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5015ab706c206dd92fe59662d7436a52

This document attempts to provide reasonable guidance for the use of antimicrobials which have uncertain benefit but may increase risk of QT interval prolongation and ventricular proarrhythmia , notably , chloroquine , hydroxychloroquine , azithromycin , and lopinavir/ritonavir .

Guidance on Minimizing Risk of Drug-Induced Ventricular Arrhythmia During Treatment of COVID-19: A Statement from the Canadian Heart Rhythm Society. The COVID-19 pandemic has led to efforts at rapid investigation and application of drugs which may improve prognosis but for which safety and efficacy are not yet established. This document attempts to provide reasonable guidance for the use of antimicrobials which have uncertain benefit but may increase risk of QT interval prolongation and ventricular proarrhythmia , notably , chloroquine , hydroxychloroquine , azithromycin , and lopinavir/ritonavir . During the pandemic, efforts to reduce spread and minimize effects on health care resources mandate minimization of unnecessary medical procedures and testing. We recommend that the risk of drug proarrhythmia be minimized by 1) discontinuing unnecessary medications that may also increase the QT interval, 2) identifying outpatients who are likely to be at low risk and do not need further testing (no history of prolonged QT interval, unexplained syncope, or family history of premature sudden cardiac death, no medications that may prolong the QT interval, and/or a previous known normal corrected QT interval [QTc]), and 3) performing baseline testing in hospitalized patients or those who may be at higher risk. If baseline electrocardiographic testing reveals a moderately prolonged QTc, optimization of medications and electrolytes may permit therapy. If the QTc is markedly prolonged, drugs that further prolong it should be avoided, or expert consultation may permit administration with mitigating precautions. These recommendations are made while there are no known effective treatments for COVID-19 and should be revisited when further data on efficacy and safety become available.

https://pubmed.ncbi.nlm.nih.gov/32299753/

fb0288ced0a121729799b63624779e1b

Phase II study of weekly paclitaxel and sorafenib as second/third-line therapy in patients with adrenocortical carcinoma .

Phase II study of weekly paclitaxel and sorafenib as second/third-line therapy in patients with adrenocortical carcinoma . There is a strong rationale in the use of antiangiogenic therapy in the management of adrenocortical carcinoma (ACC). Metronomic administration of chemotherapy and antiangiogenic drugs can be synergistic in targeting endothelial cells. ### objective We assessed the activity of sorafenib plus metronomic paclitaxel as second/third-line therapy in advanced ACC patients. We also tested the activity of sorafenib and paclitaxel against NCI-H295R in vitro. ### design Multicenter, prospective phase II trial. Setting Referral centers for ACC. ### methods Twenty-five consecutive metastatic ACC patients who progressed after mitotane plus one or two chemotherapy lines were planned to be enrolled. The patients received a combination of i.v. paclitaxel (60 mg/m(2) every week) and oral sorafenib (400 mg twice a day) till progression. The primary aim was to measure the progression-free survival rate after 4 months and the secondary aims were to assess the objective response rate and toxicity. ### results Tumor progression was observed in nine evaluable patients at the first assessment. These results led to the premature interruption of the trial. The treatment was well tolerated. The most relevant toxicities were fatigue, being grade 2 or 3 in four patients, and hypophosphatemia, being grade 3 in three patients. In the in vitro study, sorafenib impaired the viability of H295R cells with dose-response and time-response relationships. The in vitro sorafenib activity was not increased in combination with paclitaxel. ### conclusions Despite the in vitro activity, sorafenib plus weekly paclitaxel is an inactive salvage treatment in patients with advanced ACC and should not be recommended.

https://pubmed.ncbi.nlm.nih.gov/22189997/

140cd4dac5f73cd731f2811f3a528bc7

This study indicates that cyclophosphamide , doxorubicin , and methotrexate are , at best , marginally active as single agents , and new drugs with more efficacy are needed before combination chemotherapy can be expected to result in any meaningful prolongation of survival in non-small cell lung cancer .

Random prospective study cyclophosphamide, doxorubicin, and methotrexate (CAM) combination chemotherapy versus single-agent sequential chemotherapy in non small cell lung cancer. A group of 104 patients with unresectable non-small cell lung cancer were randomized to receive combination chemotherapy with cyclophosphamide, doxorubicin, and methotrexate (CAM) or single-agent sequential chemotherapy with the same three agents. CAM combination chemotherapy produced a 22% objective response rate, including two complete remissions, compared to a 9% response rate, including one complete remission, produced by single-agent therapy (P = 0.16). The median survival time was 32 weeks (range, 3-116) for CAM, compared to 25 weeks (range, 4-179 +) for sequential single agents (P = 0.24). Overall survival was 31% (1-year), (16%) (1 1/2-year), and 5% (2-year), with no difference between the study arms. Although there was no statistically significant survival advantage for the CAM arm, both arms had survival superior to that in historical controls, presumably because of better patient selection. This study indicates that cyclophosphamide , doxorubicin , and methotrexate are , at best , marginally active as single agents , and new drugs with more efficacy are needed before combination chemotherapy can be expected to result in any meaningful prolongation of survival in non-small cell lung cancer .

https://pubmed.ncbi.nlm.nih.gov/6291763/

347b9e96b7e1c1a9c50392e1f5a37cdb

The combined treatment of curcumin and docetaxel inhibited the proliferation and induced apoptosis significantly higher than the curcumin and docetaxel-treated group alone .

Combinatorial effect of curcumin with docetaxel modulates apoptotic and cell survival molecules in prostate cancer. docetaxel is the most commonly used chemotherapeutic agent to target androgen signaling in metastatic prostate cancer (PCa); however, prolonged treatment with docetaxel results in drug-resistant cancer cells. Combination therapies have the potential of increasing the effectiveness of drug treatment as well as decreasing the side effects. curcumin is a nontoxic organic compound with multifaceted chemopreventive potential. In this study, we evaluated whether curcumin can reinforce the effect of docetaxel on PCa cells. The PCa cell lines DU145 and PC3 were treated with curcumin and docetaxel alone or in combination. After completion of the treatment cell proliferation and the expression of pro-survival and anti-apoptotic markers and the signaling molecules were analyzed. The combined treatment of curcumin and docetaxel inhibited the proliferation and induced apoptosis significantly higher than the curcumin and docetaxel-treated group alone . Interestingly, the combined treatment with curcumin and docetaxel modulates the expression of RTKs, PI3K, phospho-AKT, NF-kappa B, p53, and COX-2. These results suggest that curcumin can be a potential therapeutic contender in enhancing the efficacy of docetaxel in PCa treatment.

https://pubmed.ncbi.nlm.nih.gov/28199187/

cb9d977dcda8131a2befc404d99b78d3

Previously , a study of ours showed that the combination of dabrafenib and trametinib improves progression-free survival compared with dabrafenib and placebo in patients with BRAF Val600Lys/Glu mutation-positive metastatic melanoma .

Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Previously , a study of ours showed that the combination of dabrafenib and trametinib improves progression-free survival compared with dabrafenib and placebo in patients with BRAF Val600Lys/Glu mutation-positive metastatic melanoma . The study was continued to assess the secondary endpoint of overall survival, which we report in this Article. ### methods We did this double-blind phase 3 study at 113 sites in 14 countries. We enrolled previously untreated patients with BRAF Val600Glu or Val600Lys mutation-positive unresectable stage IIIC or stage IV melanoma. Participants were computer-randomised (1:1) to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily), or dabrafenib and placebo. The primary endpoint was progression-free survival and overall survival was a secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT01584648. ### findings Between May 4, 2012, and Nov 30, 2012, we screened 947 patients for eligibility, of whom 423 were randomly assigned to receive dabrafenib and trametinib (n=211) or dabrafenib only (n=212). The final data cutoff was Jan 12, 2015, at which time 222 patients had died. Median overall survival was 25·1 months (95% CI 19·2-not reached) in the dabrafenib and trametinib group versus 18·7 months (15·2-23·7) in the dabrafenib only group (hazard ratio [HR] 0·71, 95% CI 0·55-0·92; p=0·0107). Overall survival was 74% at 1 year and 51% at 2 years in the dabrafenib and trametinib group versus 68% and 42%, respectively, in the dabrafenib only group. Based on 301 events, median progression-free survival was 11·0 months (95% CI 8·0-13·9) in the dabrafenib and trametinib group and 8·8 months (5·9-9·3) in the dabrafenib only group (HR 0·67, 95% CI 0·53-0·84; p=0·0004; unadjusted for multiple testing). Treatment-related adverse events occurred in 181 (87%) of 209 patients in the dabrafenib and trametinib group and 189 (90%) of 211 patients in the dabrafenib only group; the most common was pyrexia (108 patients, 52%) in the dabrafenib and trametinib group, and hyperkeratosis (70 patients, 33%) in the dabrafenib only group. Grade 3 or 4 adverse events occurred in 67 (32%) patients in the dabrafenib and trametinib group and 66 (31%) patients in the dabrafenib only group. ### interpretation The improvement in overall survival establishes the combination of dabrafenib and trametinib as the standard targeted treatment for BRAF Val600 mutation-positive melanoma. Studies assessing dabrafenib and trametinib in combination with immunotherapies are ongoing. ### funding GlaxoSmithKline.

https://pubmed.ncbi.nlm.nih.gov/26037941/

16eaebaa0ed50f343e560ffb251ba9e0

compared to those for rats treated with trovafloxacin or clindamycin plus gentamicin

In vivo efficacy of trovafloxacin (CP-99,217), a new quinolone, in experimental intra-abdominal abscesses caused by Bacteroides fragilis and Escherichia coli. The efficacy of trovafloxacin in treating Bacteroides fragilis and Escherichia coli infections was investigated and compared to the efficacy of combined clindamycin and gentamicin therapy in an experimental model of intra-abdominal abscesses in rats. Rats were treated with different doses of CP-116,517-27, a parenteral prodrug of trovafloxacin. Response to treatment was evaluated by mortality rate and elimination of infection (cure rate). Mortality in the control group was 85.4%, whereas in rats treated with trovafloxacin, it was close to 0%. The highest cure rate (89.3%) resulted from the administration of 40 mg of CP-116,517-27 per kg of body weight three times a day (TID) for 10 days (equivalent to 18.15 mg of active drug trovafloxacin per rat per day). The therapeutic response with trovafloxacin was comparable to that of a combination therapy of clindamycin (75 mg/kg) plus gentamicin (20 mg/kg) TID (cure rate, 74%; mortality rate, 5%). The measured peak levels of trovafloxacin in serum and abscess pus were 2.6 +/- 0.3 and 5.2 micrograms/ml, respectively. The tumor necrosis factor alpha levels in the untreated animals were high compared to those for rats treated with trovafloxacin or clindamycin plus gentamicin. These results demonstrate that trovafloxacin as a single agent appears to be as successful as clindamycin plus gentamicin in the treatment of experimental intra-abdominal abscesses in rats.

https://pubmed.ncbi.nlm.nih.gov/9055997/

b17febf31275cf49cdf832e97290339d

We suggest topoisomerase II inhibition by Aroclor 1254 , trovafloxacin , doxorubicin , and etoposide to be responsible for significant co-localization of regulated genes through the inability of the stabilized enzyme complexes to religate DNA .

Topoisomerase II inhibition involves characteristic chromosomal expression patterns. The phenomenon of co-localization of transcriptionally upregulated genes showing similar expression levels is known across all eukaryotic genomes. We recently mapped the Aroclor 1254-regulated transcriptome back onto the genome and provided evidence for the statistically significant co-localization of regulated genes. They did, however, not always show similar expression levels, and many of the regulated genes were, in fact, repressed. ### results In this study, we were able to reproduce this observation with microarray data stemming from 1) human hepatocytes treated with the gyrase and potential topoisomerase II inhibitor trovafloxacin, 2) human hepatocytes treated with the topoisomerase II inhibitor doxorubicin and 3) mouse lymphoma cells treated with the topoisomerase II inhibitor etoposide. We found statistically significant co-localization of regulated gene pairs--induced and repressed--within the window size of 0-100 kbp. Notably, by using microarray data stemming from lung tissue of a mouse transgenic line overexpressing the transcription factor c-myc, which served as a negative control, we found regulated genes to be located with regard to each other nearly in the same way as genes distributed randomly all over the genome (0-100 kbp). ### conclusion We suggest topoisomerase II inhibition by Aroclor 1254 , trovafloxacin , doxorubicin , and etoposide to be responsible for significant co-localization of regulated genes through the inability of the stabilized enzyme complexes to religate DNA . Within the permanently opened chromatin domains, neighbored genes might be allowed to be regulated. Overexpression of c-myc, however, does not inhibit topoisomerase II activity. Consequently, the enzyme is able to perform its normal function of transiently breaking and rejoining the DNA double strand. As a result, exclusively target genes are regulated.

https://pubmed.ncbi.nlm.nih.gov/18611269/

db74702684949a6a29e36d1550198204

All but one received two induction courses of the 3 day-AVI ( doxorubicin 50 mg/m(2 ) day 1 , etoposide 120 mg/m(2 ) day 1 , 2 , 3 , ifosfamide 2000 mg/m(2 ) day 1 , 2 ) regimen .

The prognostic value of etoposide area under the curve (AUC) at first chemotherapy cycle in small cell lung cancer patients: a multicenter study of the groupe Lyon-Saint-Etienne d'Oncologie Thoracique (GLOT). To assess the potential relationships between systemic exposure to doxorubicin, etoposide and ifosfamide at first chemotherapy cycle and therapeutic effect, tumor response, toxicity, and survival, in small cell lung cancer (SCLC) patients. ### Patients And Methods Twenty-four patients referred to five different centers with either thorax-limited or metastatic SCLC entered the study. All but one received two induction courses of the 3 day-AVI ( doxorubicin 50 mg/m(2 ) day 1 , etoposide 120 mg/m(2 ) day 1 , 2 , 3 , ifosfamide 2000 mg/m(2 ) day 1 , 2 ) regimen . Individual plasma samples were collected at the first course and complete concentration data on 24 courses were available. Drugs exposures were estimated using a population pharmacokinetic method and expressed as clearance (Cl), area under the curve (AUC), and AUC-intensity (AUC/cycle duration). Responding patients received thoracic irradiation+concomitant cisplatinum-etoposide (limited disease) or four more courses of AVI (extensive disease). The impact of exposure parameters on haematological toxicity, tumor response and overall survival was assessed using linear regression, the Mann-Whitney U-test and the log-rank test/Kaplan-Meier estimation, respectively. ### results Twenty-three patients could be evaluated for response and survival. We found no relationship between drug exposure and haematological toxicity but all patients had received Granulocyte-Colony Stimulating Factor support. Tumor response was marginally influenced by ifosfamide AUC. In patients with etoposide AUC>254.8 mg h/l, 1-year survival was 50.0 vs. 9.1% in the other group (median 11.4 vs. 7.1 months, P=0.02), with respect to established prognostic factors. In patients with extensive disease only (n=15), 1-year survival was 42.9 vs. 0% (median 11.3 vs. 5.3 months, P=0.01). ### conclusion This study strongly suggests that SCLC patients should benefit from sufficient etoposide exposure at first cycle to improve survival. Adaptative control based on plasma concentration measurements should be tested in further studies assessing various polychemotherapy regimens.

https://pubmed.ncbi.nlm.nih.gov/11165404/

da76229247c8564117087d25cfd3c76d

Although anti-HER2 ( trastuzumab ) and anti-VEGFR ( ramucirumab ) may yield survival benefit , anti-EGFR and anti-HGFR therapies have failed to improve outcomes .

Recent insights in the therapeutic management of patients with gastric cancer. Gastric cancer remains frequent and one of the most lethal malignancies worldwide. In this article, we aimed to comprehensively review recent insights in the therapeutic management of gastric cancer, with focus on the surgical and perioperative management of resectable forms, and the latest advances regarding advanced diseases. Surgical improvements comprise the use of laparoscopic surgery including staging laparoscopy, a better definition of nodal dissection, and the development of hyperthermic intraperitoneal chemotherapy. The best individualized perioperative management should be assessed before curative-intent surgery for all patients and can consists in perioperative chemotherapy, adjuvant chemo-radiation therapy or adjuvant chemotherapy alone. The optimal timing and sequence of chemotherapy and radiation therapy with respect to surgery should be further explored. Patients with advanced gastric cancer have a poor prognosis. Nevertheless, they can benefit from doublet or triplet chemotherapy combination, including trastuzumab in HER2-positive patients. Upon progression, second-line therapy can be considered in patients with good performance status. Although anti-HER2 ( trastuzumab ) and anti-VEGFR ( ramucirumab ) may yield survival benefit , anti-EGFR and anti-HGFR therapies have failed to improve outcomes . Nevertheless, combination regimens containing cytotoxic drugs and targeted therapies should be further evaluated; keeping in mind that gastric cancer biology is different between Asia and the Western countries.

https://pubmed.ncbi.nlm.nih.gov/27156069/

c41ce50ac2ab1d723b7b845c5638e79f

In the phase I trial , 19 patients received bolus doxorubicin ( 50 mg/m2 ) followed after a 16-hour interval by paclitaxel ( given at dose levels ranging from 130 to 250 mg/m2 ) by 3-hour infusion every 3 weeks , for a maximum of eight cycles .

