi.nlm.nih.gov/10824448/

0abbccd3e357a08b76ee3ada594b61ba

This study examines a novel regimen utilizing the combination of epidurally infused ropivacaine - hydromorphone and scheduled ketorolac .

Peri-operative pain management in children with cerebral palsy: comparative efficacy of epidural vs systemic analgesia protocols. Selective Dorsal Rhizotomy (SDR) is the only surgical intervention with class I evidence supporting permanent reduction in spasticity for children with cerebral palsy (Paediatr Anaesth, 12, 2002, 296; Neurosurg Focus, 21, 2006, e2). Postoperatively, adequate analgesia can be difficult to achieve (J Neurosurg, 105, 2006, 8; Childs Nerv Syst, 17, 2001, 556; Pediatr Neurosurg, 43, 2007, 107; Anesth Analg, 79, 1994, 340; Reg Anesth Pain Med, 24, 1999, 438; Pediatr Anesth, 19, 2009, 1213). This study examines a novel regimen utilizing the combination of epidurally infused ropivacaine - hydromorphone and scheduled ketorolac . This regimen was compared to a protocol utilizing systemic fentanyl and diazepam. ### methods Following IRB approval, 31 patients receiving epidural analgesia were compared with 41 patients who received systemic analgesia. All surgeries were performed by one surgeon with standardized anesthetic and nursing care. Studied outcomes included: pain scores; episodes of severe pain; nausea, itching; oxygen desaturation; and ICU admission. Data were analyzed using Mann-Whitney U-test, CHI square, and Fisher exact test where indicated with P < 0.05 considered significant. ### results Studied groups had similar demographics, biometrics and disease burdens. Patients in the epidural group had statistically and clinically significant reductions in peak recorded pain scores for each 4-h period in the first 24 postoperative hours. Severe pain (score >5) was markedly reduced in the epidural group with 9% of epidural patients vs. 68% of systemic patients experiencing at least one episode. Fewer epidural patients experienced oxygen desaturation during the first two postoperative days (6.5% vs. 41%, 6.5% vs. 39%). ### conclusion Epidural analgesia resulted in substantial improvements in pain control and safety. The data supports the superiority of a multimodal analgesia approach centered on epidural analgesia. A similar protocol should be considered following simple laminectomies or procedures associated with lower-extremity muscle spasm.

https://pubmed.ncbi.nlm.nih.gov/23682965/

ba59c84a3cf9e17a9d6292e9b7171f24

S-1 is a newly developed novel oral dihydrouracil dehydrogenase inhibiting fluoropyrimidine drug consisting of 1 M tegafur ( FT ) , 0.4 M 5-chloro-2 , 4-dihydroxypyrimidine ( gimeracil ) , and 1 M potassium oxonate ( oteracil ) , with efficient antitumor activity and low gastrointestinal toxicity which is widely used in Japan against advanced gastric , head and neck cancers .

A phase II study of S-1 in patients with metastatic breast cancer--a Japanese trial by the S-1 Cooperative Study Group, Breast Cancer Working Group. S-1 is a newly developed novel oral dihydrouracil dehydrogenase inhibiting fluoropyrimidine drug consisting of 1 M tegafur ( FT ) , 0.4 M 5-chloro-2 , 4-dihydroxypyrimidine ( gimeracil ) , and 1 M potassium oxonate ( oteracil ) , with efficient antitumor activity and low gastrointestinal toxicity which is widely used in Japan against advanced gastric , head and neck cancers . We investigated its clinical efficacy against metastatic breast cancer. ### methods A non-blind phase II study was carried out to evaluate the efficacy and toxicity in metastatic breast cancer patients. Patients with measurable metastasis foci (n=111) were enrolled, and 108 patients were regarded as eligible. S-1 was administered orally at a standard dose of 80 mg/m2/day b.i.d. One course consisted of 28 consecutive days of administration followed by a 14-day rest, and courses were repeated up to six times. ### results Among the eligible patients, 10 had a complete response and 35 had a partial response, with an overall response rate (CR+PR) of 41.7% (95% confidence interval: CI, 32.3-51.5%). The incidences of toxicity (> or =grade 3) were neutropenia 9.1%, anemia 0.9%, anorexia 3.6%, stomatitis 1.8%, nausea/vomiting 1.8%, diarrhea 0.9%, and fatigue 2.7%, however no treatment-related deaths were observed. The median survival time was 872 days (95% CI, 572-1,110 days). There was no difference in response rate or toxicity between the under 65-year-old group and the older group. ### conclusion S-1 was demonstrated to have high efficacy with low gastrointestinal toxicity even in older patients and will be a promising new chemotherapy drug for metastatic breast cancer.

https://pubmed.ncbi.nlm.nih.gov/15550867/

6bbff03274770e14695de22449bed79b

Patients in the HXP arm also received trastuzumab ( 8 mg/kg intravenous infusion on Day 1 ) , concurrently with capecitabine .

Pharmacokinetic analysis of capecitabine and cisplatin in combination with trastuzumab in Japanese patients with advanced HER2-positive gastric cancer. To evaluate the pharmacokinetics (PK) of capecitabine and cisplatin, administered in combination with or without trastuzumab, in Japanese patients with HER2-positive advanced gastric cancer (AGC). ### methods Patients eligible for this PK study (study JP19959), which was carried out during treatment Cycle 1 of the ToGA study, received either capecitabine and cisplatin (XP arm) or trastuzumab plus capecitabine and cisplatin (HXP arm). All patients received capecitabine (1,000 mg/m(2) orally, twice daily for 14 days) and cisplatin (80 mg/m(2) intravenous infusion on Day 1). Patients in the HXP arm also received trastuzumab ( 8 mg/kg intravenous infusion on Day 1 ) , concurrently with capecitabine . No further study medication was administered during study JP19959. Serial plasma samples for PK analysis were obtained at intervals before and after the administration of capecitabine and cisplatin on Day 1. ### results Twenty-two patients were enrolled in this PK study: eight in the HXP arm and 14 in the XP arm. All blood samples were available for PK analysis. Co-administration of trastuzumab resulted in no statistically or clinically significant changes in the PK profiles of capecitabine or its metabolites, or of cisplatin (total or unbound platinum). ### conclusions Variability in the AUC(last) and C (max) values for the capecitabine was consistent with the known PK profile of capecitabine and fell within established limits. Concurrent trastuzumab therapy is unlikely to alter the PK or safety profile of capecitabine or cisplatin in Japanese patients with HER2-positive AGC.

https://pubmed.ncbi.nlm.nih.gov/22116464/

616aeea94625bb1c07aa03e86b2018bc

Among targeted therapies , lapatinib has activity in systemic treatment of BM particularly when used in combination with capecitabine .

Chemotherapy and biological treatment options in breast cancer patients with brain metastasis: an update. Breast cancer (BC) is the second most common cause of CNS metastasis. Ten to 20% of all, and 38% of human epidermal growth factor-2(+), metastatic BC patients experience brain metastasis (BM). Prolonged survival with better control of systemic disease and limited penetration of drugs to CNS increased the probability of CNS metastasis as a sanctuary site of relapse. Treatment of CNS disease has become an important component of overall disease control and quality of life. ### Areas Covered Current standard therapy for BM is whole-brain radiotherapy, surgery, stereotactic body radiation therapy for selected cases, corticosteroids and systemic chemotherapy. Little progress has been made in chemotherapy for the treatment of BM in patients with BC. Nevertheless, new treatment choices have emerged. In this review, we aimed to update current and future treatment options in systemic treatment for BM of BC. ### Expert Opinion Cornerstone local treatment options for BM of BC are radiotherapy and surgery in selected cases. Efficacy of cytotoxic chemotherapeutics is limited. Among targeted therapies , lapatinib has activity in systemic treatment of BM particularly when used in combination with capecitabine . Novel agents are currently investigated.

https://pubmed.ncbi.nlm.nih.gov/25032884/

ff7836748885fded1e16ef3e312f2170

Anaemia was present in patients who had just been diagnosed with rheumatoid arthritis and had never taken disease modifying agents or biologicals ( non-specific therapy group ) , but not in those taking either leflunomide or adalimumab .