Paclitaxel plus doxorubicin in breast cancer: an Italian experience. Based on preclinical data, phase I/II clinical trials were performed at Istituto Oncologico Romagnolo (IOR) Operative Units (Medical Oncology Departments of Forlì, Rimini, and Ravenna, Italy) to determine the efficacy and toxicity of sequential administration of doxorubicin followed by paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in the treatment of patients with advanced breast cancer that either had been previously untreated or that had relapsed after adjuvant therapy. In the phase I trial , 19 patients received bolus doxorubicin ( 50 mg/m2 ) followed after a 16-hour interval by paclitaxel ( given at dose levels ranging from 130 to 250 mg/m2 ) by 3-hour infusion every 3 weeks , for a maximum of eight cycles . paclitaxel doses were escalated in 30-mg/m2 increments if the maximum tolerated dose had not been reached in the previous dose level. Analysis of the 128 cycles assessable for toxicity demonstrated neutropenia (<500/microL) in 26 courses (20.3%), with no significant clinical events. No relevant clinical cardiotoxicity was observed. The paclitaxel maximum tolerated dose was not reached at the 250-mg/m2 dose level (no grade 3 or 4 extramedullary toxicity). In the IOR phase II trial, 13 patients were treated with fixed doses of both drugs (doxorubicin 50 mg/m2 and paclitaxel 220 mg/m2). Grade 4 neutropenia occurred in 39 of the 95 cycles, but was complicated by fever in only eight cycles (8.4%); three cycles required granulocyte colony-stimulating factor support. Peripheral neurotoxicity was the most common extramedullary side effect noted. Overall clinical responses in the IOR trials included 10 complete responses (31.3%) and 15 partial responses (46.9%), with an objective response rate of 78.1%. Comparison of these results with those obtained from a phase I trial using the opposite drug sequence showed comparable overall response rates, but IOR's sequence was associated with a higher complete response rate, as well as less frequent and less severe nonhematologic toxicity.

https://pubmed.ncbi.nlm.nih.gov/9374087/

2c7a84317e4530aa3022349a39e71c9b

New monoclonal antibodies ( ofatumumab ) , second-generation proteasome inhibitors ( carfilzomib ) , mammalian target of rapamycin inhibitors , and Bruton 's tyrosine kinase inhibitors are promising and may expand future treatment options .

Treatment recommendations for patients with Waldenström macroglobulinemia (WM) and related disorders: IWWM-7 consensus. Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of International Workshops on WM (IWWM). As part of the IWWM-7 and based on recently published and ongoing clinical trials, the panels updated treatment recommendations. Therapeutic strategy in WM should be based on individual patient and disease characteristics (age, comorbidities, need for rapid disease control, candidacy for autologous transplantation, cytopenias, IgM-related complications, hyperviscosity, and neuropathy). Mature data show that rituximab combinations with cyclophosphamide/dexamethasone, bendamustine, or bortezomib/dexamethasone provided durable responses and are indicated for most patients. New monoclonal antibodies ( ofatumumab ) , second-generation proteasome inhibitors ( carfilzomib ) , mammalian target of rapamycin inhibitors , and Bruton 's tyrosine kinase inhibitors are promising and may expand future treatment options . A different regimen is typically recommended for relapsed or refractory disease. In selected patients with relapsed disease after long-lasting remission, reuse of a prior effective regimen may be appropriate. Autologous stem cell transplantation may be considered in young patients with chemosensitive disease and in newly diagnosed patients with very-high-risk features. Active enrollment of patients with WM in clinical trials is encouraged.

https://pubmed.ncbi.nlm.nih.gov/25027391/

a302d53a221927af726a71d0414d8b6b

Exposure of LLC-PK1 cells to hydrogen peroxide ( 2.5 mM ) resulted in a significant increase in the bleomycin-detectable iron ( iron capable of catalyzing free radical reactions ) content that was prevented by cimetidine , but not ranitidine .

Role of cytochrome P-450 in hydrogen peroxide-induced cytotoxicity to LLC-PK1 cells. The current study was designed to test the role of cytochrome P-450 in hydrogen peroxide-induced cytotoxicity, and to determine whether it may serve as a source of catalytic iron. Hydrogen peroxide led to iron release (as measured by iron/bathophenanthroline complex) from the microsomes prepared from LLC-PK1 cells. cimetidine, which inhibits cytochrome P-450 by interacting with the heme iron, significantly blocked iron release, whereas ranitidine, which has a similar structure as cimetidine but is a weak inhibitor of P-450, did not have an effect (H2O2, 0.42 +/- 0.04; H2O2 + cimetidine, 0.23 +/- 0.02 nmol/mg protein; N = 4, P < 0.01). Exposure of LLC-PK1 cells to hydrogen peroxide ( 2.5 mM ) resulted in a significant increase in the bleomycin-detectable iron ( iron capable of catalyzing free radical reactions ) content that was prevented by cimetidine , but not ranitidine . We then examined the effect of the inhibitors of cytochrome P-450 on cell death (as measured by Trypan blue exclusion) after exposure of LLC-PK1 cells to 2.5 mM hydrogen peroxide for 120 minutes. Inhibition of cytochrome P-450 by cimetidine significantly reduced the cell death; the effect was observed with 0.05 mM and was concentration dependent with 1 mM affording almost complete protection (H2O2, 59 +/- 1.3% vs. H2O2 + cimetidine, 11 +/- 0.7%; N = 5, P < 0.01). In contrast, ranitidine did not show any protection. We confirmed that the protective effect of cimetidine was not related to scavenging hydrogen peroxide or hydroxyl radicals or chelating iron. A second inhibitor of cytochrome P-450, piperonyl butoxide, had a similar dose-dependent beneficial effect against hydrogen peroxide-induced cell injury. Our data thus indicate an important role of cytochrome P-450 in hydrogen peroxide-induced cytotoxicity to LLC-PK1 cells and suggest that cytochrome P-450 may serve as a source of catalytic iron.

https://pubmed.ncbi.nlm.nih.gov/8887268/

ab42998ac768359fe5c45841e496b11f

Patients who did or did not respond to previous DIMARD therapy either on i.m . gold , D-Penicillamine or Chloroquine , did usually well when treated with Auranofin , even if severe side effects leading to withdrawal had occurred on previous therapy .

Longterm results of auranofin therapy. The results of longterm therapy with the oral gold preparation auranofin in patients with rheumatoid arthritis (RA) were evaluated based on the following data: 1) Two multicenter open uncontrolled studies (MTC06) and (162EMUA-RA), 2) the reevaluation of these data for the MTC06 study after 4 years from the beginning of the study and 3) the results of a postmarketing surveillance program (PMSP) of patients on auranofin therapy. The specific rheumatologic documentation and information system (IKR inhaltkodierte rheumatologic) serves as the basis of the follow-up studies and longterm observations. The first year data on 207 patients (MTC06) indicating that duration of the disease less than 2 years was the only discriminating factor regarding a positive treatment outcome were confirmed by the two-year (151 patients). Patients, who responded favourably to auranofin did usually well for the four-year or longer observation period. The data base of these two studies and the PMSP failed to outline any new severe or threatening side effects. Diarrhea and loose stools were more common at the beginning of the treatment. The overall withdrawal for untoward events was 11.2%. Patients who did or did not respond to previous DIMARD therapy either on i.m . gold , D-Penicillamine or Chloroquine , did usually well when treated with Auranofin , even if severe side effects leading to withdrawal had occurred on previous therapy . The favourable safety profile was confirmed by the PMSP data.

https://pubmed.ncbi.nlm.nih.gov/3690986/

afab31fe96472f7a8f44b42d27b3b11e

Patients were randomly assigned 1:1 centrally to either the docetaxel , prednisone , and custirsen combination or docetaxel and prednisone alone .

Custirsen in combination with docetaxel and prednisone for patients with metastatic castration-resistant prostate cancer (SYNERGY trial): a phase 3, multicentre, open-label, randomised trial. Clusterin is a chaperone protein associated with treatment resistance and upregulated by apoptotic stressors such as chemotherapy. Custirsen is a second-generation antisense oligonucleotide that inhibits clusterin production. The aim of the SYNERGY trial was to investigate the effect of custirsen in combination with docetaxel and prednisone on overall survival in patients with metastatic castration-resistant prostate cancer. ### methods SYNERGY was a phase 3, multicentre, open-label, randomised trial set at 134 study centres in 12 countries. Patients were eligible for participation if they had: metastatic castration-resistant prostate cancer and had received no previous chemotherapy; prostate-specific antigen greater than 5 ng/mL; and a Karnofsky performance score of 70% or higher. Patients were randomly assigned 1:1 centrally to either the docetaxel , prednisone , and custirsen combination or docetaxel and prednisone alone . Patients were not masked to treatment allocation. Randomisation was stratified by opioid use for cancer-related pain and radiographic evidence of progression. All patients received docetaxel 75 mg/m ### findings Between Dec 10, 2010, and Nov 7, 2012, 1022 patients were enrolled to the trial, of whom 510 were assigned docetaxel, prednisone, and custirsen and 512 were allocated docetaxel and prednisone. No difference in overall survival was recorded between the two groups (median survival 23·4 months [95% CI 20·9-24·8] with docetaxel, prednisone, and custirsen vs 22·0 months [19·5-24·0] with docetaxel and prednisone; hazard ratio [HR] 0·93, 95% CI 0·79-1·10; p=0·415). The most common adverse events of grade 3 or worse in the docetaxel, prednisone and custirsen group (n=501) compared with the docetaxel and prednisone alone group (n=499) were neutropenia (grade 3, 63 [13%] vs 28 [6%]; grade 4, 98 [20%] vs 77 [15%]), febrile neutropenia (grade 3, 52 [10%] vs 31 [6%]; grade 4, four [1%] vs two [<1%]), and fatigue (grade 3, 53 [11%] vs 41 [8%]; grade 4, three [1%] vs one [<1%]). One or more serious adverse events were reported for 214 (43%) of 501 patients treated with docetaxel, prednisone, and custirsen and 181 (36%) of 499 receiving docetaxel and prednisone alone. Adverse events were attributable to 23 (5%) deaths in the docetaxel, prednisone, and custirsen group and 24 (5%) deaths in the docetaxel and prednisone alone group. ### interpretation Addition of custirsen to first-line docetaxel and prednisone was reasonably well tolerated, but overall survival was not significantly longer for patients with metastatic castration-resistant prostate cancer treated with this combination, compared with patients treated with docetaxel and prednisone alone. ### funding OncoGenex Technologies.

https://pubmed.ncbi.nlm.nih.gov/28283282/

bd82da91336f74adb6da284e168c8f9b

[ Carboplatin and etoposide combination for the treatment of recurrent epithelial ovarian cancer ] .

[ Carboplatin and etoposide combination for the treatment of recurrent epithelial ovarian cancer ] . The objective of this phase II study was to determine the efficacy and toxicity of a combination of carboplatin and etoposide as salvage treatment, in previously treated patients with persistent or recurrent ovarian cancer following first-line cisplatin-based chemotherapy. ### Patients And Methods From July 1990 to August 1994, 58 patients were treated with 3-week cycles of chemotherapy consisting of carboplatin (200 mg/m2, D1) and etoposide (120 mg/m2, D1, D2). Criteria for evaluating previous response to cisplatin were strictly defined. ### results The overall response rate was 36%, with five complete responses (CR, 9%), 16 partial responses (PR, 27%) and the median duration of response was 10 months (range: 4 to 38). In the group of patients who progressed during the first year following the diagnosis, the response was 1 CR and 2 PR (12%) and in the group of patients who progressed from the second year after diagnosis, 4 CR and 14 PR (56%), with a median survival of 8.5 and 21 months respectively (p = 0.0013). The response rate was 59% in the potentially platinum sensitive group versus 8.7% in the primary resistant group (0.02 < p < 0.05). Myelotoxicity was the main side-effect but did not appear to be cumulative. Grade 3 and grade 4 anemia were observed in 26% and 3% of the patients respectively, neutropenia in 14% and 2% and thrombocytopenia in 14% and 8.5%. One patient died of sepsis associated with neutropenia. ### conclusion Treatment was easily manageable and well tolerated. The advantage of carboplatin and etoposide combination in potentially responsive patients is represented by the reduced nephrotoxicity, neurotoxicity and ototoxicity as compared with cisplatin containing regimen, with durable feasibility in outpatients. This second-line chemotherapy for ovarian cancer is effective as salvage treatment in potentially responsive patients with late recurrent tumors, while paclitaxel is the drug of choice for patients who have developped primary or secondary resistance to platin therapy.

https://pubmed.ncbi.nlm.nih.gov/8680083/

b5eed2d8dcc1d4fa698054dce7cab8b2

One-hour paclitaxel plus carboplatin in the treatment of advanced non-small cell lung cancer : results of a multicentre , phase II trial .

One-hour paclitaxel plus carboplatin in the treatment of advanced non-small cell lung cancer : results of a multicentre , phase II trial . The aim of this phase II study was to determine the activity and toxicity of paclitaxel (administered by 1-h infusion) and carboplatin in advanced non-small cell lung cancer when used in a multicentre, community-based treatment setting. 100 chemotherapy-naive patients with stage IIIB or IV non-small cell lung cancer were treated between March 1995 and February 1996. All patients had Karnofsky performance status 70-100, measurable disease and adequate bone marrow, kidney and liver function. All patients received intravenous (i.v.) paclitaxel 225 mg/m2 by 1-h infusion followed immediately by carboplatin at a targeted area under the concentration time curve (AUC) of 6.0 using the Calvert formula. Courses were repeated every 21 days. Colony stimulating factors were not used routinely. 38 of 94 evaluable patients (40%) had objective responses to treatment (3 complete responses, 35 partial responses). An additional 32 patients had stable disease at initial re-evaluation. Weight gain during treatment was experienced by 47% of patients with objective response or stable disease. The median survival in this group of 100 patients was 8 months, with an actuarial 1-year survival of 42%. Leucopenia was common, but hospitalisation for treatment of neutropenia and fever occurred in only 3% of courses. Cumulative peripheral neuropathy was common, but usually appeared after the third or fourth course and was severe (grade 3) in only 15% of patients. Other grade 3 and 4 toxicity was uncommon. There was one treatment-related death due to sepsis. This large multicentre community-based phase II trial demonstrated the efficacy of paclitaxel and carboplatin combination chemotherapy in advanced non-small cell lung cancer. When paclitaxel is given by 1-h infusion, this regimen is easily administered in the outpatient setting.

https://pubmed.ncbi.nlm.nih.gov/9713269/

cf2e5fbc7f16a5145e9318057da96476

Preliminary data combining trastuzumab with the antiangiogenic antibody bevacizumab is encouraging ; this combination will be tested in both early stage and late stage disease .

The role of trastuzumab in early stage breast cancer: current data and treatment recommendations. Treatment of early stage breast cancer requires a multimodality approach in order to eradicate residual cancer and prevent recurrent disease. Targeting the pathways that promote or sustain cancer cell growth and invasion is critical to the effective treatment of breast and other cancers. Overexpression of the family of HER receptors have been associated with a variety of malignancies; the first and best studied is the association of overexpression of the HER2/neu receptor with a more aggressive breast cancer phenotype and poorer survival. A humanized antibody to HER2/neu, trastuzumab, is now FDA approved for the treatment of early stage, HER2/neu overexpressing breast cancer sequenced with chemotherapy including doxorubicin, cyclophosphamide, and paclitaxel. Additional international and national studies support the significant impact of trastuzumab on both disease free and overall survival in women with this aggressive form of breast cancer. Toxicity includes a low but clear risk of congestive heart failure, and the large phase III trials have helped to determine which patients are at higher risk for this complication. Non-anthracycline containing regimens are an alternative therapy associated with reduced cardiac toxicity. trastuzumab therapy is now the standard of care for the treatment of early stage, HER2/neu positive breast cancer given in combination with one of several chemotherapy regimens. Ongoing questions include the appropriate duration of trastuzumab treatment as well as the optimal chemotherapy regimen and sequence. The next large phase III adjuvant trial for this subset of breast cancer is an international collaboration designed to evaluate the added or alternative benefit of an oral tyrosine kinase inhibitor targeting HER2/neu as well as the epidermal growth factor receptor (EGFR), lapatinib. Other trials are investigating differences in duration. Studies in the neoadjuvant setting should help to define markers of trastuzumab and lapatinib sensitivity and resistance. Preliminary data combining trastuzumab with the antiangiogenic antibody bevacizumab is encouraging ; this combination will be tested in both early stage and late stage disease .

https://pubmed.ncbi.nlm.nih.gov/17660958/

e1b808c61aae414e8d95d9918cb78e59

The immuno-oncology-based combinations with different types of immune checkpoint inhibitors ( PD-1/PD-L1 and CTLA-4 inhibitors such as nivolumab , pembrolizumab , atezolizumab , durvalumab , ipilimumab , tremelimumab ) , or the association of immune checkpoint inhibitors plus anti-angiogenic agents ( bevacizumab , lenvatinib , cabozantinib ) , have led to a breakthrough in the treatment of hepatocellular carcinoma .