Treatment with either leflunomide or adalimumab reduces anaemia in patients with rheumatoid arthritis. Rheumatoid arthritis is a chronic disease of the joints, which causes joint pain and disability. Anaemia is a frequent extra-articular manifestation in rheumatoid arthritis, affecting 30-70% of the patients; presenting a negative impact on patient´s quality of life. Some of the drugs used in rheumatoid arthritis treatment improve anaemia; but little is known on the beneficial effects of the anti-rheumatic leflunomide or the anti-TNFα adalimumab, in this parameter. We investigated the incidence of anaemia in rheumatoid arthritis patients treated or not with leflunomide or adalimumab. We also assessed whether anaemia correlates with disease activity. Anaemia was present in patients who had just been diagnosed with rheumatoid arthritis and had never taken disease modifying agents or biologicals ( non-specific therapy group ) , but not in those taking either leflunomide or adalimumab . The erythrocyte sedimentation rate was increased in patients with non-specific therapy in comparison with those taking either leflunomide or adalimumab. Anaemia correlated with increased erythrocyte sedimentation rate. We suggest that leflunomide and adalimumab may be useful in treating anaemia in patients with rheumatoid arthritis.

https://pubmed.ncbi.nlm.nih.gov/29947664/

480bbd37984bbf7f13020279517910d8

Growth of both Karp and AFSC-4 was strongly inhibited with both antibiotics , as measured by visual counts , although the percentage of cells infected with AFSC-4 in the presence of doxycycline was three times greater than the percentage of cells infected with Karp but was only 60 % as great as the percentage of cells infected with Karp in the presence of azithromycin .

In vitro effectiveness of azithromycin against doxycycline-resistant and -susceptible strains of Rickettsia tsutsugamushi, etiologic agent of scrub typhus. In an effort to find a potential alternative treatment for scrub typhus, we evaluated the effectiveness of the standard drug doxycycline and the new macrolide azithromycin against a doxycycline-susceptible strain (Karp) and a doxycycline-resistant strain (AFSC-4) of Rickettsia tsutsugamushi. The antibiotics were tested in an in vitro assay system in which infected mouse fibroblast cells (L929) were incubated for 3 days in various concentrations of the drugs. Rickettsial growth was evaluated by direct visual counts of rickettsiae in Giemsastained cells or by flow cytometry. Initial tests were conducted at the concentration of each antibiotic considered to be the upper breakpoint for susceptibility (16 micrograms/ml for doxycycline and 8 micrograms/ml for azithromycin). Growth of both Karp and AFSC-4 was strongly inhibited with both antibiotics , as measured by visual counts , although the percentage of cells infected with AFSC-4 in the presence of doxycycline was three times greater than the percentage of cells infected with Karp but was only 60 % as great as the percentage of cells infected with Karp in the presence of azithromycin . Flow cytometry confirmed that rickettsial growth occurred in the absence of antibiotics, but it failed to detect it in the presence of high concentrations of either drug. Visual counts of rickettsial growth at lower concentrations of the antibiotics (0.25 to 0.0078 microgram/ml) showed that the Karp strain was 16 times more susceptible that the AFSC-4 strain to doxycycline. azithromycin was much more effective than doxycycline against AFSC-4, inhibiting rickettsial growth at 0.0156 microgram/ml to levels below that achieved by 0.25 microgram of doxycycline per ml. azithromycin was also more effective than doxycycline against the Karp strain, causing greater reductions in the number of rickettsiae per cell at lower concentrations. If in vivo testing confirms the in vitro effectiveness of azithromycin, it may prove to be the drug of choice for the treatment of scrub typhus in children and pregnant women, who should not take doxycycline, and in patients with refractory disease from locations where doxycycline-resistant strains of R. tsutsugamushi have been found. When tested in an in vitro assay system, azithromycin was more effective than doxycycline against doxycycline-susceptible and -resistant strains of R. tsutsugamushi.

https://pubmed.ncbi.nlm.nih.gov/8585717/

1c074798259151bb612a3d01ec0f749a

The Society of Critical Care Medicine ( SCCM ) released updated guidelines for management of pain , agitation , and delirium in the ICU and recommended nonbenzodiazepines , such as dexmedetomidine and propofol , as first line sedation agents .

Interpatient variability in dexmedetomidine response: a survey of the literature. Fifty-five thousand patients are cared for in the intensive care unit (ICU) daily with sedation utilized to reduce anxiety and agitation while optimizing comfort. The Society of Critical Care Medicine ( SCCM ) released updated guidelines for management of pain , agitation , and delirium in the ICU and recommended nonbenzodiazepines , such as dexmedetomidine and propofol , as first line sedation agents . Dexmedetomidine, an alpha-2 agonist, offers many benefits yet its use is mired by the inability to consistently achieve sedation goals. Three hypotheses including patient traits/characteristics, pharmacokinetics in critically ill patients, and clinically relevant genetic polymorphisms that could affect dexmedetomidine response are presented. Studies in patient traits have yielded conflicting results regarding the role of race yet suggest that dexmedetomidine may produce more consistent results in less critically ill patients and with home antidepressant use. Pharmacokinetics of critically ill patients are reported as similar to healthy individuals yet wide, unexplained interpatient variability in dexmedetomidine serum levels exist. Genetic polymorphisms in both metabolism and receptor response have been evaluated in few studies, and the results remain inconclusive. To fully understand the role of dexmedetomidine, it is vital to further evaluate what prompts such marked interpatient variability in critically ill patients.

https://pubmed.ncbi.nlm.nih.gov/24558330/

a08ea9aa644400399c6f95f2ea19c86a

An in vitro assessment of azithromycin in combination with gentamicin demonstrated inhibition of growth and suggests that clinical trials may be warranted to assess the utility of this combination in treating gonorrhea infections .

In vitro assessment of dual drug combinations to inhibit growth of Neisseria gonorrhoeae. The development of resistance to first-line antimicrobial therapies has led to recommendations for combination therapies for the treatment of gonorrhea infection. Recent studies have shown the success of combination therapies in treating patients, but few have reported on the in vitro activities of these drug combinations. An in vitro assessment of azithromycin in combination with gentamicin demonstrated inhibition of growth and suggests that clinical trials may be warranted to assess the utility of this combination in treating gonorrhea infections .

https://pubmed.ncbi.nlm.nih.gov/25624328/

e0bf2084b1a8a8bf198f94062b7fbefa

Among antimicrobials , ciprofloxacin ( 22 ( 22.7 % ) ) was the most common drug followed by metronidazole ( 21 ( 18.5 % ) ) .

Prescription pattern in the department of surgery in a tribal district hospital of andhra pradesh, India. Usually, surgical management cannot be completed without the use of antimicrobial and analgesic drugs. Irrational prescription may lead to severe postoperative complications. ### aim The objective of this study was to evaluate the prescription trend in the surgery department of a tribal district hospital so as to determine the extent of rational use of medicines. ### Materials And Methods It was a retrospective study in which 50 cases were selected randomly. Case records were analyzed for prescription trend. Data was analyzed using Microsoft Office Excel 2007 and values were presented descriptively. ### results Most of the cases were between the age group of 21 and 40 years, 18 cases (36%). Commonest cause of hospitalization was renal calculi (10 (20%)) followed by acute abdomen and abscess (6, (12%)). Total of 255 numbers of drugs were used with an average of 5.1 drugs per patient. Most preferred route was intravenous route (174 drugs, 68.2%). Antimicrobial was the most common (97 (38.0%)) group of drugs followed by analgesic/antipyretics (50 (19.6%)). Among antimicrobials , ciprofloxacin ( 22 ( 22.7 % ) ) was the most common drug followed by metronidazole ( 21 ( 18.5 % ) ) . All the cases were managed by empirical treatment. Two different antimicrobials were prescribed to 20 (40%) of cases. Dosage of 83 (32.6%) drugs was inappropriate while frequency was inappropriate in 26 (10.2%) cases. ### conclusion Urgent steps like specific guidelines, training, and monitoring of drugs use are needed to correct some irrational approaches.

https://pubmed.ncbi.nlm.nih.gov/24116329/

c23445106fee40505d6ccd1d1c8ee609

Clinical efficacy of immunochemotherapy with rituximab , fludarabine and mitoxantrone followed by 2-monthly rituximab maintenance was evaluated in 29 patients with previously untreated follicular lymphoma in a prospective phase II trial ( AGMT-NHL9 ) .

Rituximab serum concentrations during immuno-chemotherapy of follicular lymphoma correlate with patient gender, bone marrow infiltration and clinical response. Treatment of follicular lymphoma with rituximab is currently recommended at a dose of 375 mg/m(2). We aimed to provide a rationale for optimal dosing and scheduling of this anti-CD20 antibody based on pharmacokinetics. ### Design And Methods Clinical efficacy of immunochemotherapy with rituximab , fludarabine and mitoxantrone followed by 2-monthly rituximab maintenance was evaluated in 29 patients with previously untreated follicular lymphoma in a prospective phase II trial ( AGMT-NHL9 ) . Pharmacokinetic analysis was assessed in 17 patients. ### results Induction treatment resulted in high clinical response rates (complete remission 66%; ORR 100%). Significantly higher complete remission rates were observed in female patients (86 vs. 47%; Odds Ratio 6.8, 95% CI: 1.12; 41.82; P=0.05). rituximab pharmacokinetic analysis showed a high variability ranging over almost 1 order of magnitude at maintenance cycle 1 (area under the curve 1,540-12,025 g/L*days). Median area under the curve was lower in men (81%) and in patients with initial bone marrow infiltration (76%). Higher rituximab serum concentrations before next therapy (C(trough)) were associated with female sex (P=0.04) as well as with absence of initial bone marrow infiltration (P=0.001). C(trough) correlated with remission quality (complete vs. partial remission; P=0.005) and progression-free survival (P=0.03). A decline in rituximab C(trough) below 25,000 ng/mL was observed 9.5 to 62 months before clinical relapse (P=0.008). ### conclusions The results of this pilot trial suggest that more differentiated dosing schedules based on gender and bone marrow infiltration should be explored for rituximab therapy for lymphoma. This study was registered in ClinicalTrials.gov (Identifier: NCT01560117).

https://pubmed.ncbi.nlm.nih.gov/22511498/

1d8fbabbaa29b8243097f0ffe742dcc4

Palliative chemotherapy with carboplatin and etoposide produced a minimal response .

Merkel cell carcinoma: A case of palliative upper limb amputation in a patient with refractory in-transit metastases. We report an unusual case of Merkel cell carcinoma in a 70-year-old woman with the rapid development of left upper limb in-transit and hepatic metastases. The patient had a preceding history of left-sided breast cancer. Palliative chemotherapy with carboplatin and etoposide produced a minimal response . The in-transit metastases rapidly progressed and were refractory to chemotherapy and a single fraction of palliative radiotherapy, leading to a marked impact on her quality of life, secondary to sepsis and bleeding. After lengthy discussion, she consented to an above-elbow amputation resulting in a marked improvement in her well-being. In this case, we believe that palliative amputation of the involved arm was justified and beneficial to the patient.

https://pubmed.ncbi.nlm.nih.gov/25754425/

7a765b6c37dfd52980521a00277bb151

In vitro susceptibilities of ocular Bacillus cereus isolates to clindamycin , gentamicin , and vancomycin alone or in combination .

In vitro susceptibilities of ocular Bacillus cereus isolates to clindamycin , gentamicin , and vancomycin alone or in combination . A broth dilution assay was used to determine the in vitro susceptibilities of 10 ocular isolates of Bacillus cereus to clindamycin, gentamicin, and vancomycin both alone and in combination. The checkerboard technique was used to determine fractional inhibitory and bactericidal concentration indices for combinations of clindamycin-gentamicin and vancomycin-gentamicin.

https://pubmed.ncbi.nlm.nih.gov/1901697/

de0c335311bff300b085c7c5d7917de8

Most ( ≥ 75 % ) patients received ESHAP ( etoposide , methylprednisolone , cytarabine , cisplatin ) or DHAP ( cisplatin , cytosine arabinoside , dexamethasone ) as salvage chemotherapy .

Treatment response and overall outcome of patients with relapsed and refractory peripheral T-cell lymphoma compared to diffuse large B-cell lymphoma. The purpose of the study was to assess treatment response and overall outcome in a cohort of patients with relapsed and refractory peripheral T-cell lymphoma and to compare the results with those for patients with diffuse large B-cell lymphoma treated in a similar manner. We retrospectively analyzed data of 40 consecutive adult patients with relapsed and refractory peripheral T-cell lymphoma referred to our institution for consideration of second-line chemotherapy aiming for autologous stem cell transplant between January 1999 and December 2006. A cohort of 126 patients with diffuse large B-cell lymphoma managed similarly served as a comparison group. Most ( ≥ 75 % ) patients received ESHAP ( etoposide , methylprednisolone , cytarabine , cisplatin ) or DHAP ( cisplatin , cytosine arabinoside , dexamethasone ) as salvage chemotherapy . From first relapse/progression, overall survival at 2 years was 54% (95% confidence interval [CI]: 38-76) for the peripheral T-cell lymphoma cohort and 49% (95% CI: 39-60) for the diffuse large B-cell lymphoma cohort (p = 0.098). Overall response rate to salvage chemotherapy was similar between both groups (63% vs. 52%). Post-autologous stem cell transplant, 1-year progression-free survival was 20% (95% CI: 9-48) for patients with peripheral T-cell lymphoma and 47% (95% CI: 36-61) for patients with diffuse large B-cell lymphoma. Two-year overall survival post-autologous stem cell transplant was 43% (95% CI: 26-71) and 54% (95% CI: 43-68), respectively. Patients with relapsed and refractory peripheral T-cell lymphoma and diffuse large B-cell lymphoma showed a similar response to salvage chemotherapy and overall survival. Likely due to imbalances in risk factors at relapse, progression-free survival post-autologous stem cell transplant was inferior in the peripheral T-cell lymphoma group. Strategies aiming to maintain response duration post-autologous stem cell transplant could improve the outcome of patients with peripheral T-cell lymphoma.

https://pubmed.ncbi.nlm.nih.gov/22897731/

02c33d81ce0c8812a656cd04ddcfa86a

Patients treated on CCG-3881 ( n = 116 ) received four-drug chemotherapy for 9 months ( cisplatin , cyclophosphamide , doxorubicin , and etoposide ) , with surgery and local radiation to residual disease .