The New Immuno-Oncology-Based Therapies and Their Perspectives in Hepatocellular Carcinoma. Hepatocellular carcinoma is a poor prognosis tumor. Systemic therapies are frequently used due to frequent recurrences after surgical or radiologic treatments. Anti-angiogenic tyrosine kinase inhibitors have shown efficacy in monotherapy, but with very low rates of long survival and exceptional recovery. Immuno-oncology based on immune checkpoint inhibitors has revolutionized the systemic therapies since showing long survival rates without any tumor progression or recurrence for some patients in partial or complete response, and possibly for some patients in stable disease. However, the rate of responders under immuno-oncology monotherapy is too low to increase significantly the median overall survival of the treated patients. The immuno-oncology-based combinations with different types of immune checkpoint inhibitors ( PD-1/PD-L1 and CTLA-4 inhibitors such as nivolumab , pembrolizumab , atezolizumab , durvalumab , ipilimumab , tremelimumab ) , or the association of immune checkpoint inhibitors plus anti-angiogenic agents ( bevacizumab , lenvatinib , cabozantinib ) , have led to a breakthrough in the treatment of hepatocellular carcinoma . Indeed, the first phase-3 trial, combining atezolizumab with bevacizumab, has dramatically changed the outcome of patients. Data from several other types of combinations assessed in phase-3 trials are pending, and if positive, will drastically arm the physicians to efficiently treat the patients, and disrupt the current algorithm of hepatocellular carcinoma treatment.

https://pubmed.ncbi.nlm.nih.gov/33440630/

3c6b70d58429d686c73e83b352f07573

A decrease in VEGF-A expression in the tumor node and salivary gland was found after monotherapy with melatonin and cyclophosphamide and , especially , after combined treatment , which proves maximum therapeutic efficiency of combined administration of chemical agents with various mechanisms of action .

Expression of vascular endothelial growth factor (VEGF-A) in rat mandibular salivary gland during paraneoplastic process and treatment with cyclophosphamide and melatonin. Expression of VEGF-A in Walker 256 carcinosarcoma and mandibular salivary gland of rats during paraneoplastic process and various regimens of chemotherapy with melatonin and cyclophosphamide were studied by immunohistochemical methods. VEGF-A expression increased in the tumor node and salivary gland after monotherapy with melatonin and cyclophosphamide during progression of tumor growth and paraneoplastic syndrome. A decrease in VEGF-A expression in the tumor node and salivary gland was found after monotherapy with melatonin and cyclophosphamide and , especially , after combined treatment , which proves maximum therapeutic efficiency of combined administration of chemical agents with various mechanisms of action . Overexpression of VEGF-A in the mandibular salivary gland can have diagnostic and predictive value in early diagnostics of neoplasms.

https://pubmed.ncbi.nlm.nih.gov/25778658/

349d1fcc0bd239b41bf562c7dc761e11

The combination of rituximab , bendamustine , and cytarabine ( R-BAC ) was highly active in a pilot trial of mantle cell lymphoma , but its use was restricted by high haematological toxicity .

Rituximab, bendamustine, and low-dose cytarabine as induction therapy in elderly patients with mantle cell lymphoma: a multicentre, phase 2 trial from Fondazione Italiana Linfomi. The combination of rituximab , bendamustine , and cytarabine ( R-BAC ) was highly active in a pilot trial of mantle cell lymphoma , but its use was restricted by high haematological toxicity . We aimed to assess the efficacy and safety of an R-BAC regimen with low-dose cytarabine (RBAC500). ### methods In this multicentre, phase 2 trial, we recruited previously untreated patients with an established histological diagnosis of mantle cell lymphoma from 29 Fondazione Italiana Linfomi centres in Italy. Patients had to be older than 65 years and fit according to the comprehensive geriatric assessment, or aged 60-65 years if they were ineligible for high-dose chemotherapy plus autologous stem-cell transplantation and were fit or unfit. All patients received RBAC500 (rituximab 375 mg/m ### findings Between May 2, 2012, and Feb 25, 2014, we enrolled 57 patients (median age 71 years, IQR 67-75). 54 (95%) patients received at least four RBAC500 cycles (three discontinued because of toxicity), and 38 (67%) completed six cycles. Two (4%) had disease progression (one after the fourth cycle and one after the sixth cycle). All 52 (91%, lower limit of one-sided 95% CI 85%) remaining patients achieved complete response at the end of treatment. 23 (40%, upper limit of one-sided 95% CI 53%) of 57 patients had at least one episode of relevant toxicity. The most frequent grade 3-4 haematological toxicities were neutropenia (149 [49%] of 304 cycles) and thrombocytopenia (158 [52%]). Most treatment-related non-haematological adverse events were of grade 1-2, with the most frequent ones being fatigue (14 [25%] patients), nausea or vomiting (12 [21%]), and infusion-related reactions or tumour lysis syndrome (12 [21%]). 41 (72%) patients required a dose reduction. 12 patients died during the study, but no deaths were related to treatment. ### interpretation RBAC500 is an effective treatment for elderly patients with mantle cell lymphoma and, despite not meeting our prespecified safety boundary, haematological toxicity was manageable with appropriate supportive care and dose reduction. Since maintenance therapy is not required, RBAC500 could be considered an option and should be studied in phase 3 trials. ### funding Fondazione Italiana Linfomi and Mundipharma.

https://pubmed.ncbi.nlm.nih.gov/27927586/

437b8cee1d2a36e2af081d283529e4be

Despite treatment with PH specific therapy ( sildenafil , ambrisentan , and epoprostenol ) , her condition worsened rapidly with acute right heart failure ( RHF ) .

Subacute right heart failure revealing three simultaneous causes of post-embolic pulmonary hypertension in metastatic dissemination of breast cancer. A 72-year-old woman with history of breast cancer only treated surgically was referred to our department for pulmonary hypertension (PH) suspicion. Echocardiogram revealed elevated right ventricular systolic pressure. Computed tomography (CT) angiogram showed no pulmonary embolism (PE), but lung scan revealed two ventilation-perfusion mismatch areas. Right cardiac catheterization established precapillary PH. Despite treatment with PH specific therapy ( sildenafil , ambrisentan , and epoprostenol ) , her condition worsened rapidly with acute right heart failure ( RHF ) . She died 22 days after admission. Post-mortem microscopic examination showed a rare combination of PH etiologies consistent with metastasis of breast cancer in pulmonary vasculature including the rare pulmonary tumour thrombotic microangiopathy (PTTM).

https://pubmed.ncbi.nlm.nih.gov/28217316/

a9d8ce2f770a3ecc77884a8a973f8efa

Data from the present study show the feasibility and tolerability of combination ixabepilone plus carboplatin , with ixabepilone administered on day 1 or on days 1 and 8 on a 21-day cycle .

A phase I and pharmacokinetic study of ixabepilone in combination with Carboplatin in patients with advanced solid malignancies. To determine the recommended phase II dose of combination ixabepilone plus carboplatin based on the maximum tolerated dose, pharmacokinetics, optimum schedule, and safety. ### Experimental Design Patients with advanced solid malignancies were treated with escalating doses of carboplatin plus ixabepilone administered on day 1 (schedule A) or days 1 and 8 (schedule B) of a 21-day cycle. Blood was sampled during cycle 1 for pharmacokinetic analysis of ixabepilone (both schedules) and carboplatin (schedule B). ### results Fifty-two patients were treated with ixabepilone doses ranging from 30 to 50 mg/m2 per 21-day cycle plus carboplatin area under curve (AUC) 5 or 6 (Calvert formula). On schedule A (ixabepilone 40 mg/m2 over 1 hour plus carboplatin AUC 6), 2 of 2 patients experienced dose-limiting toxicity (DLT). On schedule B (ixabepilone 25 mg/m2 over 1 hour on days 1 and 8 plus carboplatin AUC 6), 3 of 3 patients experienced DLT. DLT was myelosuppression; however, cumulative sensory neuropathy limited extended dosing on schedule A. ixabepilone and carboplatin pharmacokinetics were similar to those using either drug as monotherapy, indicating an absence of pharmacokinetic drug interactions. Based on DLTs and tolerability with repeated dosing, the recommended doses were 30 mg/m2 ixabepilone (1-hour infusion) d1 q3w plus carboplatin AUC 6 (schedule A) and 20 mg/m2 ixabepilone (1 hour infusion) d1, d8 q3w plus carboplatin AUC 6 (schedule B). ### conclusions Data from the present study show the feasibility and tolerability of combination ixabepilone plus carboplatin , with ixabepilone administered on day 1 or on days 1 and 8 on a 21-day cycle .

https://pubmed.ncbi.nlm.nih.gov/19088046/

4068259c823edd9ba35db8fef046b4ca

Compared to other glucose lowering agents except metformin , gliclazide was slightly more effective ( -0.13 % ( 95%CI : -0.25 , -0.02 , I(2 ) 55 % ) ) .

Safety and efficacy of gliclazide as treatment for type 2 diabetes: a systematic review and meta-analysis of randomized trials. gliclazide has been associated with a low risk of hypoglycemic episodes and beneficial long-term cardiovascular safety in observational cohorts. The aim of this study was to assess in a systematic review and meta-analysis of randomized controlled trials the safety and efficacy of gliclazide compared to other oral glucose-lowering agents (PROSPERO2013:CRD42013004156). ### Data Sources Medline, EMBASE, Clinicaltrials.gov, Trialregister.nl, Clinicaltrialsregister.eu and the Cochrane database. ### selection Included were randomized studies of at least 12 weeks duration with the following outcomes: HbA1c change, incidence of severe hypoglycemia, weight change, cardiovascular events and/or mortality when comparing gliclazide with other oral blood glucose lowering drugs. Bias was assessed with the Cochrane risk of bias tool. The inverse variance random effects model was used. ### results Nineteen trials were included; 3,083 patients treated with gliclazide and 3,155 patients treated with other oral blood glucose lowering drugs. There was a considerable amount of heterogeneity between and bias in studies. Compared to other glucose lowering agents except metformin , gliclazide was slightly more effective ( -0.13 % ( 95%CI : -0.25 , -0.02 , I(2 ) 55 % ) ) . One out of 2,387 gliclazide users experienced a severe hypoglycemic event, whilst also using insulin. There were 25 confirmed non-severe hypoglycemic events (2.2%) in 1,152 gliclazide users and 22 events (1.8%) in 1,163 patients in the comparator group (risk ratio 1.09 (95% CI: 0.20, 5.78, I² 77%)). Few studies reported differences in weight and none were designed to evaluate cardiovascular outcomes. ### conclusions The methodological quality of randomized trials comparing gliclazide to other oral glucose lowering agents was poor and effect estimates on weight were limited by publication bias. The number of severe hypoglycemic episodes was extremely low, and gliclazide appears at least equally effective compared to other glucose lowering agents. None of the trials were designed for evaluating cardiovascular outcomes, which warrants attention in future randomized trials.

https://pubmed.ncbi.nlm.nih.gov/24533045/

17b4fa14d7486f05c30b5ad38ba9389f

Thirteen stage III B and 13 stage IV patients received intermediate doses of ifosfamide ( 1000 mg/m2 ) , carboplatin ( 120 mg/m2 ) and etoposide ( 120 mg/m2 ) given intravenously on day 1 to 3 every 4 weeks .

Phase II study with ifosfamide, carboplatin, etoposide (ICE regimen) at intermediate dosage for advanced non small cell lung cancer (NSCLC). We have evaluated the combination of ifosfamide, carboplatin and etoposide (ICE regimen) along with mesna in 26 previously untreated patients with non small cell lung cancer (NSCLC). Thirteen stage III B and 13 stage IV patients received intermediate doses of ifosfamide ( 1000 mg/m2 ) , carboplatin ( 120 mg/m2 ) and etoposide ( 120 mg/m2 ) given intravenously on day 1 to 3 every 4 weeks . Except for one patient who experienced grade 3 transient thrombocytopenia no major events of hematological or systemic toxicity were observed. Response rate (27%, 95% C.I., 10 to 44%), median duration of response (9 months, range 6-15), and survival (9.5 months, range 2-44+) were comparable to those achieved with conventional cisplatin-containing regimens. Our ICE combination, as compared to standard or high dose schedules appears effective, safe, well tolerated, and devoid of severe hematological toxicity.

https://pubmed.ncbi.nlm.nih.gov/9876059/

9d575fee5bce79fec6085979adb25d0d

This study compared immediate ( overnight ) and progressive switching to oxcarbazepine monotherapy in patients with partial seizures unsatisfactorily treated with carbamazepine monotherapy .

Immediate (overnight) switching from carbamazepine to oxcarbazepine monotherapy is equivalent to a progressive switch. This study compared immediate ( overnight ) and progressive switching to oxcarbazepine monotherapy in patients with partial seizures unsatisfactorily treated with carbamazepine monotherapy . Patients were randomised to either an overnight (n = 140) or a progressive switch (n = 146) from carbamazepine to oxcarbazepine monotherapy at a dose ratio of 1:1.5. The difference between the two switch groups in the mean monthly seizure frequency supported the equivalence of overnight and progressive switching (difference of 0.02 excluding outliers; 95% confidence interval (CI) -0.74, 0.78). Following the switch from carbamazepine to oxcarbazepine, there was a reduction in median monthly seizure frequency in both the overnight group (from 1.5 to 0; P = 0.0005) and the progressive group (from 1.0 to 0.4; P = 0.003). The proportion of seizure-free patients increased from 38 to 51% (P = 0.002) and 39 to 49% (P = -0.01) in the overnight and progressive groups, respectively. In addition, the proportion of patients experiencing no clinically significant adverse events did not differ between the two switch methods (difference of 2.5; 95% CI -4.1, 9.0). For patients who are unsatisfactorily treated with carbamazepine monotherapy, overnight switch to oxcarbazepine monotherapy is as effective and well tolerated as a progressive switch, therefore allowing simple and flexible individualised treatment. Switching to oxcarbazepine monotherapy appears to be beneficial for patients who are unsatisfactorily treated with carbamazepine monotherapy, independently of the switch method used.

https://pubmed.ncbi.nlm.nih.gov/15121136/

c6cedbb5fed19bf8144d7f964131c07b

In conclusion , prasugrel can be used successfully in most patients with a history of clopidogrel hypersensitivity .

Use of prasugrel in the setting of clopidogrel hypersensitivity: Case report and systematic review of the literature. Allergic reactions to clopidogrel soon after coronary stent implantation pose an important and challenging clinical problem. We describe a 44-year-old man who developed a diffuse maculopapular rash four days after initiation of clopidogrel with drug-eluting coronary stent placement. An initial treat-through strategy was unsuccessful due to patient intolerance to corticosteroids. Because of persistent hypersensitivity, clopidogrel was substituted with prasugrel which was continued successfully for one year without reaction. A systematic review of the literature was performed which identified 10 prior case reports of patients with clopidogrel hypersensitivity who were subsequently treated with prasugrel. Patient characteristics and clinical outcomes of these patients plus the current case were reviewed. There were 9 men and 2 women with ages from 44 to 76 years. All patients had undergone coronary stent procedures. prasugrel was successfully used without cross-reactivity in 9 of the 11 patients (82%). Cross-reactivity was reported in two patients who developed hypersensitivity reactions to prasugrel similar to those experienced on clopidogrel. In conclusion , prasugrel can be used successfully in most patients with a history of clopidogrel hypersensitivity . However, potential cross-reactivity between these two thienopyridines may occur in some patients.

https://pubmed.ncbi.nlm.nih.gov/27494368/

354e50c6bec6e5f799e569449cf54fa4

Fresh , clinical P. falciparum isolates were also tested in the presence of several drugs , including chloroquine , mefloquine , quinine , halofantrine , atovaquone and qinghaosu derivatives .

The microculture tetrazolium assay (MTA): another colorimetric method of testing Plasmodium falciparum chemosensitivity. Malarial lactate dehydrogenase (LDH), which uses 3-acetyl pyridine adenine dinucleotide as coenzyme in a reaction leading to the formation of pyruvate from L-lactate, may be used to study the susceptibility of Plasmodium falciparum to a drug in vitro. Several methods to determine the activity of this enzyme are available. One, the colorimetric method of Makler and colleagues, was modified slightly, by using sodium-2,3-bis-[2-methoxy-4-nitro-5-sulphophenyl]-2H-tetrazolium-5 - carboxanilide (XTT) and following the reaction by measuring the optical density at 450 nm. Using two, culture-adapted strains of P. falciparum, this LDH assay was compared with the unmodified Makler's assay and with the isotopic microtest based on the incorporation of tritium-labelled hypoxanthine. Fresh , clinical P. falciparum isolates were also tested in the presence of several drugs , including chloroquine , mefloquine , quinine , halofantrine , atovaquone and qinghaosu derivatives . The results of the three assays were correlated for all the drugs tested except atovaquone. The two enzymatic assays are non-radioactive, rapid, reliable, inexpensive to perform and semi-automatic. However, they do require an initial parasitaemia of 2% with a haematocrit of 1.8%.

https://pubmed.ncbi.nlm.nih.gov/10492669/

8b855ef5d611be57b0e69fb8aa6f117f

The null hypothesis was there is no difference with respect to pain scores between ketorolac and iliac crest bupivacaine infusion as analgesic adjuncts to intravenous opioids .

Continuous bupivacaine infusion post-iliac crest bone graft harvesting in pediatric cleft surgery: role and comparison with ketorolac. To investigate the use of intravenous ketorolac and iliac crest bupivacaine infusion in the management of iliac crest donor-site pain in the pediatric cleft population. The null hypothesis was there is no difference with respect to pain scores between ketorolac and iliac crest bupivacaine infusion as analgesic adjuncts to intravenous opioids . ### methods A total of 54 children and adolescents (27 boys, 27 girls) undergoing alveolar cleft repair or Le Fort I osteotomy were assigned randomly in a prospective, single-blinded fashion to one of three groups: intravenous ketorolac plus iliac crest normal saline infusion, intravenous ketorolac plus iliac crest bupivacaine infusion, or iliac crest bupivacaine infusion alone. Iliac crest infusions and ketorolac were administered for 48 hours or until discharge, whichever occurred first. All patients received morphine via a patient-controlled analgesia device. ### Main Outcome Measure S Primary outcome was pain score, and secondary outcomes were morphine consumption and satisfaction scores. ### results Pain scores, morphine consumption, and satisfaction scores were not significantly different among groups. Estimated costs were significantly higher for bupivacaine infusion than intravenous ketorolac. ### conclusions Iliac crest donor-site pain is well managed in this patient population. Intravenous ketorolac and iliac crest bupivacaine infusion provide comparable analgesia for iliac crest bone graft donor-site pain in children and adolescents.

https://pubmed.ncbi.nlm.nih.gov/21091369/

c807c19adaebe7abb343c158259a5a8c

Etoposide in combination with low-dose CAG ( cytarabine , aclarubicin , G-CSF ) for the treatment of relapsed or refractory acute myeloid leukemia : a multicenter , randomized control trial in southwest China .

Etoposide in combination with low-dose CAG ( cytarabine , aclarubicin , G-CSF ) for the treatment of relapsed or refractory acute myeloid leukemia : a multicenter , randomized control trial in southwest China . In a well-controlled multi-center randomized trial in southwestern China, 228 patients with refractory or relapsed AML were received a low-dose CAG regimen either with etoposide (E-CAG) or without etoposide (CAG). The complete remission (CR) rate, overall survival (OS) and toxicity were evaluated. Patients with E-CAG had a higher CR rate (71.1% vs. CAG 50.9%, P=0.0002). The tolerability appeared to be equivalent. Patients with CR who underwent allogenic hematopoietic stem cell transplantation (allo-HSCT) had a higher five-year OS over those without allo-HSCT (73.8% vs. 10.8%, P=0.000). The E-CAG regimen is expected to become a bridge between relapsed or refractory AML and allo-HSCT.

https://pubmed.ncbi.nlm.nih.gov/23537708/

628a6d576b395f5bcea10e9d60b16658

were randomized in an open-label , crossover fashion to treatment A ( dolasetron 100 mg on day 1 ) and treatment B ( dolasetron 100 mg plus aprepitant 125 mg on day 1 , aprepitant 80 mg on days 2 - 3 ) .

Lack of effect of aprepitant on hydrodolasetron pharmacokinetics in CYP2D6 extensive and poor metabolizers. To prevent chemotherapy-induced nausea and vomiting, aprepitant is given with a corticosteroid and a 5-hydroxytryptamine type 3 antagonist, such as dolasetron. dolasetron is converted to the active metabolite hydrodolasetron, which is cleared largely via CYP2D6. The authors determined whether aprepitant, a moderate CYP3A4 inhibitor, alters hydrodolasetron pharmacokinetics in CYP2D6 poor and extensive metabolizers. Six CYP2D6 poor and 6 extensive metabolizers were randomized in an open-label , crossover fashion to treatment A ( dolasetron 100 mg on day 1 ) and treatment B ( dolasetron 100 mg plus aprepitant 125 mg on day 1 , aprepitant 80 mg on days 2 - 3 ) . For hydrodolasetron area under the concentration-versus-time curve (AUC0-infinity) and peak plasma concentration (Cmax), geometric mean ratios (B/A) and 90% confidence intervals (CIs) fell below the predefined limit (2.0) for clinical significance (AUC0-infinity, 1.09 [90% CI, 1.01-1.18], Cmax, 1.08 [90% CI, 0.94-1.24]). aprepitant did not affect the pharmacokinetics of hydrodolasetron, regardless of CYP2D6 metabolizer type, and was generally well tolerated when coadministered with dolasetron in volunteers.

https://pubmed.ncbi.nlm.nih.gov/16809805/

d7a9823a05c84cd6642567852a3a0b2b

The regimen of gemcitabine combined with ifosfamide and anthracycline is feasible , tolerable and effective in patients with recurrent platinum resistant/refractory epithelial ovarian cancer .

[Gemcitabine based combination chemotherapy, a new salvage regimen for recurrent platinum resistant epithelial ovarian cancer]. To evaluate the efficacy and toxicities of gemcitabine combined with ifosfamide and anthracycline chemotherapy for recurrent platinum resistant ovarian epithelial cancer. ### methods gemcitabine 800 mg/m(2) (day 1, 8), ifosfamide 1.5 g/m(2) (day 1 - 3), adriamycin 40 mg/m(2) or epirubicin 60 mg/m(2) (day 1) or mitoxantrone 10 mg/m(2) (day 1, 8) were used in recurrent platinum resistant/refractory ovarian cancer patients, the cycle was repeated at interval of 21 to 28 days. ### results A total of 60 patients received 172 cycles combined chemotherapy. There were no one cases complete response, while partial response 22 (37%, 22/60), stable 23 (38%, 23/60) and progression 15 (25%, 15/60) were observed, with clinical benefit rate 75% (45/60). The median time of progression-free survival was 7 months, and the median overall survival time was 20 months. The main side effect was hematologic toxicity with leukopenia rate of 82% (49/60), among which III-IV accounted for 31% (15/49). Digestive reaction was all in I-II, accounted for 42% (25/60). ### conclusion The regimen of gemcitabine combined with ifosfamide and anthracycline is feasible , tolerable and effective in patients with recurrent platinum resistant/refractory epithelial ovarian cancer .

https://pubmed.ncbi.nlm.nih.gov/21211276/

ce6a8e4d2639c00add811419673116fe

Second-line treatments consisted of cetuximab plus irinotecan for arm A , and oxaliplatin plus either 5-fluorouracil ( FOLFOX ) or capecitabine ( CapeOX ) for the control arms .

Second-line cetuximab/irinotecan versus oxaliplatin/fluoropyrimidines for metastatic colorectal cancer with wild-type KRAS. The goal of the present study was to compare the efficacy of the combination of cetuximab and irinotecan to the combination of oxaliplatin and fluoropyrimidines as second-line chemotherapy in patients with irinotecan-refractory and oxaliplatin-naïve metastatic colorectal cancer (mCRC) harboring wild-type KRAS. The study included 120 patients with mCRC who had progressed after irinotecan-containing first-line chemotherapy and were never treated with oxaliplatin; 40 patients with wild-type KRAS were accrued prospectively in the experimental arm (arm A), and 80 patients accrued retrospectively were divided into control arms B (n = 46) and C (n = 34) according to KRAS genotype. Second-line treatments consisted of cetuximab plus irinotecan for arm A , and oxaliplatin plus either 5-fluorouracil ( FOLFOX ) or capecitabine ( CapeOX ) for the control arms . The median progression-free survival (PFS) was 8.3, 5.8 and 3.9 months, for arms A, B and C, respectively, with statistical significance favoring arm A (P = 0.007). Differences in overall survival did not reach statistical significance (18.3 vs 12.6 vs 12.9, P = 0.138), although there was a trend toward longer overall survival in arm A. In terms of benefit from oxaliplatin-containing regimens either as second-line or third-line therapy, the median PFS was 5.0 months in arms B and C as second-line therapy, and 4.0 months in arm A as third-line therapy, with no statistical significance (P = 0.385). Second-line cetuximab plus irinotecan is a valid treatment strategy for mCRC patients with irinotecan-refractory and oxaliplatin-naïve tumors harboring wild-type KRAS. oxaliplatin-containing chemotherapy resulted in equivalent PFS both as a second-line and a third-line therapy, enabling delay of the administration of FOLFOX and CapeOX until subsequent treatment cycles.

https://pubmed.ncbi.nlm.nih.gov/23298313/

7f313ee61854c59c64f076e46778537a

In the UT-EC-1 cell line the growth inhibition was 72 % with paclitaxel , 54 % with carboplatin and 73 % with the combination of these compounds .

Paclitaxel, Carboplatin and 1,25-D3 Inhibit Proliferation of Endometrial Cancer Cells Endometrial cancer cells are known to be sensitive to carboplatin and paclitaxel. Furthermore, vitamin D (1,25-D3) has been reported to inhibit endometrial cancer cell growth both as a single agent and combined with carboplatin. However, there are no studies comparing the effect of paclitaxel and carboplatin as single agents vs. in combination in endometrial cancer cell lines. Neither has the effect of 1,25-D3 been studied with paclitaxel. The present study investigated the effect of paclitaxel, carboplatin and 1,25-D3 on the growth of endometrial cancer cells in vitro. ### Materials And Methods Two endometrial adenocarcinoma cell lines (UT-EC-1 and UT-EC-3) were cultured with different doses of paclitaxel, carboplatin and 1,25-D3. The cellular VDR (vitamin D receptor) mRNA levels were measured and the expression of estrogen (ER) and progesterone (PR) receptors by the cells was determined. ### results In the UT-EC-1 cell line the growth inhibition was 72 % with paclitaxel , 54 % with carboplatin and 73 % with the combination of these compounds . The corresponding numbers in UT-EC-3 were 70%, 33% and 65%, respectively. 1,25-D3 suppressed cell growth 88% with paclitaxel, 63% with carboplatin and 87% with their combination in the UT-EC-1 cell line. ### conclusion In both cell lines, single-agent paclitaxel was as effective as the combination of the compounds and more effective than single carboplatin. 1,25-D3 may further contribute to the cytotoxic effect of these agents.

https://pubmed.ncbi.nlm.nih.gov/29187432/

1557b8cc8b1f0bca1472c9420dce5370

Several lines of evidence implicate serotonin ( 5-HT ) as the mediator of this enhancement : ( 1 ) Tranyclypromine-enhanced nicotine reinforcement was blocked by the 5-HT₂ receptor antagonists , ritanserin and ketanserin ; ( 2 ) parachloroamphetamine ( PCA ) , a 5-HT releaser , also enhanced nicotine self-administration in animals in which MAO activity was inhibited ; ( 3 ) pretreatment with tranylcypromine increased PCA-induced 5-HT overflow in the nucleus accumbens .

Serotonergic mechanism underlying tranylcypromine enhancement of nicotine self-administration. Although nicotine is generally considered to be the main psychoactive component of tobacco, growing evidence highlights the importance of nonnicotine compounds in smoking reinforcement. Monoamine oxidase (MAO) inhibition is a major consequence of smoking and MAO inhibitors, such as tranylcypromine, increase nicotine reinforcement. tranylcypromine has multiple pharmacological effects, increasing monoamine release for a few hours immediately after its administration and blocking MAO activity for several days. To assess the relative role of these two actions, adult male rats were tested in consecutive daily 3-h sessions for self-administration of nicotine (3 μg kg⁻¹) inj⁻¹, i.v.) either 20 or 1 h following administration of tranylcypromine (3 mg kg⁻¹). Both paradigms were shown to produce highly significant inhibition of MAO activity. However, whereas animals readily acquired self-administration when pretreated with tranylcypromine 1 h prior to testing, they did not with the longer pretreatment interval. Such animals did immediately acquire nicotine self-administration when the tranylcypromine pretreatment interval was switched to 1 h prior to testing on Day 4, indicating that an acute effect of the MAO inhibitor was responsible for enhanced nicotine reinforcement. Several lines of evidence implicate serotonin ( 5-HT ) as the mediator of this enhancement : ( 1 ) Tranyclypromine-enhanced nicotine reinforcement was blocked by the 5-HT₂ receptor antagonists , ritanserin and ketanserin ; ( 2 ) parachloroamphetamine ( PCA ) , a 5-HT releaser , also enhanced nicotine self-administration in animals in which MAO activity was inhibited ; ( 3 ) pretreatment with tranylcypromine increased PCA-induced 5-HT overflow in the nucleus accumbens . These findings suggest that MAO inhibition enhances serotonergic transmission, which serves a critical role in the reinforcing effects of nicotine.

https://pubmed.ncbi.nlm.nih.gov/20936688/

9d5b1dd36deadb367392e8c2cbef88d4

Measurement and simulation results obtained in the batch experiments , spiked with the diclofenac and carbamazepine content of preclarified municipal wastewater shows comparably high biotransformation rates in the presence of growth substrates .

An activated sludge modeling framework for xenobiotic trace chemicals (ASM-X): assessment of diclofenac and carbamazepine. Conventional models for predicting the fate of xenobiotic organic trace chemicals, identified, and calibrated using data obtained in batch experiments spiked with reference substances, can be limited in predicting xenobiotic removal in wastewater treatment plants (WWTPs). At stake is the level of model complexity required to adequately describe a general theory of xenobiotic removal in WWTPs. In this article, we assess the factors that influence the removal of diclofenac and carbamazepine in activated sludge, and evaluate the complexity required for the model to effectively predict their removal. The results are generalized to previously published cases. Batch experimental results, obtained under anoxic and aerobic conditions, were used to identify extensions to, and to estimate parameter values of the activated sludge modeling framework for Xenobiotic trace chemicals (ASM-X). Measurement and simulation results obtained in the batch experiments , spiked with the diclofenac and carbamazepine content of preclarified municipal wastewater shows comparably high biotransformation rates in the presence of growth substrates . Forward dynamic simulations were performed using full-scale data obtained from Bekkelaget WWTP (Oslo, Norway) to evaluate the model and to estimate the level of re-transformable xenobiotics present in the influent. The results obtained in this study demonstrate that xenobiotic loading conditions can significantly influence the removal capacity of WWTPs. We show that the trace chemical retransformation in upstream sewer pipes can introduce considerable error in assessing the removal efficiency of a WWTP, based only on parent compound concentration measurements. The combination of our data with those from the literature shows that solids retention time (SRT) can enhance the biotransformation of diclofenac, which was not the case for carbamazepine. Model approximation of the xenobiotic concentration, detected in the solid phase, suggest that between approximately 1% and 16% of the total solid carbamazepine and diclofenac concentrations, respectively, is due to sorption-the remainder being non-bioavailable and sequestered. We demonstrate the effectiveness of the model's predictive power over conventional tools in a statistical analysis, performed at four levels of structural complexity. To assess WWTP retrofitting needs to remove xenobiotic trace chemicals, we suggest using mechanistic models, e.g., ASM-X, in regional risk assessments. For preliminary evaluations, we present operating charts that can be used to estimate average xenobiotic removal rates in WWTPs as a function of SRT and the xenobiotics mass loads normalised to design treatment capacity.

https://pubmed.ncbi.nlm.nih.gov/22565415/

3e46fd4068d1a8ced5f4ad0790a02540

Ursodeoxycholic acid is conjugated with taurine to promote secretin-stimulated biliary hydrocholeresis in the normal rat .