Biologic factors determine prognosis in infants with stage IV neuroblastoma: A prospective Children's Cancer Group study. A prospective Children's Cancer Group study, CCG-3881, has been completed to determine if a more accurate prediction of prognosis by biologic features can identify subgroups of infants with stage IV neuroblastoma (NBL) who require differing intensities of treatment. ### Patients And Methods One hundred thirty-four infants were registered from June 1989 to August 1995, with a median follow-up of 47.1 months (range, 0 to 88 months). The biologic factors examined were tumor MYCN copy number, Shimada histopathologic classification, serum ferritin, and bone marrow immunocytology (sensitivity, one tumor cell per 10(5) bone marrow cells). Patients treated on CCG-3881 ( n = 116 ) received four-drug chemotherapy for 9 months ( cisplatin , cyclophosphamide , doxorubicin , and etoposide ) , with surgery and local radiation to residual disease . After January 1991, all subsequent infants with tumor MYCN amplification (n = 18) were transferred after one cycle of therapy to the high-risk CCG-3891 protocol (open January 1991 to April 1996) for more intensive treatment. ### results The 3-year event-free survival (EFS) and overall survival (mean +/- SD) for the 134 infants were 63% +/- 5% and 71% +/- 5%, respectively. Patients whose tumors were without MYCN amplification had a 93% +/- 4% 3-year EFS, whereas those with amplified MYCN had a 10% +/- 7% 3-year EFS (P <. 0001). Each of the other biologic features studied had prognostic significance in univariate analysis but not after stratifying by MYCN copy number. ### conclusion Infants less than 1 year of age at diagnosis with stage IV NBL have a much improved outcome compared with children >/= 1 year of age. Nonamplified MYCN tumors identify a group of infants with a 93% +/- 4% EFS, whereas amplified MYCN copy number clearly identifies patients who are unlikely to survive despite intensive chemotherapy.

https://pubmed.ncbi.nlm.nih.gov/10715296/

541e4b1e01753806de482ac53c89b090

184 ( 62·0 % , 95 % CI 56·2 - 67·5 ) patients in the cetuximab group achieved an objective response compared with 171 ( 58·0 % , 52·1 - 63·7 ) in the bevacizumab group ( odds ratio 1·18 , 95 % CI 0·85 - 1·64 ; p=0·18 ) .

FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. cetuximab and bevacizumab have both been shown to improve outcomes in patients with metastatic colorectal cancer when added to chemotherapy regimens; however, their comparative effectiveness when partnered with first-line fluorouracil, folinic acid, and irinotecan (FOLFIRI) is unknown. We aimed to compare these agents in patients with KRAS (exon 2) codon 12/13 wild-type metastatic colorectal cancer. ### methods In this open-label, randomised, phase 3 trial, we recruited patients aged 18-75 years with stage IV, histologically confirmed colorectal cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, an estimated life expectancy of greater than 3 months, and adequate organ function, from centres in Germany and Austria. Patients were centrally randomised by fax (1:1) to FOLFIRI plus cetuximab or FOLFIRI plus bevacizumab (using permuted blocks of randomly varying size), stratified according to ECOG performance status, number of metastatic sites, white blood cell count, and alkaline phosphatase concentration. The primary endpoint was objective response analysed by intention to treat. The study has completed recruitment, but follow-up of participants is ongoing. The trial is registered with ClinicalTrials.gov, number NCT00433927. ### findings Between Jan 23, 2007, and Sept 19, 2012, 592 patients with KRAS exon 2 wild-type tumours were randomly assigned and received treatment (297 in the FOLFIRI plus cetuximab group and 295 in the FOLFIRI plus bevacizumab group). 184 ( 62·0 % , 95 % CI 56·2 - 67·5 ) patients in the cetuximab group achieved an objective response compared with 171 ( 58·0 % , 52·1 - 63·7 ) in the bevacizumab group ( odds ratio 1·18 , 95 % CI 0·85 - 1·64 ; p=0·18 ) . Median progression-free survival was 10·0 months (95% CI 8·8-10·8) in the cetuximab group and 10·3 months (9·8-11·3) in the bevacizumab group (hazard ratio [HR] 1·06, 95% CI 0·88-1·26; p=0·55); however, median overall survival was 28·7 months (95% CI 24·0-36·6) in the cetuximab group compared with 25·0 months (22·7-27·6) in the bevacizumab group (HR 0·77, 95% CI 0·62-0·96; p=0·017). Safety profiles were consistent with the known side-effects of the study drugs. The most common grade 3 or worse adverse events in both treatment groups were haematotoxicity (73 [25%] of 297 patients in the cetuximab group vs 62 [21%] of 295 patients in the bevacizumab group), skin reactions (77 [26%] vs six [2%]), and diarrhoea (34 [11%] vs 40 [14%]). ### interpretation Although the proportion of patients who achieved an objective response did not significantly differ between the FOLFIRI plus cetuximab and FOLFIRI plus bevacizumab groups, the association with longer overall survival suggests that FOLFIRI plus cetuximab could be the preferred first-line regimen for patients with KRAS exon 2 wild-type metastatic colorectal cancer. ### funding Merck KGaA.

https://pubmed.ncbi.nlm.nih.gov/25088940/

4c5a498fed553d821b8f2a8a00d1d861

These data suggest that weekly docetaxel plus carboplatin may be an important therapeutic second-line treatment option for patients with DRPC .

Carboplatin plus weekly docetaxel as salvage chemotherapy in docetaxel-resistant and castration-resistant prostate cancer. There is no proven, effective, standard second-line chemotherapy for castration- and docetaxel-resistant prostate cancer (DRPC). Recent data suggest that carboplatin may be effective in combination with docetaxel in this setting; however, the optimal docetaxel/carboplatin-based regimen is still unclear. ### Aim Of The Study We identified 43 consecutive patients with DRPC treated with carboplatin (AUC5 d1) and docetaxel (35 mg/m(2) d1, 8, 15 q4w i.v.) as a second-line or subsequent salvage chemotherapy until discontinuation of therapy due to disease progression or unacceptable toxicity. ### results Decreased prostate-specific antigen (> or =50% PSA) was observed in 22/43 (51.2%, 95% CI, 35.5, 66.7%) patients, with > or =90% reduction in 12/43 patients (27.9%). At the time of analysis, the median follow-up time for all patients was 10.4 months. Median progression-free survival (PFS) for all patients was 6.5 months (95% CI 4.1, 8.9), and median overall survival (OS) was 15.8 months (95% CI 12.1, 18.5). In PSA responders, PFS was 9.5 (95% CI 8.2, 19.0) months versus 3.3 (95% CI 2.6, 4.0) months in PSA non-responders (P < 0.0001; hazard ratio (HR) 0.108) and OS was 24.4 months (95% CI 19.5, 29.4) versus 7.8 (95% CI 5.2, 10.3) months (P = 0.001; HR 0.232). Established prognostic factors were associated with survival. This regimen was reasonably well tolerated, with leukopenia/neutropenia as the most common reversible grade 3/4 toxicity (41.9/39.5%). ### conclusion These data suggest that weekly docetaxel plus carboplatin may be an important therapeutic second-line treatment option for patients with DRPC .

https://pubmed.ncbi.nlm.nih.gov/20229232/

d06ffe27a43f3698e5557482f82a036b

' Side-effects ' such as tiredness , decreased inclination to work , and dryness of the mouth were somewhat more frequent after the higher clonidine dose than after both doses of guanfacine , and peaked 2 h after clonidine but only 4 - 6 h after guanfacine .

Central effects of guanfacine and clonidine during wakefulness and sleep in healthy subjects. 1. Three double-blind studies in young normotensive male volunteers were carried out: a study in ten awake subjects, comparing guanfacine 2.0 and 4.0 mg with clonidie 0.15 and 0.30 mg and placebo; and two polygraphic sleep studies each with six subjects, comparing guanfacine 1.0 and 2.0 mg with placebo, and clonidine 0.15 and 0.30 mg with placebo, respectively. 2. In awake subjects, both drugs reduced systolic blood pressure without significantly altering diastolic blood pressure, pulse rate and objective performance parameters. ' Side-effects ' such as tiredness , decreased inclination to work , and dryness of the mouth were somewhat more frequent after the higher clonidine dose than after both doses of guanfacine , and peaked 2 h after clonidine but only 4 - 6 h after guanfacine . 3. clonidine 0.15 and 0.30 mg given in the evening was followed by a substantial and dose-dependent reduction in rapid eye movement (REM) sleep. guanfacine 1.0 mg did not alter REM sleep and 2.0 mg of guanfacine had less effect than both doses of clonidine in this respect. clonidine's effect on REM sleep began after about 2 h, whereas guanfacine's action on REM sleep began 5 h after the dose. 4. guanfacine and clonidine possess a qualitatively similar pattern of activity with regard to the parameters studied; but the central effects are less pronounced and occur later after guanfacine than after clonidine in equiactive doses.

https://pubmed.ncbi.nlm.nih.gov/6994771/

0af2862b59df99b0532361a20f92de95

The recommended phase II dose is bortezomib 1.0 mg/m on days 1 , 4 , 8 , and 11 plus docetaxel 75 mg/m on day 1 , cycled every 21 days .

Bortezomib plus docetaxel in advanced non-small cell lung cancer and other solid tumors: a phase I California Cancer Consortium trial. This phase I study was performed to determine the dose-limiting toxicity and maximum tolerated dose (MTD) of docetaxel in combination with bortezomib in patients with advanced non-small cell lung cancer (NSCLC) or other solid tumors. ### methods Patients were enrolled in cohorts of three over six dose levels. Each treatment cycle was 3 weeks long and consisted of one docetaxel infusion (day 1) and four bortezomib injections (days 1, 4, 8, and 11). Dose escalation and MTD determination were based on the occurrence of dose-limiting toxicities in cycle 1 only. ### results A total of 36 patients were enrolled, 26 of whom had NSCLC. All patients received at least one dose of study drug at one of five dose levels. The MTD of the combined regimen was determined to be 1.0/75 mg/m bortezomib/docetaxel. The combination was generally well tolerated. Toxicities were manageable, and no additive toxicities were observed. The most common adverse events were fatigue (67% of patients), nausea (50%), diarrhea (39%), and neutropenia (39%). Two patients with NSCLC achieved a partial response, and seven (19%) patients achieved stable disease (including six patients with NSCLC). ### conclusion The combination of bortezomib and docetaxel was feasible and well tolerated in patients with advanced NSCLC or other solid tumors. The recommended phase II dose is bortezomib 1.0 mg/m on days 1 , 4 , 8 , and 11 plus docetaxel 75 mg/m on day 1 , cycled every 21 days . Therapeutic doses of docetaxel and bortezomib are achievable for this combination.

https://pubmed.ncbi.nlm.nih.gov/17409841/

ba671ded376e5c6516f0848405d9eaf8

Budesonide/formoterol pMDI affords equivalent formoterol-related bronchodilatory effects versus formoterol DPI at formoterol doses of 4.5 , 9 , and 18 microg , indicating that practitioners can expect and patients will experience similar bronchodilation from the same dose of formoterol whether it is delivered as monotherapy via a DPI or as combination therapy with budesonide via one pMDI .

Bronchodilation of formoterol administered with budesonide: device and formulation effects. Previous single-dose crossover studies have established therapeutic equivalence of formoterol when administered at the same nominal dose via a dry powder inhaler (DPI) or pressurized hydrofluoroalkane (HFA) metered-dose inhaler (pMDI). Demonstration of equivalent bronchodilation for formoterol administered as formoterol DPI or combined with budesonide in one pMDI (budesonide/formoterol pMDI) would indicate that the greater clinical efficacy of the budesonide/formoterol pMDI combination is due to the budesonide contribution and not to differences in formoterol formulation or delivery device. ### objective To determine whether the formoterol-related bronchodilatory effects of formoterol DPI and budesonide/formoterol pMDI are similar, despite formoterol formulation and delivery device differences. ### methods This was a multicenter, open-label, five-period crossover study conducted in 201 adult patients with stable asthma. The study included a screening visit, a 7- to 14-day run-in period, during which patients were treated with budesonide pMDI (80 microg per inhalation, two inhalations twice daily), and a randomized treatment period that included five single-day treatment periods, during which patients received single-dose crossover treatments, each of which was separated by a 3- to 14-day washout period. Patients were randomized to five of seven single-dose treatments (one, two, or four inhalations of budesonide/formoterol pMDI 80/4.5 microg; four inhalations of budesonide pMDI 80 microg plus one, two, or four inhalations of formoterol DPI 4.5 microg; or four inhalations of budesonide pMDI 80 microg alone). At clinic visits, the budesonide pMDI dose was coordinated with the budesonide dose delivered via the budesonide/formoterol pMDI such that all patients received a 320-microg dose of budesonide. The primary variable was average forced expiratory volume in 1 s (FEV1) from the area under the curve divided by time from 12-h serial spirometry. ### results Average 12-h FEV1 values were similar, regardless of delivery device, among treatments with the same nominal formoterol doses and dose-ordered within each device; mean FEV1 values were significantly higher for treatments containing formoterol versus budesonide alone. The formoterol dose potency ratio for budesonide/formoterol pMDI:formoterol DPI (0.97; 95% confidence interval, 0.73-1.27) demonstrated clinical equivalence in bronchodilation at the same formoterol dose. ### conclusion Budesonide/formoterol pMDI affords equivalent formoterol-related bronchodilatory effects versus formoterol DPI at formoterol doses of 4.5 , 9 , and 18 microg , indicating that practitioners can expect and patients will experience similar bronchodilation from the same dose of formoterol whether it is delivered as monotherapy via a DPI or as combination therapy with budesonide via one pMDI .

https://pubmed.ncbi.nlm.nih.gov/17625985/

9662c83eea1af48ce3ddb410a6ff064f

In this review , we will discuss the use of anti-EGFR MoAbs in the treatment of mCRC , with focus on cetuximab and panitumumab .

Novel approaches to treatment of advanced colorectal cancer with anti-EGFR monoclonal antibodies. The standard treatment of metastatic colorectal cancer (mCRC) is combination of 5- fluorouracil/folinic acid with irinotecan or oxaliplatin-based chemotherapy. Epidermal growth factor receptor (EGFR) is overexpressed in 70%-80% of colorectal cancers (CRC). EGFR overexpression is known to be involved in carcinogenic processes, such as cell proliferation, apoptosis, angiogenesis and metastasis. Monoclonal antibodies targeting EGFR have shown antitumor activity and improved the efficacy of chemotherapy. cetuximab is a chimeric immunoglobulin (Ig) G1 anti-EGFR monoclonal antibody (MoAb). Several clinical studies have shown cetuximab, either as a single agent or in combination with irinotecan, having promising efficacy in patients with metastatic CRC. cetuximab with 5-fluorouracil/LV (leucovorin) plus irinotecan or oxaliplatin-based chemotherapy has shown higher response rate and longer time to progression as first-line treatment of mCRC. Currently, there are no data showing that addition of cetuximab would prolong overall survival in randomized studies. panitumumab, a fully human IgG2 monoclonal antibody, has also shown antitumor activity against EGFR-expressing mCRC with less allergic reaction. Anti-EGFR MoAbs are well tolerated and have limited overlapping toxicities in combination with other cytotoxic drugs. The most common side effect of anti-EGFR MoAb is an acneform skin rash, which is a surrogate marker of efficacy of treatment with MoAbs. In this review , we will discuss the use of anti-EGFR MoAbs in the treatment of mCRC , with focus on cetuximab and panitumumab .

https://pubmed.ncbi.nlm.nih.gov/17438669/

4efd21316f0481148a77a63c76a5f6f0

A 29-year-old white man with recurrent Hodgkin 's disease received doxorubicin , bleomycin , vinblastine , and dacarbazine ( ABVD ) chemotherapy once every two weeks for 12 cycles .