Ursodeoxycholic acid is conjugated with taurine to promote secretin-stimulated biliary hydrocholeresis in the normal rat . Secretin induces bicarbonate-rich hydrocholeresis in healthy individuals, but not in untreated patients with primary biliary cirrhosis (PBC). Ursodeoxycholic acid (UDCA)--the first choice treatment for PBC--restores the secretin response. Compared with humans, secretin has poor effect in experimental normal-rat models with biliary drainage, although it may elicit hydrocholeresis when the bile-acid pool is maintained. In view of the benefits of UDCA in PBC, we used normal-rat models to unravel the acute contribution of UDCA (and/or taurine-conjugated TUDCA) for eliciting the biliary secretin response. ### methods Intravascular and/or intrabiliary administration of agonists and inhibitors was performed in normal rats with biliary monitoring. Secretin/bile-acid interplay was analyzed in 3D cultured rat cholangiocytes that formed expansive cystic structures with intralumenal hydroionic secretion. ### results In vivo, secretin stimulates hydrocholeresis upon UDCA/TUDCA infusion, but does not modify the intrinsic hypercholeretic effect of dehydrocholic acid (DHCA). The former effect is dependent on microtubule polymerization, and involves PKCα, PI3K and MEK pathways, as shown by colchicine (i.p.) and retrograde biliary inhibitors. In vitro, while secretin alone accelerates the spontaneous expansion of 3D-cystic structures, this effect is enhanced in the presence of TUDCA, but not UDCA or DHCA. Experiments with inhibitors and Ca(2+)-chelator confirmed that the synergistic effect of secretin plus TUDCA involves microtubules, intracellular Ca(2+), PKCα, PI3K, PKA and MEK pathways. Gene silencing also demonstrated the involvement of the bicarbonate extruder Ae2. ### conclusions UDCA is conjugated in order to promote secretin-stimulated hydrocholeresis in rats through Ae2, microtubules, intracellular Ca(2+), PKCα, PI3K, PKA, and MEK.

https://pubmed.ncbi.nlm.nih.gov/22194894/

76f84f3b23071ee7871063887fb9eaf3

This study assessed the efficacy and safety of telaprevir in combination with peginterferon-α-2b ( PEG IFN ) and ribavirin ( RBV ) , for Japanese difficult-to-treat patients with hepatitis C virus ( HCV ) genotype 2 who had not achieved sustained virological response ( SVR ) during prior treatment .

Efficacy of telaprevir-based therapy for difficult-to-treat patients with genotype 2 chronic hepatitis C in Japan. This study assessed the efficacy and safety of telaprevir in combination with peginterferon-α-2b ( PEG IFN ) and ribavirin ( RBV ) , for Japanese difficult-to-treat patients with hepatitis C virus ( HCV ) genotype 2 who had not achieved sustained virological response ( SVR ) during prior treatment . ### methods In total, 108 relapsed (median age, 59.0 years) and 10 non-responding (median age, 59.0 years) patients with genotype 2 HCV participated. Patients received telaprevir (750 mg, every 8 h) for 12 weeks and PEG IFN/RBV for 24 weeks. ### results The SVR rates for relapsers and non-responders were 88.0% (95/108) and 50.0% (5/10), respectively. The SVR rates did not differ significantly between patients with rs8099917 TT and non-TT. The SVR rates for relapsers and non-responders with extended rapid viral response (eRVR) were 97.6% (82/84) and 100% (5/5), respectively. On the other hand, the SVR rates for relapsers and non-responders completing the treatment protocol were 98.4% (61/62) and 100% (5/5), respectively. The overall safety profiles of telaprevir-based regimens were similar for Japanese patients with genotype 1 and 2 HCV infection who experienced treatment failure. ### conclusion telaprevir, in combination with PEG IFN/RBV, provided a high SVR rate for genotype 2 HCV, difficult-to-treat patients who had not achieved SVR during prior IFN-based treatment. The eRVR had a strong influence on the cure rate of telaprevir-based therapy. In addition, the continuation of telaprevir-based treatment for up to 24 weeks was a significant predictor of SVR.

https://pubmed.ncbi.nlm.nih.gov/25196718/

3e1d02e4636033bbd6a561cdeb9a34d9

The binding affinity profile of 5-HT1D binding sites [ 5-CT > 5-HT > d-LSD > 5-MeOT > sumatriptan > RU 24,969 > metergoline > tryptamine = rauwolscine = methylsergide > yohimbine = methiothepin > TFMPP = 8-OH-DPAT > 2-methyl-5-HT > mCPP = quipazine = CP 93,129 > ketanserin > (-)-propranolol = haloperidol = ipsapirone ] compares well to that reported for 5-HT1D receptor sites in human caudate and cortex ( correlation coefficient : 0.99 and 0.98 ) .

Identification of 5-hydroxytryptamine1D binding sites in sheep caudate nucleus membranes. Radioligand binding measurements were performed in membranes of sheep caudate nucleus using [3H]5-hydroxytryptamine (5-HT). [3H]5-HT labeled a population of high affinity binding sites with a Kd of 1.9 +/- 0.1 nM and a Bmax of 19.8 +/- 2.2 fmol/mg tissue. Combined 5-HTID/E binding sites were the predominant 5-HT1 subtype, accounting for 78% of the total population of 5-HT1 binding sites. 5-Carboxamidotryptamine (5-CT) and sumatriptan yielded inhibition curves which best fitted a two-site model with high affinity values of 0.8 and 10.1 nM, and 1000 and 206 nM for their low affinity components. The proportion of the high affinity 5-CT and sumatriptan binding sites was 79 and 72%. The binding affinity profile of 5-HT1D binding sites [ 5-CT > 5-HT > d-LSD > 5-MeOT > sumatriptan > RU 24,969 > metergoline > tryptamine = rauwolscine = methylsergide > yohimbine = methiothepin > TFMPP = 8-OH-DPAT > 2-methyl-5-HT > mCPP = quipazine = CP 93,129 > ketanserin > (-)-propranolol = haloperidol = ipsapirone ] compares well to that reported for 5-HT1D receptor sites in human caudate and cortex ( correlation coefficient : 0.99 and 0.98 ) . The present results indicate that sheep caudate nucleus is a valid tissue for studying interaction of compounds with 5-HT1D binding sites in the relative absence of 5-HT1E binding sites.

https://pubmed.ncbi.nlm.nih.gov/8394085/

da874424ca816f4450484050fadb2cc8

The MX2 cells are cross-resistant to etoposide , teniposide , bisantrene , dactinomycin , 4'-(9-acridinylamino)methanesulfon-m-anisidide , and the anthracyclines daunorubicin and doxorubicin but retain sensitivity to the Vinca alkaloids melphalan and mitomycin C. In addition , the MX2 cells display slight collateral sensitivity to bleomycin .

Multidrug resistance in mitoxantrone-selected HL-60 leukemia cells in the absence of P-glycoprotein overexpression. A multidrug-resistant variant of the human HL-60 promyelocytic leukemia cell line (HL-60/MX2) has been isolated in vitro by subculturing these cells in progressively increasing concentrations of mitoxantrone. The MX2 cells are cross-resistant to etoposide , teniposide , bisantrene , dactinomycin , 4'-(9-acridinylamino)methanesulfon-m-anisidide , and the anthracyclines daunorubicin and doxorubicin but retain sensitivity to the Vinca alkaloids melphalan and mitomycin C. In addition , the MX2 cells display slight collateral sensitivity to bleomycin . Despite being 30-35-fold less sensitive to mitoxantrone, net [14C]mitoxantrone accumulation at 60 min was reduced by only 10% in the mitoxantrone-resistant cells compared to the parental line. Furthermore, at later time points, e.g., 120 and 180 min, mitoxantrone accumulation in the MX2 cells exceeded that in HL-60 cells by 8.5 and 6.4%, respectively. No significant differences were observed between the sensitive and resistant cell lines in the initial (first 60 s) accumulation of mitoxantrone, and only minor (3-6%) enhancement of mitoxantrone efflux was detected in the resistant cell type. Monoclonal antibodies to P-glycoprotein had no detectable reactivity with membrane vesicles from either the sensitive or resistant cell types as determined by standard immunoblotting techniques. The mitoxantrone-resistant cells displayed a reciprocal translocation [rcpt(1;3)-(q21;p23)] not found in the sensitive parent, but there were no demonstrable double minute chromosomes or homogeneous staining regions in cells from either line. Thus, these mitoxantrone-resistant human leukemia cells display many features which are atypical for the "classic" multidrug resistance phenotype and should provide a useful model for the study of multidrug resistance which is not mediated by P-glycoprotein.

https://pubmed.ncbi.nlm.nih.gov/2568172/

de0dcd8c471a172926ff4fda7ff64e35

Combination of a betalactam antibiotic ( ampicillin or azlocillin ) or polymyxin B with rifampicin were studied with their administration in succession at various intervals in an experimental model of plague infection of albino mice .

[A method of sequential administration of antibiotics in preventive treatment of experimental plague in albino mice]. Combination of a betalactam antibiotic ( ampicillin or azlocillin ) or polymyxin B with rifampicin were studied with their administration in succession at various intervals in an experimental model of plague infection of albino mice . It was shown that when the administration of the betalactams or polymyxin B preceded the administration of rifampicin, the efficacy of the preventive therapy considerably increased. The time of the intervals was noted to be of importance and should be predetermined for every subsequent administration.

https://pubmed.ncbi.nlm.nih.gov/7857160/

4ff7eb5de90244479006b9ab113b7bef

Between August 1993 and September 1994 , 6010 patients were randomized to receive either reteplase ( n = 3004 ) or streptokinase ( n = 3006 ) .

Mega-trials and equivalence trials: experience from the INJECT study. As treatments for acute myocardial infarction have grown in number and effectiveness, the post-infarction mortality rate has fallen, and new therapies can provide only a small additional advantage in extending survival. To prove such an advantage of a new drug over its predecessors in the same drug class requires a trial of at least 20,000 patients. Proving 'equivalence' rather than superiority requires only 6000 patients. The INJECT trial was designed with the modest goal of determining whether the novel agent reteplase (recombinant plasminogen activator) has an effect on mortality equivalent to that of streptokinase. Between August 1993 and September 1994 , 6010 patients were randomized to receive either reteplase ( n = 3004 ) or streptokinase ( n = 3006 ) . Both treatment groups had similar rates of bleeding events, extension or recurrence of myocardial infarction, and in-hospital stroke followed by 6 months of disability. reteplase recipients had a lower incidence of cardiac events in hospital and fewer allergic reactions. Although the number of diagnosed haemorrhagic strokes was higher in reteplase recipients, more patients receiving streptokinase had strokes of uncertain aetiology. At 35 days, the mortality rate associated with reteplase use was approximately 0.5% lower than that associated with streptokinase administration, and the upper limit of the 90% confidence interval for the difference between these rates was a superiority of streptokinase of 0.73%. Because the INJECT trial provided a probability of 0.95 that the mortality rate associated with reteplase use would be either lower than that with streptokinase administration or at most 0.73% worse, reteplase and streptokinase were proved equivalent according to the trial definition and limits.

https://pubmed.ncbi.nlm.nih.gov/11824001/

c30fd03fd3ba28d6e84af21763f91461

In patients coinfected and treated for both HIV-1 and hepatitis C virus ( HCV ) , administration of ribavirin ( RBV ) may result in altered intracellular drug levels of nucleoside reverse transcriptase inhibitors through inhibition of inosine 5'-monophosphate dehydrogenase .

In vitro combination studies of tenofovir and other nucleoside analogues with ribavirin against HIV-1. In patients coinfected and treated for both HIV-1 and hepatitis C virus ( HCV ) , administration of ribavirin ( RBV ) may result in altered intracellular drug levels of nucleoside reverse transcriptase inhibitors through inhibition of inosine 5'-monophosphate dehydrogenase . Drug interactions between tenofovir and RBV were studied in vitro in order to provide insights into the safety of co-administration of tenofovir disoproxil fumarate (DF) and RBV in HCV/HIV-1-coinfected patients. In accordance with previous in vitro studies, strongly increased anti-HIV activity was observed when RBV was combined with didanosine (ddl). In contrast, low-level anti-HIV antagonism was observed when RBV was combined with either tenofovir or abacavir. Significantly stronger anti-HIV antagonism was observed when RBV was combined with either zidovudine, stavudine, emtricitabine or lamivudine. Thus, although tenofovir and ddl are both adenosine analogues, their in vitro interactions with RBV are markedly different. These results suggest a low potential for increased toxicity upon co-administration of tenofovir DF with RBV in patients.

https://pubmed.ncbi.nlm.nih.gov/15865229/

93bf31fa37027c4b544f7054db9cbb20

Previous treatments with rituximab and with rituximab plus high dose glucocorticoids , as well as with cyclophosphamide , azathioprine , plasma exchange , hyperbaric therapy , VAC therapy , prostacyclin , mycophenolate mofetil and surgery , had previously failed .

Sequential therapy with belimumab followed by rituximab in Sjögren's syndrome associated with B-cell lymphoproliferation and overexpression of BAFF: evidence for long-term efficacy. The overexpression of B-cell activating factor (BAFF) in mucosa-associated lymphoid tissue (MALT) may decrease the efficacy of rituximab treatment in Sjögren's syndrome (SS). Anti-CD20 therapy was effective on marginal zone B cells, in the murine model for human CD20 expression only when preceded by anti-BAFF therapy. The possible efficacy of a sequential anti-BAFF/anti-CD20 therapy in SS was investigated. ### methods We treated with belimumab, a monoclonal anti-BAFF antibody, and soon after with rituximab a patient with severe, refractory SS, parotid low-grade B-cell MALT lymphoma and cryoglobulinaemic vasculitis. Previous treatments with rituximab and with rituximab plus high dose glucocorticoids , as well as with cyclophosphamide , azathioprine , plasma exchange , hyperbaric therapy , VAC therapy , prostacyclin , mycophenolate mofetil and surgery , had previously failed . Treatment with belimumab was then given, but it also failed. A new course of rituximab (375 mg/m2; four weekly infusions) was started 49 days after the last infusion of belimumab. ### results This sequential belimumab-rituximab treatment was followed by a marked amelioration, with the complete and persistent regression of lymphoma and healing of a refractory skin ulcer. A full cycle of rituximab was then repeated 6 and 12 months later; no further treatment was given in the following 22 months up to now. Serum cryoglobulins and rheumatoid factor became persistently negative and serum BAFF and C4 persistently normal. No relevant side effects were noticed, except for a marked decrease in serum IgM. The follow up after belimumab-rituximab sequential therapy is now three and a half years. ### conclusions Therapy with belimumab followed by rituximab may be effective for SS-related B-cell lymphoproliferation. The efficacy and safety of the sequential or concomitant targeting of BAFF and CD20 deserves further evaluation in SS.

https://pubmed.ncbi.nlm.nih.gov/24802131/

e1adee12863f0b3a46ecd91b601ae0e4

The decision to test a triple combination has led to the development of Fansimef , a fixed combination with tablets containing 250 mg mefloquine , 500 mg sulfadoxine and 25 mg pyrimethamine .

[Current drugs for the treatment of tropical malaria]. The occurrence in the early 60's of stable resistance to chloroquine among Plasmodium falciparum strains in the Amazonas and on the Thai-Cambodian border has been a shock for all malariologists. This led to the search for new antimalarials without cross resistance with chloroquine. For each new drug, one of the major concerns was to define how rapidly parasites would develop resistance to this compound. Drug combinations were taken into consideration so as to achieve a delay in the appearance of resistance. The decision to test a triple combination has led to the development of Fansimef , a fixed combination with tablets containing 250 mg mefloquine , 500 mg sulfadoxine and 25 mg pyrimethamine . A very relevant delay in the development of resistance was found both in-vivo--in the P. berghei model--and in-vitro using P. falciparum. Fansimef has also been under investigations for malaria. Controlled clinical trials were performed in Africa, South America and South East Asia. The documentation for this new indication will be submitted to registration authorities in 1991. A preference alternative to continuous chemoprophylaxis is stand-by malaria treatment for travellers to regions where the malaria risk is relatively low. Stand-by treatment is under investigations in France and in Switzerland. In the search for alternative remedies against drug resistant P. falciparum malaria our attention was directed to Yingzhaosu, a new sesquiterpene peroxide of plant origin from traditional Chinese medicine. A short and convenient synthesis of this ring system gave access to a variety of structural analogues of Yingzhaosu.(ABSTRACT TRUNCATED AT 250 WORDS)

https://pubmed.ncbi.nlm.nih.gov/1998081/

60a28eefe9aa1c0cc21287ec8b322bb8

The aim of this study was to evaluate three active agents , bleomycin ( BLM ) , epirubicin and carboplatin in a new combination ( BECA ) in terms of feasibility , activity and toxicity in patients with recurrent and metastatic squamous cell carcinoma of the head and neck .