Ototoxicity associated with vinblastine. To describe a patient with ototoxicity associated with vinblastine chemotherapy. ### Case Summary A 29-year-old white man with recurrent Hodgkin 's disease received doxorubicin , bleomycin , vinblastine , and dacarbazine ( ABVD ) chemotherapy once every two weeks for 12 cycles . He reported tinnitus after each treatment, with an onset of about six hours and a duration of seven to 10 days. This interfered with reading, watching television, and general concentration. Symptoms returned to baseline prior to the beginning of each subsequent cycle. Audiograms performed before and after several cycles showed mild sensorineural hearing loss in the high-decibel range, but no loss of speech recognition. ### discussion No reported cases of ototoxicity or tinnitus from ABVD were found. All concomitant medications were eliminated as possible causes either due to lack of temporal association with the symptoms or no reports of ototoxicity in the literature. vincristine, a more commonly used vinca alkaloid very similar to vinblastine, was noted to have caused several cases of sensorineural hearing loss. ### conclusions This case suggests that vinblastine may cause ototoxicity.

https://pubmed.ncbi.nlm.nih.gov/10332533/

721292621e495e6bbdfd29d25c905670

This review focuses on the activity and toxicity of the time-limited combination of venetoclax plus rituximab for the treatment of relapsed or refractory CLL , presenting clinical trial results and data from correlative studies , with the aim of highlighting the strengths of this treatment approach and discuss weaknesses and possible areas of improvement .

The combination of venetoclax and rituximab for the treatment of patients with recurrent chronic lymphocytic leukemia. In patients with recurrent chronic lymphocytic leukemia (CLL), treatment with targeted agents such as Bruton tyrosine kinase inhibitors and the Bcl-2 inhibitor venetoclax is rapidly replacing chemo-immunotherapy regimens. venetoclax has demonstrated efficacy as monotherapy in patients with previously treated CLL and has been evaluated in combination with the anti-CD20 monoclonal antibody rituximab. ### Areas Covered This review focuses on the activity and toxicity of the time-limited combination of venetoclax plus rituximab for the treatment of relapsed or refractory CLL , presenting clinical trial results and data from correlative studies , with the aim of highlighting the strengths of this treatment approach and discuss weaknesses and possible areas of improvement . Data from PubMed indexed papers as well as from abstracts presented at major international conferences are included. ### Expert Opinion Deep responses with venetoclax-based regimens have been shown to allow time-limited treatment and prolonged remission off-therapy in patients with CLL. The clinical benefit of venetoclax and rituximab over chemo-immunotherapy has been demonstrated in recurrent CLL. Potential advantages of time-limited treatment approaches include avoidance of long-term toxicities, high drug costs, and the selection of resistant subclones.

https://pubmed.ncbi.nlm.nih.gov/32700593/

5b765f09ddf9ed7800e75e50233d9dda

Advanced male breast cancer treatment with the LH-RH analogue buserelin alone or in combination with the antiandrogen flutamide .

Advanced male breast cancer treatment with the LH-RH analogue buserelin alone or in combination with the antiandrogen flutamide . Ten men with advanced breast cancer were evaluated for response to treatment with the luteinizing hormone-releasing hormone (LH-RH) analogue, buserelin, alone or in combination with the antiandrogen, flutamide. One of five patients receiving buserelin as a single agent had a partial remission lasting 12 months, and with the addition of flutamide, this lasted over 24 additional months. Three patients had stable disease with a median duration of 6 months (range, two to 14). One patient had progressive disease. Of five patients receiving the combination of buserelin and flutamide from the beginning of therapy, four patients had a partial remission with a median duration of over 15 months (range, over five to 16). One patient's disease remained stable for 12 months. Major side effects were hot flushes, loss of libido, and impotence. buserelin initiates a castration-like endocrine response and has potential in the treatment of men with disseminated breast cancer when used either alone or in combination with flutamide.

https://pubmed.ncbi.nlm.nih.gov/3134119/

9bc8203e277056b06b80ff1c46a3b6ba

A double-blind multicentre trial of piroxicam and naproxen in osteoarthritis .

A double-blind multicentre trial of piroxicam and naproxen in osteoarthritis . A multicentre, double-blind study of unprecedented size was conducted to compare the safety and efficacy of piroxicam and naproxen in the treatment of osteoarthritis. The study comprised 2,035 patients and a treatment period of 12 weeks. The dosage was 20 mg piroxicam and 750 mg naproxen daily with the option to reduce to 10 and 500 mg, respectively, at week 4 or 8. No major difference between the drugs was observed with regard to overall incidence of adverse events. The frequency of serious adverse events was about 1% for both drugs. A statistically significant decline of adverse events with age was found in both sexes. piroxicam was significantly superior to naproxen for pain at rest and pain on movement at 12 weeks and degree of restriction in daily activity at 4 weeks. A significantly increasing beneficial effect was observed with both drugs between 4 and 12 weeks of treatment. The comparable safety observed for the two drugs is in contrast to perceptions based on spontaneous reports to official monitoring systems.

https://pubmed.ncbi.nlm.nih.gov/3514082/

522231d038b48f5d5f178e20d202d187

Effects of estradiol , cyproterone acetate , tibolone and raloxifene on uterus and aorta atherosclerosis in oophorectomized cholesterol-fed rabbits .

Effects of estradiol , cyproterone acetate , tibolone and raloxifene on uterus and aorta atherosclerosis in oophorectomized cholesterol-fed rabbits . Different hormonal replacement regimens are used for treating climacteric complaints; however, not all of them have the same clinical profile. Cardiovascular disease (CVD) is a major health problem and tibolone, raloxifene, estradiol (alone or with cyproterone acetate) have been added to cholesterol-fed rabbits to study atherosclerosis. ### methods A total of 48 cholesterol-fed New Zealand white rabbits were studied for 4 months. Forty rabbits underwent bilateral ovariectomy and the other eight were sham operated (group S). The ovariectomized rabbits were allocated to five groups of eight animals each receiving tibolone (Group T, 6 mg/day), raloxifene (R, 35 mg/day), estradiol valerate (E, 3 mg/day), estradiol valerate plus cyproterone acetate (EC, 3+0.5 mg/day, respectively), and no treatment for the control group (C). The sham group received no treatment too. ### results After 4 months the percentage of the extent of atherosclerosis in the aorta was 30.4% in C group, 24.5% in S group, 10.2% in T group, 30.3% in R group, 17.9% in E group and 28.1% in EC group (P<0.05 T vs. C, R, EC). The aortic cholesterol content compared with aortic weight was 8.55 microg/mg in C group, 11.97 microg/mg in S group, 1.86 microg/mg in T group, 3.82 microg/mg in R group, 2.86 microg/mg in E group and 5.24 microg/mg in EC group (P<0.05 T vs. EC, C, S; R vs. C, S; E vs. C, S). Uterine weights in grams were: 1.89 (C group), 2.24 (S), 7.38 (T), 1.94 (R), 9.92 (E), and 5.94 (EC); P<0.05 (C, S, R, vs. T, E, EC; T vs. E; EC vs. T, E). ### conclusion Our study showed a decrease in the extent of aortic atherosclerosis in oophorectomized cholesterol-fed rabbits treated with tibolone or estradiol, and a decrease in aortic cholesterol content in rabbits treated with tibolone, raloxifene and estradiol. However, rabbits treated with tibolone showed an increased uterine weight, which is contrary to that observed in humans.

https://pubmed.ncbi.nlm.nih.gov/12753945/

6c2565fadd59a9088ef00ee067a33af8

Patients were randomly divided into three groups : group I : band ligation ; group II : propranolol ; group III : carvedilol .

Efficacy of carvedilol versus propranolol versus variceal band ligation for primary prevention of variceal bleeding. Band ligation and propranolol are the current therapies for primary prevention of variceal bleeding. carvedilol is a rising nonselective beta-blocker used for reducing portal pressure with favorable outcome. The aim of this study to assess the efficacy of carvedilol, propranolol, and band ligation for primary prevention of variceal bleeding based on the effect of each regimen on progression of Child score and portal hypertensive gastropathy after 1 year. ### methods The study included 264 cirrhotic patients with medium/large-sized varices who were candidates for primary prophylaxis of variceal bleeding. Patients were randomly divided into three groups : group I : band ligation ; group II : propranolol ; group III : carvedilol . ### results Group I showed higher success rate of 75 %, followed by group III with 70.2 % and group II with 65.2 %. Risk of bleeding was comparable between the three groups, with group II carrying the highest rate of complications (34.7 %) followed by group III (14.2 %) and finally group I (5.7 %). After 1 year of follow-up, Child score did not improve in any of the studied groups, while portal hypertensive gastropathy significantly increased in group I but decreased in groups II and III. ### conclusions Band ligation is the best treatment option for primary prevention of variceal bleeding with minimal complications. carvedilol is a good pharmaceutical alternative medicine to propranolol with lesser side-effects. Progress of liver disease as represented by Child score is not affected by any of the primary variceal prophylactic regimens, although medical treatment reduces portal hypertensive gastropathy. Choice of treatment depends on patient will, compliance with treatment, and endoscopist competence.

https://pubmed.ncbi.nlm.nih.gov/29185106/

64e45e423684bb5204c4c8609ec162af

Nevertheless , there are serious doubts as to the specificity of these actions of DA as a number of other substances like naloxone , nicotine , acetylcholine or glutamate-diethylester occasionally had very similar effects on membrane potential , firing rate and cortically evoked EPSP-IPSP sequences .

Iontophoretically applied dopamine depolarizes and hyperpolarizes the membrane of cat caudate neurons. Dopamine (DA) was applied iontophoretically on intracellularly recorded cat caudate neurons. Ejected approximately 100 micrometers away from the cell soma, it caused slow depolarizations of the membrane while the ongoing firing rate was reduced. This last effect was not due to sodium inactivation. Cortically evoked EPSP-IPSP sequences were inhibited during the depolarizations. The latency of cortically evoked action potentials was consistently increased during DA-ejections. These effects were blocked by fluphenazine, relatively selective blocker of the DA-sensitive adenylate cyclase. Nevertheless , there are serious doubts as to the specificity of these actions of DA as a number of other substances like naloxone , nicotine , acetylcholine or glutamate-diethylester occasionally had very similar effects on membrane potential , firing rate and cortically evoked EPSP-IPSP sequences . If DA was applied nearer to the soma, approximately 50 micrometers away, 70% of the recorded neurons continued to display the slow depolarizations above described, while 30% of the cells now reacted by a hyperpolarization accompanied also by a reduced firing rate. If DA was applied for prolonged periods on such cells, the initial hyperpolarization was followed by the slow depolarization. The observation that during the slow depolarization there is a decrease in firing rate and amplitude of the cortically evoked IPSP is explained by the assumption that the region of the axon hillock is hyperpolarized by DA, and that the slow depolarization is a phenomenon restricted to the distant recording site and possibly to the dendritic region. None of the 74 responsive neurons displayed an increased firing fate when DA was ejected either continuously, i.e. for more than 5 sec, or in short pulses of 50--500 msec.

https://pubmed.ncbi.nlm.nih.gov/7378798/

cee5496f94c2c2a1f3b6457c5f9fea7d

Here , we validated an indirect competitive enzyme-linked immunosorbent assay ( icELISA ) for quantification of ARTs and found that 50 % of inhibitory concentrations of dihydroartemisinin , artemether , and artesunate were 8.1 , 207.0 , and 4.7 ng/mL , respectively .

Validation of ELISA for quantitation of artemisinin-based antimalarial drugs. The circulation of counterfeit or substandard artemisinins (ARTs) in malaria-endemic areas poses a serious threat to the long-term use of these drugs. Here , we validated an indirect competitive enzyme-linked immunosorbent assay ( icELISA ) for quantification of ARTs and found that 50 % of inhibitory concentrations of dihydroartemisinin , artemether , and artesunate were 8.1 , 207.0 , and 4.7 ng/mL , respectively . We compared the icELISA with high-performance liquid chromatography (HPLC) for quantifying ART and its derivatives in 22 convenience samples of commercial antimalarial drugs. Paired t tests showed a borderline significant difference between the two methods (mean = 0.03, 95% confidence interval [CI] 0.00-0.07, P = 0.074) and the icELISA results were more variable than those of the HPLC analysis (P < 0.001), suggesting that further improvement is needed to enhance the performance of the icELISA. Our results showed that the icELISA has the potential to be improved for quality assurance of ARTs at the point of care in endemic settings.

https://pubmed.ncbi.nlm.nih.gov/24080636/

bf232023efbbd15ef0b3176d7706a57c

In an effort to improve its efficacy , mitoxantrone was tested for synergistic activity with cidofovir .

Inhibition of cowpox virus and monkeypox virus infection by mitoxantrone. mitoxantrone, an FDA-approved therapeutic for the treatment of cancer and multiple sclerosis, was previously reported to exhibit antiviral activity against vaccinia virus. To determine whether this activity extends to other orthopoxviruses, mitoxantrone was tested against cowpox and monkeypox. mitoxantrone demonstrated an EC(50) of 0.25 μM against cowpox and 0.8 μM against monkeypox. Intraperitoneal treatment of cowpox virus-challenged C57Bl/6 mice with 0.5 mg/kg mitoxantrone resulted in 25% survival and a significant increase in survival time. In an effort to improve its efficacy , mitoxantrone was tested for synergistic activity with cidofovir . In vitro tests demonstrated significant synergy between the two drugs against cowpox; however, no synergistic effect on animal survival or median time-to-death was seen in intranasally-infected BALB/c mice. Significantly fewer animals survived when treated with a combination of 0.5 mg/kg mitoxantrone and 100 mg/kg cidofovir than with 100 mg/kg cidofovir alone. This is, to our knowledge, the first report of limited anti-orthopoxvirus activity by mitoxantrone in an animal model.

https://pubmed.ncbi.nlm.nih.gov/22182595/

cf9e40c666bed03242c02340d9cd3df4

In our study , the -491A/T polymorphism in the apo E gene promoter region modulated the lipid-lowering efficiency of atorvastatin and bezafibrate in CHL patients .

Allelic polymorphism -491A/T in apo E gene modulates the lipid-lowering response in combined hyperlipidemia treatment. Combined hyperlipidemia (CHL) is one of the dyslipidemias more frequently found in clinical practice, and lipid-lowering drugs are often necessary in its management. Some genetic loci have been associated with CHL expression, and some studies have shown modulation of drugs efficiency in the treatment of dyslipidemias by genetic polymorphisms. We have investigated whether common polymorphisms and mutations in the apolipoprotein (apo) E, lipoprotein lipase (LPL), and apo CIII genes influence atorvastatin or bezafibrate responses in patients with CHL. ### design One hundred and sixteen subjects participating in the ATOMIX study (atorvastatin in Mixed dyslipidemia) were randomized to treatment with either atorvastatin or bezafibrate. Apolipoprotein E genotype and common -491A/T and -219T/G polymorphisms in the apo E gene promoter region, Sst I polymorphism in the apo CIII gene (3238C/G), and D9N and N291S common mutations in the LPL gene were determined by polymerase chain reaction (PCR) and restriction enzyme digestion. ### results Statistical analysis showed the influence of the -491A/T polymorphism in atorvastatin and bezafibrate treatments. Subjects carrying the -491T allele showed an increased LDL-cholesterol-lowering effect with atorvastatin compared with -491T allele noncarriers (-35% vs. -27%, P = 0.037). Subjects carrying the -491T allele, when on bezafibrate treatment, showed a lower triglyceride reduction compared with -491T allele noncarriers (-23% vs. -39%, P = 0.05). ### conclusions In our study , the -491A/T polymorphism in the apo E gene promoter region modulated the lipid-lowering efficiency of atorvastatin and bezafibrate in CHL patients . Such influence might explain some of the interindividual response variabilities observed for the two drugs, and could help in CHL management.

https://pubmed.ncbi.nlm.nih.gov/12059987/

8527f70e6e09f5dd3955194e23024012

A prospective open-label study comparing the efficacy and safety of methotrexate ( MTX ) and chloroquine ( CQ ) in articular and cutaneous manifestations of systemic lupus erythematosus ( SLE ) .