Bleomycin, epirubicin, carboplatin (BECA) in the treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck. The aim of this study was to evaluate three active agents , bleomycin ( BLM ) , epirubicin and carboplatin in a new combination ( BECA ) in terms of feasibility , activity and toxicity in patients with recurrent and metastatic squamous cell carcinoma of the head and neck . From April 1992 to February 1993 15 pts (12M/3F), median age 53 years, all pretreated (6 surgery + radiotherapy; 3 radiotherapy + chemotherapy; 6 radiotherapy), were treated with BLM 15 mg/m2 days 1-14; epirubicin 30 mg/m2 days 1-14 and carboplatin 300 mg/m2 day 1 every 28 days. In the 14 evaluable pts we observed 1 complete response, CR (7.1%), 4 partial responses, PR (28.6%), 5 stable disease, SD and 4 disease progression, PD with an overall response of 35.7%. The treatment was globally well tolerated, 1 pt with grade 3 leukopenia and 1 pt with grade 3 thrombocytopenia, 1 pt with grade 3 emesis and 1 pt with grade 3 mucositis. At the last follow-up the duration of CR was 34 months, the duration of PRs were respectively 22-10-10-7 months, but the SD ranged from 4 to 6 months. The overall median survival was 8 months (3-36), 14 for responders and 4 for non-responders. This final report seems to confirm the activity and efficacy of the BECA regimen, suitable for outpatient administration with an overall response equal to other more aggressive combinations.

https://pubmed.ncbi.nlm.nih.gov/9106022/

9ff502fca23aae0a92144e74f6e602cd

Survival Benefits of Second-line Axitinib Versus Everolimus After First Line Sunitinib Treatment in Metastatic Renal Cell Carcinoma .

Survival Benefits of Second-line Axitinib Versus Everolimus After First Line Sunitinib Treatment in Metastatic Renal Cell Carcinoma . Targeted therapies significantly improve clinical outcomes among patients with metastatic renal cell carcinoma (mRCC). Several new agents have been approved for first- and second-line use. However, there is a lack of compelling evidence comparing sequencing strategies, and available comparative data regarding the real-world effectiveness of different therapeutic sequences are limited. ### Materials And Methods We identified mRCC patients who initiated targeted therapy between January 1, 2008 and May 31, 2017 from the National Health Insurance Fund (NHIF) database of Hungary. Overall survival (OS) and duration of first-line treatment (DFT) were obtained for patients receiving sunitinib-everolimus, sunitinib-axitinib, or pazopanib-everolimus treatment sequences. OS of sunitinib-everolimus and sunitinib-axitinib sequences was also determined for patients having better or worse response to sunitinib first-line therapy. ### results Median OS was significantly longer among patients treated with sunitinib-axitinib compared to those receiving sunitinib-everolimus. Median DFT was also significantly longer in the sunitinib-axitinib vs. sunitinib-everolimus group. sunitinib-axitinib was associated with significantly longer median OS compared to sunitinib-everolimus in patients with better response to first-line sunitinib in the pooled sunitinib population. In patients with worse response to sunitinib, sunitinib-axitinib was associated with a trend towards greater OS compared to sunitinib-everolimus, but the difference did not reach statistical significance. ### conclusions In this nationwide database analysis, mRCC patients treated with the sunitinib-axitinib sequence had significantly longer OS compared to those receiving sunitinib-everolimus therapy. The OS benefits of second-line axitinib were consistent among patients with better response to sunitinib defined by DFT values.

https://pubmed.ncbi.nlm.nih.gov/32291570/

6ddb94cc099e39aa12aa362ef6bf389c

A phase II trial of cytarabine , cisplatin , and etoposide was conducted in 38 patients with refractory stage III and IV non-Hodgkin 's lymphoma .

Cytarabine, cisplatin, and etoposide chemotherapy for refractory non-Hodgkin's lymphoma. A phase II trial of cytarabine , cisplatin , and etoposide was conducted in 38 patients with refractory stage III and IV non-Hodgkin 's lymphoma . There were two complete and nine partial responses (32%) among 35 evaluable patients. Response rate in patients with large cell lymphoma was 45%. The dose-limiting toxic effect was myelosuppression in 66% of patients.

https://pubmed.ncbi.nlm.nih.gov/3802114/

4d51155fe860c0a0ffe3f7da6461332d

The combination of camrelizumab plus gemcitabine and cisplatin has a manageable toxicity profile and promising preliminary antitumour activity for this disease in treatment-naive patients .

Camrelizumab (SHR-1210) alone or in combination with gemcitabine plus cisplatin for nasopharyngeal carcinoma: results from two single-arm, phase 1 trials. Platinum-based doublet chemotherapy regimens, preferentially gemcitabine plus cisplatin, are generally considered the first-line standard of care for patients with recurrent or metastatic nasopharyngeal carcinoma. However, no consensus has been reached regarding treatment following progression after first-line therapy. camrelizumab (SHR-1210) is a humanised anti-programmed death-1 (anti PD-1) antibody. We present safety and preliminary antitumour activity of camrelizumab alone as second-line therapy in patients with recurrent or metastatic nasopharyngeal carcinoma and combined with gemcitabine and cisplatin as first-line therapy in this patient population. ### methods We report the results from two single-arm, phase 1 trials. Both trials included patients aged 18-70 years with histologically or cytologically confirmed nasopharyngeal carcinoma and confirmed metastatic disease or locoreginal recurrence, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients who received at least one previous line of treatment were enrolled at five academic hospitals in China into the dose-escalation and expansion trial to receive camrelizumab monotherapy intravenously at escalating doses of 1 mg/kg, 3 mg/kg, and 10 mg/kg, and a bridging dose of 200 mg per dose once every 2 weeks (monotherapy trial). Treatment-naive patients were enrolled from a single centre in China to receive six cycles of camrelizumab 200 mg (day 1), gemcitabine 1 g/m ### findings In the camrelizumab monotherapy trial, between March 31, 2016, and Sept 20, 2017, 121 patients were assessed for eligibility, of whom 93 patients were enrolled across the dose-escalation and expansion cohorts and received at least one dose of camrelizumab (safety population). 15 (16%) of 93 patients had treatment-related adverse events of grade 3 or 4, the most common of which were elevated conjugated bilirubin concentration (three [3%] of 93 patients), stomatitis, anaemia, and increased concentrations of aspartate aminotransferase, alanine aminotransferase, and total bilirubin, each of which occurred in two (2%) patients. Eight (9%) patients had a treatment-related serious adverse event. No dose-limiting toxic effects were observed during the dose-escalation phase. 31 (34%; 95% CI 24-44) of 91 evaluable patients on camrelizumab monotherapy had an overall response with a median follow-up of 9·9 months (IQR 8·1-11·7). In the camrelizumab combination trial, between April 18, 2017, and Aug 15, 2017, 24 patients were assessed for eligibility, of whom 23 patients were enrolled and treated (safety population). 20 (87%) of 23 patients had grade 3 or 4 treatment-related adverse events: neutropenia (13 [57%] of 23 patients), anaemia (11 [48%] patients), leucopenia (11 [48%] patients), thrombocytopenia (seven [30%] patients), oedema (two [9%] patients), hyponatraemia (two [9%] patients), hypochloraemia (one [4%] patients), and rash (one [4%] patient). Two patients had treatment-related serious adverse events. No treatment-related deaths occurred in these trials. 20 (91% [95% CI 72-97]) of 22 evaluable patients had an overall response with a median follow-up time of 10·2 months (IQR 9·7-10·8). ### interpretation camrelizumab is a well tolerated, potential treatment option for patients with recurrent or metastatic nasopharyngeal carcinoma. The combination of camrelizumab plus gemcitabine and cisplatin has a manageable toxicity profile and promising preliminary antitumour activity for this disease in treatment-naive patients . Randomised controlled trials are needed to further establish the role of immune checkpoint inhibition for nasopharyngeal carcinomas. ### funding Hengrui Medicine Co, Chinese National Natural Science Foundation project, Science and Technology Program of Guangdong, Pearl River Nova Program of Guangzhou.

https://pubmed.ncbi.nlm.nih.gov/30213452/

15545b66b51591bff60b6079fb33a85d

His infection failed to respond to combinations of surgery , fluconazole and itraconazole .

Experience with infection by Scedosporium prolificans including apparent cure with fluconazole therapy. Five cases of human infection with Scedosporium prolificans are described. There were two groups of patients. In group one, two were immunocompetent males with localized bone and joint infections, a man with post-traumatic septic arthritis, responded to surgical treatment alone and a boy with post-traumatic septic arthritis, appeared to respond to treatment with oral fluconazole, without surgery. The second group consisted of three immunocompromised patients. S. prolificans was isolated at autopsy from the lungs of one patient with acute leukaemia, and from the lungs, liver, and kidneys of another. Nosocomial S. prolificans infection of a synthetic vascular graft occurred in the third patient with end-stage renal failure on corticosteroid therapy for idiopathic hypereosinophilia. His infection failed to respond to combinations of surgery , fluconazole and itraconazole . All isolates of S. prolificans were resistant in vitro to antifungal drugs, including the first case, which responded clinically to fluconazole.

https://pubmed.ncbi.nlm.nih.gov/8945709/

1f85070a60bf9fba78c465d651b3df65

The protective effect of tianeptine against PTZ seizures was mitigated when tianeptine was administered with naloxone .

Anticonvulsant activity of the antidepressant drug, tianeptine, against pentylenetetrazole-induced seizures mitigates cognitive impairment in rats. Treatment of depression, a common comorbidity in patients with epilepsy, is restricted as certain antidepressants are considered to be proconvulsants. In contrast, anticonvulsant effects have been reported with some antidepressants. In the present study, the effect of tianeptine, an antidepressant, was evaluated against pentylenetetrazole (PTZ)-induced seizures, cognitive impairment and oxidative stress in rats. tianeptine was administered in three doses (20, 40 and 80 mg/kg) 30 min before PTZ (60 mg/kg, intraperitoneally). MK801, an N-methyl-D-aspartate antagonist, and naloxone, an opioid receptor antagonist, were administered with tianeptine to evaluate the involvement of N-methyl-D-aspartate and opioid receptors, respectively. Morris water maze, elevated plus maze and passive avoidance tests were performed for behavioural assessment. Brain malondialdehyde and reduced glutathione levels were estimated as markers of oxidative stress. tianeptine showed dose-dependent protection against PTZ seizures. Coadministration of tianeptine with MK801 potentiated the anticonvulsant effect of tianeptine. The protective effect of tianeptine against PTZ seizures was mitigated when tianeptine was administered with naloxone . Impairment of learning and memory by PTZ was prevented by tianeptine. tianeptine also attenuated the seizure-induced increased oxidative stress. Thus, tianeptine showed an anticonvulsant effect along with amelioration of seizure-induced cognitive impairment and oxidative stress. Hence, tianeptine could be a useful drug in epileptic patients with depression, with the advantage of having both antidepressant and antiepileptic effects.

https://pubmed.ncbi.nlm.nih.gov/27561095/

a85acb22dd609031341e06c9b9af4fea

Twenty-one trials involving 3646 patients were included : 11 trials using beta-blockers ( 6 drugs ; 866 patients ) , 6 clonidine or mivazerol ( 614 patients ) , 3 diltiazem or verapamil ( 121 patients ) , and 1 nitroglycerin ( 45 patients ) .

Pharmacologic myocardial protection in patients undergoing noncardiac surgery: a quantitative systematic review. A number of drugs have been tested in clinical trials to decrease cardiac complications in patients undergoing noncardiac surgery. To compare the results of these studies, we conducted a quantitative systematic review. Medline, Embase, and Cochrane databases were searched for randomized trials that assessed myocardial ischemia, myocardial infarction, 30-day cardiac mortality, and adverse effects. Data were combined using a fixed-effect model and expressed as Peto odds ratios (OR) with 95% confidence interval (CI) and as numbers-needed-to-treat/harm (NNT/H). Twenty-one trials involving 3646 patients were included : 11 trials using beta-blockers ( 6 drugs ; 866 patients ) , 6 clonidine or mivazerol ( 614 patients ) , 3 diltiazem or verapamil ( 121 patients ) , and 1 nitroglycerin ( 45 patients ) . All trials had an inactive control; there were no direct comparisons. beta-blockers decreased ischemic episodes during surgery (7.6% versus 20.2% with placebo; OR 0.32 [95% CI, 0.17-0.58]; NNT 8) and after surgery (15.2% versus 27.9% with control; OR 0.46 [95% CI, 0.26-0.81]; NNT 8). alpha(2)-agonists decreased ischemia during surgery only (19.4% versus 32.8%; OR 0.47 [95% CI, 0.33-0.68]; NNT 7). beta-blockers reduced the risk of myocardial infarction (0.9% versus 5.2%; OR 0.19 [95% CI, 0.08-0.48]; NNT 23) but only when 2 trials with high-risk patients were included. The effect of alpha(2)-agonists on myocardial infarction was not significant (6.1% versus 7.3%; OR 0.85 [95% CI, 0.62-1.14]). beta-blockers significantly decreased the risk of cardiac death from 3.9% to 0.8% (OR 0.25 [95% CI, 0.09-0.73], NNT 32). alpha(2)-agonists significantly decreased the risk of cardiac death from 2.3% to 1.1% (OR 0.50 [95% CI, 0.28-0.91], NNT 83). For calcium channel blockers and nitroglycerin, evidence of any benefit was lacking. The most common adverse effect was bradycardia, which occurred in 24.5% of patients receiving a beta adrenergic blocker versus 9.1% of controls (OR 3.76 [95% CI, 2.45-5.77], NNH 6).

https://pubmed.ncbi.nlm.nih.gov/12933373/

a9a3f350e52c4bb1da0057b2840d8031

The sensitivity of human neuroblastoma-derived cell lines , cell line-derived , and patient-derived xenograft ( PDX ) models with varying ALK statuses to crizotinib combined with topotecan and cyclophosphamide ( topo/cyclo ) was examined .

Crizotinib Synergizes with Chemotherapy in Preclinical Models of Neuroblastoma. The presence of an ALK aberration correlates with inferior survival for patients with high-risk neuroblastoma. The emergence of ALK inhibitors such as crizotinib has provided novel treatment opportunities. However, certain ALK mutations result in de novo crizotinib resistance, and a phase I trial of crizotinib showed a lack of response in patients harboring those ALK mutations. Thus, understanding mechanisms of resistance and defining circumvention strategies for the clinic is critical. ### Experimental Design The sensitivity of human neuroblastoma-derived cell lines , cell line-derived , and patient-derived xenograft ( PDX ) models with varying ALK statuses to crizotinib combined with topotecan and cyclophosphamide ( topo/cyclo ) was examined . Cultured cells and xenografts were evaluated for effects of these drugs on proliferation, signaling, and cell death, and assessment of synergy. ### results In neuroblastoma murine xenografts harboring the most common ALK mutations, including those mutations associated with resistance to crizotinib (but not in those with wild-type ALK), crizotinib combined with topo/cyclo enhanced tumor responses and mouse event-free survival. crizotinib + topo/cyclo showed synergistic cytotoxicity and higher caspase-dependent apoptosis than crizotinib or topo/cyclo alone in neuroblastoma cell lines with ALK aberrations (mutation or amplification). ### conclusions Combining crizotinib with chemotherapeutic agents commonly used in treating newly diagnosed patients with high-risk neuroblastoma restores sensitivity in preclinical models harboring both sensitive ALK aberrations and de novo-resistant ALK mutations. These data support clinical testing of crizotinib and conventional chemotherapy with the goal of integrating ALK inhibition into multiagent therapy for ALK-aberrant neuroblastoma patients.

https://pubmed.ncbi.nlm.nih.gov/26438783/

95b15547d7d7b7581b23bb1097bf9780

Patients were randomised to either receive additional tretinoin ( 45mg/m(2)/day ) for 12 weeks ( arm A ) , or peg-interferon and ribavirin alone ( arm B ) .

No beneficial effect of all-trans retinoic acid in previous non-responder patients with chronic hepatitis C: the ATRACTION study, a phase II randomised trial. Preclinical data suggested all-trans retinoic acid (tretinoin) as a potential antiviral agent against chronic hepatitis C infection. ### aims To assess efficacy, safety, and tolerability of tretinoin in combination with peg-interferon and ribavirin in genotype-1 infected patients with prior non-response. ### method We performed an open-label multicentre clinical trial. Patients were randomised to either receive additional tretinoin ( 45mg/m(2)/day ) for 12 weeks ( arm A ) , or peg-interferon and ribavirin alone ( arm B ) . Primary endpoint was the slope of the third phase of viral decline (Mδ) as determined in an established kinetic model known to correlate with treatment outcome. Secondary endpoints were additional kinetic parameters, viral response rates, safety, and tolerability. ### results 27 patients in arm A and 30 patients in arm B were treated per protocol until week 12. Viral kinetic parameters did not differ. Rates of early virological response (>2log10 drop at week 12) were similar (10/27 versus 11/30 patients). In arm A, patients experienced a higher rate and intensity of adverse events, most commonly skin and mucosal dryness, and headache. ### conclusion Addition of tretinoin was safe and acceptably well tolerated. However, it did not influence viral kinetics and thus cannot be further considered as a treatment option.

https://pubmed.ncbi.nlm.nih.gov/23245590/

387e1c79c33690ab0ea431972cc837d3

This study sought to determine the efficacy and toxicity of weekly paclitaxel and carboplatin in CUP .