Efficacy and safety of methotrexate in articular and cutaneous manifestations of systemic lupus erythematosus. A prospective open-label study comparing the efficacy and safety of methotrexate ( MTX ) and chloroquine ( CQ ) in articular and cutaneous manifestations of systemic lupus erythematosus ( SLE ) . ### methods Consecutive SLE patients were randomly assigned to either 10 mg MTX weekly or 150 mg CQ daily during 24 weeks. Outcome measures were: numbers of swollen and tender joints, duration of morning stiffness, visual analog scale (VAS) for articular pain, physician global assessment index, patient global assessment index, SLE Disease Activity Index (SLEDAI), disappearance of skin rash and erythrocyte sedimentation rate (ESR). ### results Forty-one patients consented to participate, 15 were allocated in the MTX group and 26 in the CQ group. Two patients on MTX dropped out due to side-effects and two in the CQ group, one due to side-effects and one due to inefficacy. Baseline demographic, clinical and laboratory parameters of the two groups were nearly identical. In both groups the clinical and laboratory parameters improved significantly over 24 weeks, except the ESR in the MTX group. The results of the outcome measures at the end of the trial did not differ significantly between the two groups, except morning stiffness (P < 0.05 in favor of the MTX group) and ESR (P < 0.01 in favor of the CQ group). Rise of serum alanine aminotransferase was observed in two cases in the MTX group and in none in the CQ group. ### conclusion Low-dose MTX appears to be as effective as CQ in patients with articular and cutaneous manifestations of SLE, having an acceptable toxicity profile. Results of this prospective study need to be confirmed in a larger study.

https://pubmed.ncbi.nlm.nih.gov/22324948/

101863d8e60e61f4ea40f098ce840a75

In the current study , we investigated the hypothesis that targeting of P-gp by diltiazem can enhance the cytotoxicity of gemcitabine and 5-FU against human pancreatic cancer cells .

Diltiazem potentiates the cytotoxicity of gemcitabine and 5-fluorouracil in PANC-1 human pancreatic cancer cells through inhibition of P-glycoprotein. Pancreatic cancer (PC) is one of the most aggressive tumors with dismal survival and a high death rate due to chemotherapeutic failure. P-glycoprotein (P-gp) plays a pivotal role in PC response to gemcitabine and 5-fluorouracil (5-FU). diltiazem, a calcium channel blocker, is a P-gp inhibitor. In the current study , we investigated the hypothesis that targeting of P-gp by diltiazem can enhance the cytotoxicity of gemcitabine and 5-FU against human pancreatic cancer cells . ### Main Methods The cytotoxic effect of diltiazem, gemcitabine, and 5-FU in single and combined forms against PANC-1 and AsPC-1 cells were assayed by MTT. Flow cytometric analysis was used for the determination of cell cycle, apoptosis, and stemness markers in PC cells. Besides, immunoblotting was used for assessment of Bax, caspase 3, cyclin D1, and P-gp expressions. ### Key Findings diltiazem co-treatment, either with gemcitabine or 5-FU, synergistically reduced cell viability, induced apoptosis, and caused cell cycle arrest. In addition, diltiazem co-treatment decreased the expressions of stem cell markers CD24 and CD44, increased the expressions of Bax and cleaved caspase 3, enhanced DNA fragmentation, and attenuated cyclin D1 and P-gp expressions as compared to cells treated with either gemcitabine or 5-FU alone. ### significance Our findings suggest that diltiazem may be potential neoadjuvant therapy to enhance the response of PC to gemcitabine or 5-FU treatment.

https://pubmed.ncbi.nlm.nih.gov/33011221/

e6511ffdb1212e6e1b04d1c32e5a0aea

An additional 2 patients ( 1 in each group ) met the protocol definition of virologic failure between weeks 48 and 96 ; no known resistance mutations were observed in the raltegravir recipient ; the efavirenz recipient had nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor resistance mutations .

Sustained antiretroviral effect of raltegravir after 96 weeks of combination therapy in treatment-naive patients with HIV-1 infection. The purpose of this study was to evaluate the safety and efficacy of raltegravir vs efavirenz-based antiretroviral therapy after 96 weeks in treatment-naive patients with HIV-1 infection. ### methods Multicenter, double-blind, randomized study of raltegravir (100, 200, 400, or 600 mg twice a day) vs efavirenz (600 mg every day), both with tenofovir/lamivudine (TDF/3TC), for 48 weeks, after which raltegravir arms were combined and all dosed at 400 mg twice a day. Eligible patients had HIV-1 RNA > or =5000 copies per milliliter and CD4 T cells > or =100 cells per microliter. ### results One hundred ninety-eight patients were randomized and treated; 160 received raltegravir and 38 received efavirenz. At week 96, 84% of patients in both groups achieved HIV-1 RNA <400 copies per milliliter; 83% in the raltegravir group and 84% in the efavirenz group achieved <50 copies per milliliter (noncompleter = failure). Both groups showed similar increases in CD4 T cells (221 vs 232 cells/uL, respectively). An additional 2 patients ( 1 in each group ) met the protocol definition of virologic failure between weeks 48 and 96 ; no known resistance mutations were observed in the raltegravir recipient ; the efavirenz recipient had nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor resistance mutations . Investigator reported drug-related clinical adverse events (AEs) were less frequent with raltegravir (51%) than efavirenz (74%). Drug-related AEs occurring in >10% of patients in either group were nausea in both groups and dizziness and headache in the efavirenz group. Laboratory AEs remained infrequent. raltegravir had no adverse effect on total or low-density lipoprotein cholesterol or on triglycerides. Neuropsychiatric AEs remained less frequent with raltegravir (34%) than efavirenz (58%). There were no drug-related serious AEs in patients receiving raltegravir. ### conclusions In antiretroviral therapy-naive patients, raltegravir with TDF/3TC had potent antiretroviral activity, which was similar to efavirenz/TDF/3TC and was sustained to week 96. raltegravir was generally well tolerated; drug-related AEs were less frequent in patients treated with raltegravir compared with efavirenz.

https://pubmed.ncbi.nlm.nih.gov/19648823/

30dbeb9740d6e87d257a7122b0ad6aed

In all , 171 patients with histologically verified non-small cell lung carcinoma were treated with ifosfamide 2.0 g/m2 on days 1 - 5 in combination with ( 91 patients ) etoposide 120 mg/m2 on day 1 .

Experience with ifosfamide combinations (etoposide or DDP) in non-small cell lung cancer. In all , 171 patients with histologically verified non-small cell lung carcinoma were treated with ifosfamide 2.0 g/m2 on days 1 - 5 in combination with ( 91 patients ) etoposide 120 mg/m2 on day 1 . Therapeutic regimens were repeated after 4 weeks. Supportive treatment with mesna (20% of the ifosfamide doses at 0, 4, and 8 h) was performed. cisplatin treatment was supported by mannitol-induced diuretic hydration. The overall response rate of ifosfamide/etoposide was calculated to be 27%, with 1 complete and 24 partial remissions. The median survival time for all patients was 8.5 months, for responders 14 months (P less than 0.05), for patients with no change 9.5 months, and for patients with tumor progression 4 months. With ifosfamide/cisplatin, there were 4 complete and 21 partial remissions (response rate 35%). The median survival time for all patients was 8.3 months, for responders 11.5 months, and for patients with tumor progression 4 months. Age, sex, and histological tumor type had no significant effect on survival. Patients with better performance stage and limited disease lived significantly longer. The main side-effects of the cisplatin combination were vomiting, bone marrow depression, and neuropathy. The etoposide combination was tolerated better. Urotoxicity was not significant, as a consequence of treatment with mesna. The results show that the combination ifosfamide/etoposide or ifosfamide/cisplatin are effective in the treatment of non-small cell lung cancer, being comparable to other combinations of etoposide/cisplatin and vindesine/cisplatin. Because of the better tolerability, the combination ifosfamide/etoposide is superior to cisplatin combinations.

https://pubmed.ncbi.nlm.nih.gov/3028662/