Results of a phase II study of weekly paclitaxel plus carboplatin in advanced carcinoma of unknown primary origin: a reasonable regimen for the community-based clinic? Optimal treatment for cancer of unknown primary (CUP) can challenge clinicians. This study sought to determine the efficacy and toxicity of weekly paclitaxel and carboplatin in CUP . Forty-two subjects enrolled. Treatment was intravenous paclitaxel (80 mg/m2) plus carboplatin (AUC = 2) on Days 1, 8, and 15 every 28 days. Seven (18 percent) responded (complete = 2, partial = 5); median survival was 8.5 months; estimated survival (12 and 24-month) was 33 and 17 percent, respectively. Median time to progression was 3.7 months, and estimated progression-free survival (12 and 24 months) was 14 and 7 percent, respectively. Median duration of response was 17.3 months. This combination produced modest antitumor activity in advanced CUP.

https://pubmed.ncbi.nlm.nih.gov/17364554/

f0b62b80ed586651ac34c24cba622bb2

To investigate the presence of extended spectrum and metallo β-lactamases ( MBLs ) in Pseudomonas aeruginosa isolates which are resistant to imipenem and ceftazidime that were isolated in a hospital in Mexico .

Unusual diversity of acquired β-lactamases in multidrug-resistant Pseudomonas aeruginosa isolates in a Mexican hospital. To investigate the presence of extended spectrum and metallo β-lactamases ( MBLs ) in Pseudomonas aeruginosa isolates which are resistant to imipenem and ceftazidime that were isolated in a hospital in Mexico . ### results Pulsed-field gel electrophoresis (PFGE) revealed the presence of four clonal types among the 14 isolates. All these genes were found either alone or simultaneously in the P. aeruginosa strains in the following five different arrangements: ; ; ; ; and . Class 1 integrons were detected and contained the cassettes bla(GES-5) and bla(OXA-2), but not that of bla(VIM). bla(VIM) genes occurred only in the chromosome, while bla(GES-5) was located in the chromosome and in the plasmids. ### conclusions To our knowledge, this is the first description of P. aeruginosa strains simultaneously producing the VIM-2 and VIM-11 variants, and the combination of GES-5 and MBL carbapenemases, which determines a major challenge for the clinical microbiology laboratory and a remarkable epidemiological risk for the nosocomial spread of multidrug-resistant determinants.

https://pubmed.ncbi.nlm.nih.gov/22554004/

1e54b672b78e32994abee52c7548ec9f

The patient achieved complete remission after two cycles of chemotherapy of daunorubicin , cytarabine and etoposide .

Trisomy 21 with t(5; 11) chromosomal translocation as new unfavorable cytogenetic abnormalities in pediatric acute myeloid leukemia type M2: One case report of nine-year follow-up and literature review. We report one case of pediatric acute myeloid leukemia type 2 (AML-M2) who presented with karyotypic aberration of trisomy 21 with the t(5;11) chromosomal translocation. The patient achieved complete remission after two cycles of chemotherapy of daunorubicin , cytarabine and etoposide . Then, follow-up cytogenetic analysis from bone marrow cell cultures demonstrated a normal karyotype of 46, XY. After 9 years, the patient relapsed and the karyotypic abnormalities of trisomy 21 with t(5;11) reappeared. It was concluded that trisomy 21 with t(5; 11) is a new unfavorable cytogenetic aberration in AML-M2.

https://pubmed.ncbi.nlm.nih.gov/29058300/

4f164dbb352c4d132b31c07b28784632

We included 10 pharmacological ( modafinil , intravenous immunoglobulin ( IVIg ) , pyridostigmine , lamotrigine , amantadine , prednisone ) and three non-pharmacological ( muscle strengthening , rehabilitation in a warm climate ( that is temperature ± 25 ° C , dry and sunny ) and a cold climate ( that is temperature ± 0 ° C , rainy or snowy ) , static magnetic fields ) studies with a total of 675 participants with PPS in this review .

Treatment for postpolio syndrome. Postpolio syndrome (PPS) may affect survivors of paralytic poliomyelitis and is characterised by a complex of neuromuscular symptoms leading to a decline in physical functioning. The effectiveness of pharmacological treatment and rehabilitation management in PPS is not yet established. This is an update of a review first published in 2011. ### objectives To systematically review the evidence from randomised and quasi-randomised controlled trials for the effect of any pharmacological or non-pharmacological treatment for PPS compared to placebo, usual care or no treatment. ### Search Methods We searched the following databases on 21 July 2014: Cochrane Neuromuscular Disease Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO and CINAHL Plus. We also checked reference lists of all relevant articles, searched the Database of Abstracts of Reviews of Effects (DARE), the Health Technology Assessment (HTA) Database and trial registers and contacted investigators known to be involved in research in this area. ### Selection Criteria Randomised and quasi-randomised trials of any form of pharmacological or non-pharmacological treatment for people with PPS. The primary outcome was self perceived activity limitations and secondary outcomes were muscle strength, muscle endurance, fatigue, pain and adverse events. ### Data Collection And Analysis We used standard methodological procedures expected by The Cochrane Collaboration. ### Main Results We included 10 pharmacological ( modafinil , intravenous immunoglobulin ( IVIg ) , pyridostigmine , lamotrigine , amantadine , prednisone ) and three non-pharmacological ( muscle strengthening , rehabilitation in a warm climate ( that is temperature ± 25 ° C , dry and sunny ) and a cold climate ( that is temperature ± 0 ° C , rainy or snowy ) , static magnetic fields ) studies with a total of 675 participants with PPS in this review . None of the included studies were completely free from any risk of bias, the most prevalent risk of bias being lack of blinding.There was moderate- and low-quality evidence that IVIg has no beneficial effect on activity limitations in the short term and long term, respectively, and inconsistency in the evidence for effectiveness on muscle strength. IVIg caused minor adverse events in a substantial proportion of the participants. Results of one trial provided very low-quality evidence that lamotrigine might be effective in reducing pain and fatigue, resulting in fewer activity limitations without generating adverse events. Data from two single trials suggested that muscle strengthening of thumb muscles (very low-quality evidence) and static magnetic fields (moderate-quality evidence) are safe and beneficial for improving muscle strength and pain, respectively, with unknown effects on activity limitations. Finally, there was evidence varying from very low quality to high quality that modafinil, pyridostigmine, amantadine, prednisone and rehabilitation in a warm or cold climate are not beneficial in PPS. ### Authors Conclusions Due to insufficient good-quality data and lack of randomised studies, it was impossible to draw definite conclusions about the effectiveness of interventions for PPS. Results indicated that IVIg, lamotrigine, muscle strengthening exercises and static magnetic fields may be beneficial but need further investigation to clarify whether any real and meaningful effect exists.

https://pubmed.ncbi.nlm.nih.gov/25984923/

dee911198ad44dbe0c7a3ba2c021ac37

Protection against CsA-induced PST cell death was afforded by reduction in extracellular calcium levels in the media or addition of the calcium entry antagonists : verapamil , nifedipine or diltiazem .

Mechanisms of cyclosporine A toxicity in defined cultures of renal tubule epithelia: a role for cysteine proteases. The mechanisms of toxicity of cyclosporine A (CsA) were studied in primary cultures of individually microdissected rabbit and human renal tubules of proximal and distal regions of the nephron. A direct toxic effect of CsA on renal tubule epithelia was demonstrated using nigrosine uptake and LDH release as indicators of cell death. Proximal convoluted tubules (PCT) and proximal straight tubules (PST) were shown to be highly sensitive, while thick ascending limbs of Henle (TAL) were much less sensitive and cortical collecting tubules (CCT) relatively resistant. The effects of CsA were time and dose dependent over the range 50 ng/ml to 100 micrograms/ml. Protection against CsA-induced PST cell death was afforded by reduction in extracellular calcium levels in the media or addition of the calcium entry antagonists : verapamil , nifedipine or diltiazem . In addition, treatment with the cysteine protease inhibitor, E64, attenuated CsA-induced cell damage. A role for the lysosomal cysteine proteases (cathepsins), however, was ruled out on the basis of identical activity levels in all cell types; no beneficial effects of lysosomal enzyme depletion and no evidence of lysosomal rupture prior to death. By contrast, a role for the cytoplasmic, calcium-dependent cysteine protease calpain was suggested since activity levels were significantly higher in PST than CCT cultures and were inducible by CsA.

https://pubmed.ncbi.nlm.nih.gov/1802407/

a3ea338f47124692a7ae19b005445176

This synergy was abrogated through siRNA knockdown of IkB. The synergistic effect of combining selinexor and bortezomib in vitro provides rationale for further investigation of this combination treatment for patients with high-risk neuroblastoma .

XPO1 inhibition with selinexor synergizes with proteasome inhibition in neuroblastoma by targeting nuclear export of IkB. Across many cancer types in adults, upregulation of the nuclear-to-cytoplasmic transport protein Exportin-1 (XPO1) correlates with poor outcome and responsiveness to selinexor, an FDA-approved XPO1 inhibitor. Similar data are emerging in childhood cancers, for which selinexor is being evaluated in early phase clinical studies. Using proteomic profiling of primary tumor material from patients with high-risk neuroblastoma, as well as gene expression profiling from independent cohorts, we have demonstrated that XPO1 overexpression correlates with poor patient prognosis. Neuroblastoma cell lines are also sensitive to selinexor in the low nanomolar range. Based on these findings and knowledge that bortezomib, a proteasome inhibitor, blocks degradation of XPO1 cargo proteins, we hypothesized that combination treatment with selinexor and bortezomib would synergistically inhibit neuroblastoma cellular proliferation. We observed that selinexor promoted nuclear retention of IkB and that bortezomib augmented the ability of selinexor to induce cell-cycle arrest and cell death by apoptosis. This synergy was abrogated through siRNA knockdown of IkB. The synergistic effect of combining selinexor and bortezomib in vitro provides rationale for further investigation of this combination treatment for patients with high-risk neuroblastoma .

https://pubmed.ncbi.nlm.nih.gov/33975179/

0eb278770a9abdd4d268af47db1c9aa1

Therapy included 4 or 8 intensive therapy elements N1 ( Etoposide 125 mg/m2 day 1 - 4 , Vindesine 3 mg/m2 day 1 , Cisplatin 40 mg/m2 day 1 - 4 ) and N2 ( Vincristine 1.5 mg/m2 day 1 + 8 , Dacarbazine 200 mg/m2 day 1 - 5 , Ifosfamide 1500 mg/ m2 day 1 - 5 , Doxorubicin 30 mg/m2 day 6 + 7 ) in alternating order .

[Kinetics of myelopoietic regeneration and mobilization of CD34-positive cells within the scope of the NB90 Neuroblastoma Therapy Study]. Hematological and clinical data of 14 children with neuroblastoma treated according to the German neuroblastoma therapy study NB 90 were analyzed. Therapy included 4 or 8 intensive therapy elements N1 ( Etoposide 125 mg/m2 day 1 - 4 , Vindesine 3 mg/m2 day 1 , Cisplatin 40 mg/m2 day 1 - 4 ) and N2 ( Vincristine 1.5 mg/m2 day 1 + 8 , Dacarbazine 200 mg/m2 day 1 - 5 , Ifosfamide 1500 mg/ m2 day 1 - 5 , Doxorubicin 30 mg/m2 day 6 + 7 ) in alternating order . The hematological recovery was studied after 86 therapy elements N1/N2. G-CSF had been given in 23 therapy courses, while no cytokine was administered in 63 therapy courses. Mobilization of CD34+ cells was studied in 13 therapy courses with G-CSF. Severe myelosuppression with an absolute neutrophil count < 500/microL was noted 2-4 weeks after each therapy element. The use of G-CSF did not prevent, but shortened neutropenia. There was no difference in the number of infections nor time delay of therapy between the courses with or without G-CSF. In 11 therapy courses G-CSF was started on the day following the last chemotherapy dose (N1: day 5; N2: day 9). In 12 therapy courses G-CSF was given delayed, starting day 12 after the initiation of therapy. Kinetics of granulocyte recovery was similar in the early or delayed application of G-CSF. Neutrophil recovery after the therapy element N1 was earlier and faster compared to that of therapy element N2. The more rapid rise of the neutrophils after the N1 element was accompanied by an effective mobilization of CD34+ cells. Taking into account the limitations of this retrospective study, the data may help to optimize the application of G-CSF in a very intensive therapy study like NB90.

https://pubmed.ncbi.nlm.nih.gov/9340428/

0dd21b716b4b6f9c9648a6933f01760b

Mycophenolate mofetil , the prodrug of mycophenolic acid , is widely used for maintenance immunosuppressive therapy in renal transplant recipients .

Influence of renal graft function on mycophenolic acid pharmacokinetics during the early period after kidney transplant. Mycophenolate mofetil , the prodrug of mycophenolic acid , is widely used for maintenance immunosuppressive therapy in renal transplant recipients . The effect of renal graft function on mycophenolic acid pharmacokinetics parameters is still controversial. The aim of this study is to investigate the impact of renal graft function on mycophenolic acid pharmacokinetics during the early posttransplant period. ### Materials And Methods Our study was done on 13 patients with severe renal impairment (glomerular filtration rate < 30 mL/min, impaired group) and 13 patients with normal graft function (glomerular filtration rate < 70 mL/min, control group), at a steady mycophenolic acid plasma level, during the first month after transplant. All patients received a fixed dose of mycophenolate mofetil (1 g twice daily) in combination with cyclosporine and steroids. mycophenolic acid plasma levels were determined by a validated high-performance liquid chromatography method. mycophenolic acid area under the time concentration curve from 0 to 12 hours and apparent mycophenolic acid plasma clearance (CL/f) were measured for each patient. ### results mycophenolic acid area under the time-concentration curve (0-12 h), mycophenolic acid area under the time-concentration curve (6-10 h), first peak concentration (Cmax1), and secondary peak concentration (Cmax2) were higher in the impaired group, while mycophenolic acid plasma clearance was higher in the control group (P < .05). Trough levels (C0) were similar for both groups (P < .05). There was a negative correlation between glomerular filtration rate and area under the time-concentration curve (r=-0.422, P = .04), while there was a positive correlation between glomerular filtration rate and mycophenolic acid plasma clearance (r=0.463, P = .02). ### conclusions mycophenolic acid pharmacokinetics parameters in normal renal function patients and severe renal impairment patients are different, and renal graft function correlates with total mycophenolic acid area under the time-concentration curve and apparent mycophenolic acid plasma clearance. However, the necessity of dosage adjustment based on renal graft function requires further studies.

https://pubmed.ncbi.nlm.nih.gov/19338489/

1aaf0d88c992f34d862f98e4754879c3

Efficacy and safety of tacrolimus and low-dose prednisone in Chinese children with steroid-resistant nephrotic syndrome .

Efficacy and safety of tacrolimus and low-dose prednisone in Chinese children with steroid-resistant nephrotic syndrome . tacrolimus, a calcineurin inhibitor, is recommended by the recent guidelines from the Kidney Disease Improving Global Outcomes Group as the first-line treatment for steroid-resistant nephrotic syndrome (SRNS), but its clinical application in China is still limited. We investigated the efficacy and safety of tacrolimus combined with low-dose corticosteroids in a population of Chinese children with SRNS. ### methods In this prospective non-randomized, non-controlled study, Chinese children with SRNS who failed the previous full-dose prednisone treatment were given tacrolimus (0.1 mg/kg/day) and low-dose prednisone (0.25-0.50 mg/kg/day). We compared the overall remission rate (ORR) and adverse events in the follow-up period with this therapeutic regimen. ### results A total of 76 children were enrolled into the study with an average follow-up period of 18 ± 6 months (maximum 36 months). ORR achieved by the first, third, and sixth months was 94.7%, 94.7%, and 96.0%, respectively. All patients who attained an initial tacrolimus trough concentration (FK506C ### conclusions Combination of tacrolimus and low-dose prednisone was safe and effective for the treatment of children with SRNS, with high remission rates observed as early as the first month. Relapses were infrequent, but tended to increase significantly with decreases in FK506C

https://pubmed.ncbi.nlm.nih.gov/31049814/

5bad8c80ea7a45c05dd96dec6ee34e0b

Vandetanib inhibited hENT1 , hENT2 , hCNT1 , hCNT2 , and hCNT3 , whereas erlotinib inhibited hENT1 and hCNT3 and gefitinib inhibited hENT1 and hCNT1 .

Erlotinib, gefitinib, and vandetanib inhibit human nucleoside transporters and protect cancer cells from gemcitabine cytotoxicity. Combinations of tyrosine kinase inhibitors (TKI) with gemcitabine have been attempted with little added benefit to patients. We hypothesized that TKIs designed to bind to ATP-binding pockets of growth factor receptors also bind to transporter proteins that recognize nucleosides. ### Experimental Design TKI inhibition of uridine transport was studied with recombinant human (h) equilibrative (E) and concentrative (C) nucleoside transporters (hENT, hCNT) produced individually in yeast. TKIs effects on uridine transport, gemcitabine accumulation, regulation of hENT1 activity, and cell viability in the presence or absence of gemcitabine were evaluated in human pancreatic and lung cancer cell lines. ### results erlotinib, gefitinib and vandetanib inhibited [(3)H]uridine transport in yeast and [(3)H]uridine and [(3)H]gemcitabine uptake in the four cell lines. Treatment of cell lines with erlotinib, gefitinib, or vandetanib for 24 hours reduced hENT1 activity which was reversed by subsequent incubation in drug-free media for 24 hours. Greater cytotoxicity was observed when gemcitabine was administered before erlotinib, gefitinib, or vandetanib than when administered together and synergy, evaluated using the CalcuSyn Software, was observed in three cell lines resulting in combination indices under 0.6 at 50% reduction of cell growth. ### conclusions Vandetanib inhibited hENT1 , hENT2 , hCNT1 , hCNT2 , and hCNT3 , whereas erlotinib inhibited hENT1 and hCNT3 and gefitinib inhibited hENT1 and hCNT1 . The potential for reduced accumulation of nucleoside chemotherapy drugs in tumor tissues due to inhibition of hENTs and/or hCNTs by TKIs indicates that pharmacokinetic properties of these agents must be considered when scheduling TKIs and nucleoside chemotherapy in combination.

https://pubmed.ncbi.nlm.nih.gov/24170548/

21d29533c154290f74bdd47153d6d15c

Genistein reduced Bcl-2 phosphorylation triggered by paclitaxel and vincristine without changing Bax protein expression .

Genistein inversely affects tubulin-binding agent-induced apoptosis in human breast cancer cells. genistein, a natural isoflavone phytoestrogen present in soybeans, has been extensively studied as a chemopreventive or therapeutic agent in several types of cancer. The traditional Asian diet is rich in soy products may explain in part why the incidence of breast cancer in Asian women is relatively low. To improve therapeutic benefits, we investigated the combination of genistein with chemotherapeutic agents in phenotypically dissimilar human breast cancer cells, MCF-7 and MDA-MB-231, in which estrogen receptor expression is positive and negative, respectively. In the present study, genistein significantly decreased cell apoptosis induced by tubulin-binding agents, paclitaxel and vincristine. FACScan analysis revealed that genistein also diminished the accumulation of the G2/M phase in the cell cycle caused by tubulin-binding agents. In situ staining of microtubules revealed that genistein could decrease paclitaxel-induced tubulin polymerization. However, in vivo tubulin polymerization assay revealed that simultaneous treatment of genistein did not change the tubulin/microtubule dynamic. Genistein reduced Bcl-2 phosphorylation triggered by paclitaxel and vincristine without changing Bax protein expression . p53 and p21 expression, monitored by Western blotting, was not altered by genistein. However, the expression of cyclin B1 and CDC2 kinase was markedly decreased in combination with genistein. In conclusion, genistein inversely affected tubulin-binding agent-induced apoptosis via down-regulation of cyclin B1/CDC2 kinase expression resulting in reduced Bcl-2 phosphorylation.

https://pubmed.ncbi.nlm.nih.gov/15135300/

42fec02a03a414794d003db8641e9586

Combinations of antibiotics with gentamicin or rifampin in vitro did not significantly alter the killing rate but prevented emergence of subpopulations resistant to the latter .

Therapy of methicillin-resistant Staphylococcus epidermidis experimental endocarditis. Antibiotic therapy of methicillin-resistant Staphylococcus epidermidis endocarditis was investigated with the rabbit endocarditis model. Time-kill studies in vitro demonstrated that gentamicin and rifampin had the most rapid early bactericidal rates. With rifampin alone, rifampin-resistant subpopulations emerged. Combinations of antibiotics with gentamicin or rifampin in vitro did not significantly alter the killing rate but prevented emergence of subpopulations resistant to the latter . In the rabbit endocarditis model, gentamicin and vancomycin were the most effective single antibiotic regimens in terms of ability to reduce the bacterial densities on cardiac valve vegetations. Five treatment regimens were equally effective, including vancomycin, gentamicin, vancomycin plus rifampin or gentamicin, and rifampin plus gentamicin. The three-drug combination of vancomycin, rifampin, and gentamicin did not significantly improve the results. cephalothin therapy was significantly less effective than any of the regimens noted above. It was no more effective than no treatment at 2 days and was only slightly more effective at 4 days. This result with cephalothin treatment was not predicted by routine types of in vitro antibiotic susceptibility testing. Treatment of rabbits with methicillin or cephalothin was associated with an increase in the subpopulation of bacteria resistant to the respective drugs. A number of regimens show potential for therapy of these infections, including vancomycin plus rifampin or gentamicin, rifampin plus gentamicin, and vancomycin alone.

https://pubmed.ncbi.nlm.nih.gov/6919570/

830ca5507df108bc2bbf567931cc475c

This Nordic multicenter phase II study evaluated the efficacy and safety of oxaliplatin combined with the Nordic bolus schedule of fluorouracil ( FU ) and folinic acid ( FA ) as first-line treatment in metastatic colorectal cancer .

Multicenter phase II study of Nordic fluorouracil and folinic acid bolus schedule combined with oxaliplatin as first-line treatment of metastatic colorectal cancer. This Nordic multicenter phase II study evaluated the efficacy and safety of oxaliplatin combined with the Nordic bolus schedule of fluorouracil ( FU ) and folinic acid ( FA ) as first-line treatment in metastatic colorectal cancer . ### Patients And Methods Eighty-five patients were treated with oxaliplatin 85 mg/m(2) as a 2-hour infusion on day 1, followed by a 3-minute bolus injection with FU 500 mg/m(2) and, 30 minutes later, by a bolus injection with FA 60 mg/m(2) every second week. The same doses of FU and FA were also given on day 2. ### results Fifty-one of 82 assessable patients achieved a complete (n = 4) or partial (n = 47) response, leading to a response rate of 62% (95% CI, 52% to 72%). Nineteen patients showed stable disease, and 12 patients had progressive disease. Thirty-eight of the 51 responses were radiologically confirmed 8 weeks later (confirmed response rate, 46%; 95% CI, 36% to 58%). The estimated median time to progression was 7.0 months (95% CI, 6.3 to 7.7 months), and the median overall survival was 16.1 months (95% CI, 12.7 to 19.6 months) in the intent-to-treat population. Neutropenia was the main adverse event, with grade 3 to 4 toxicity in 58% of patients. Febrile neutropenia developed in seven patients. Nonhematologic toxicity consisted mainly of neuropathy (grade 3 in 11 patients and grade 2 in another 27 patients). ### conclusion oxaliplatin combined with the bolus Nordic schedule of FU+FA (Nordic FLOX) is a well-tolerated, effective, and feasible bolus schedule as first-line treatment of metastatic colorectal cancer that yields comparable results compared with more complex schedules.

https://pubmed.ncbi.nlm.nih.gov/14701765/

d4d5aaea92988a2d24eba988296fde7f

In xenograft studies , the combination of trastuzumab plus letrozole is equally effective in inhibiting growth of MCF-7Ca tumors as letrozole alone .

Trastuzumab reverses letrozole resistance and amplifies the sensitivity of breast cancer cells to estrogen. In this study, we investigated adaptive mechanisms associated with aromatase inhibitor (AI) resistance in breast cancer cells and show that sensitivity to AIs can be extended through dual inhibition of estrogen receptor (ER) and human epidermal receptor-2 (Her-2) signaling. We used human ER-positive breast cancer cells stably transfected with the aromatase gene (MCF-7Ca). These cells grow as tumors in nude mice and are inhibited by AIs. Despite continued treatment, tumors eventually become insensitive to AI letrozole. The cells isolated from these long-term letrozole-treated tumors (LTLT-Ca) were found to have decreased ERalpha levels. Our results suggest that LTLT-Ca cells survive estrogen deprivation by activation of Her-2/mitogen-activated protein kinase (MAPK) pathway. Here, we show that trastuzumab (antibody against Her-2; IC(50) = 0.4 mg/mL) was very effective in restoring the ERalpha levels and sensitivity of LTLT-Ca cells to endocrine therapy by down-regulation of Her-2/MAPK pathway and up-regulation of ERalpha. In contrast, trastuzumab was ineffective in the parental hormone-responsive MCF-7Ca cells (IC(50) = 4.28 mg/mL) and xenografts. By blocking Her-2, trastuzumab also up-regulates ERalpha and aromatase expression and hypersensitized MCF-7Ca cells to E(2). We show that trastuzumab is beneficial in hormone-refractory cells and xenografts by restoring ER, implicating Her-2 as a negative regulator of ERalpha. In xenograft studies , the combination of trastuzumab plus letrozole is equally effective in inhibiting growth of MCF-7Ca tumors as letrozole alone . However, on the acquisition of resistance and increased Her-2 expression, the combination of letrozole plus trastuzumab provided superior benefit over letrozole or trastuzumab alone.

https://pubmed.ncbi.nlm.nih.gov/19190349/

5a9c33040304bf924aecd9aea4f0e248

Reduction of rpS6 expression in Jurkat and HeLa cells attenuated apoptosis induced by TRAIL , but not those by other cell death signals , including tumor necrosis factor-alpha and cycloheximide , etoposide , doxorubicin , tunicamycin and staurosporine .

Ribosomal protein S6 is a selective mediator of TRAIL-apoptotic signaling. TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is a potent inducer of apoptosis in tumor cells and holds a promise as a therapeutic agent against cancer. To elucidate the death signaling evoked by TRAIL, we performed a functional genetic screening and rescued TRAIL-resistant Jurkat clones harboring ribosomal protein S6 (rpS6) cDNA in anti-sense frame. Reduction of rpS6 expression in Jurkat and HeLa cells attenuated apoptosis induced by TRAIL , but not those by other cell death signals , including tumor necrosis factor-alpha and cycloheximide , etoposide , doxorubicin , tunicamycin and staurosporine . Death receptor (DR) 4, but not DR5, was downregulated in rpS6 knockdown cells. Conversely, the sensitivity to TRAIL was increased by the ectopic expression of wild-type rpS6 and further by phospho-defective rpS6 mutant (S6-SS235,6AA), but not by phospho-mimic rpS6 mutant (S6-SS235,6DD). Also, unphosphorylatable rpS6 knock-in mouse embryo fibroblasts (rpS6(P-/-) MEFs) were more sensitive to TRAIL than control MEFs. In addition, SKHep-1 tumor cells, which express less phospho-rpS6 and are more sensitive to TRAIL than other tumor cells, became effectively desensitized to TRAIL after rpS6 knockdown. These results suggest that rpS6, especially in its unphosphorylated form, is a selective mediator of TRAIL-induced apoptosis.

https://pubmed.ncbi.nlm.nih.gov/18362888/

5a23872a890b090d0faad993a4ddcad4

The patient showed a substantial response to treatment with a combination of antimicrobial therapies consisting of clarithromycin , amikacin , and cefoxitin for 6 months .

Identification of Cutaneous Mycobacterium massiliense Infections Associated with Repeated Surgical Procedures. Mycobacterium massiliense, an emerging pathogen that is increasingly reported as a causative agent in infections occurring during medical procedures, is difficult to be identified using conventional methods. Here we report the case of a cutaneous M. massiliense infection that was associated with repeated surgical procedures and that was identified via a comparative sequence analysis of rpoB and hsp65. The patient showed a substantial response to treatment with a combination of antimicrobial therapies consisting of clarithromycin , amikacin , and cefoxitin for 6 months .

https://pubmed.ncbi.nlm.nih.gov/20548899/

08bc2fa158724cdf7c4a1e19c146ecbe

The methods have been utilized to evaluate the pharmacokinetics and bioavailability of oral dosage forms containing levodopa and carbidopa .

Simultaneous high-performance liquid chromatographic analysis of carbidopa, levodopa and 3-O-methyldopa in plasma and carbidopa, levodopa and dopamine in urine using electrochemical detection. Two assay procedures are described for the analysis of levodopa, carbidopa and 3-O-methyldopa in plasma and levodopa, carbidopa and dopamine in urine. The methods are suitable for quantifying the analytes following therapeutic administration of levodopa and carbidopa. Both were based on reversed-phase high-performance liquid chromatography (HPLC) with electrochemical detection and with methyldopa as the internal standard. Plasma samples were prepared by perchloric acid precipitation followed by the direct injection of the supernatant. Urine was prepared by alumina adsorption, and the analytes were desorbed with perchloric acid solution containing disodium EDTA and sodium metabisulfite prior to injection into the HPLC system. The methods have been utilized to evaluate the pharmacokinetics and bioavailability of oral dosage forms containing levodopa and carbidopa .

https://pubmed.ncbi.nlm.nih.gov/2094725/

7f288b72f1a2e66fe9a29da2975cafbf

Increasing the temperature from 60 ° C to 100 ° C decreased the half-life of amoxicillin ( 372 to 50 min ) , ampicillin ( 741 to 26 min ) , cloxacillin ( 367 to 46 min ) , and penicillin G ( 382 to 43 min ) .

Effect of heat treatments on stability of β-lactams in milk. The presence of residues of antimicrobial substances in milk may have serious toxicological and technical consequences. To date, few studies have been done to evaluate the effect of heat treatments on β-lactam residues in milk. However, the few studies that have been conducted estimate losses of antimicrobial activity under different combinations of temperature and time using microbiological methods. The aims of this study were to calculate the kinetic parameters for the degradation of β-lactam antibiotics in milk and to develop prediction models to estimate the concentration losses of these compounds in conventional dairy heat treatments. To do so, we employed a quantitative HPLC method to calculate losses in concentrations of 10 β-lactam antibiotics in milk with different combinations of temperature and time. Increasing the temperature from 60 ° C to 100 ° C decreased the half-life of amoxicillin ( 372 to 50 min ) , ampicillin ( 741 to 26 min ) , cloxacillin ( 367 to 46 min ) , and penicillin G ( 382 to 43 min ) . These increases in temperature caused further degradation in cephalosporins, which was accompanied by a decrease in half-life times to reach very low values; for instance, 4, 5, and 6 min for cefoperazone, cephurexime, and cephapirin, respectively. Kinetic equations were applied to different heat treatments used in dairy processing. Heat treatments at high temperatures and long times (e.g., 120°C for 20 min) led to a further degradation of β-lactam antibiotics with percentages close to 100% for cefoperazone and cefuroxime. In contrast, when milk was subjected to heat treatments at lower temperatures and times (e.g., 72°C for 15s), the degradation of β-lactam in milk did not exceed 1% for the 10 antibiotics tested.

https://pubmed.ncbi.nlm.nih.gov/21338781/

381196cee26baefb6995f35a4de37b15

Contribution of moxifloxacin or levofloxacin in second-line regimens with or without continuation of pyrazinamide in murine tuberculosis .

Contribution of moxifloxacin or levofloxacin in second-line regimens with or without continuation of pyrazinamide in murine tuberculosis . High-dose levofloxacin (L) (1,000 mg) was as active as moxifloxacin (M) (400 mg) in an early bactericidal activity trial, suggesting these fluoroquinolones could be used interchangeably. Whether pyrazinamide (Z) contributes sterilizing activity beyond the first 2 months in fluoroquinolone-containing second-line regimens remains unknown. ### objectives We compared the efficacy of M and high-dose L alone or in combination with ethionamide (Et), amikacin (A), and Z given for 2 or 7 months. ### methods A pharmacokinetic study was performed to determine the L dose equivalent to 1,000 mg in humans. Treatment started 2 weeks after aerosol infection with Mycobacterium tuberculosis H37Rv. Mice received M or L alone or in combination with 2 months of EtZA followed by 5 months of Et or EtZ. ### Measurements And Main Results After 2 months of treatment, lung colony-forming unit (CFU) counts were similar in mice receiving either fluoroquinolone alone, but, after 4 and 5 months, CFU counts were 2 log10 lower in mice receiving M. Mice receiving 2MEtZA/3MEt and 2LEtZA/3LEt had 1.0 and 2.7 log10 lung CFUs, respectively. When Z was given throughout, both regimens rendered mice culture negative by 5 months, and most mice did not relapse after 7 months of treatment, with fewer relapses observed in the M group after 6 and 7 months of treatment. ### conclusions In murine tuberculosis, M had superior efficacy compared with L despite lower serum drug exposures and may remain the fluoroquinolone of choice for second-line regimens. Z contributed substantial sterilizing activity beyond 2 months in fluoroquinolone-containing second-line regimens, largely compensating for L's weaker activity.

https://pubmed.ncbi.nlm.nih.gov/23593945/

31a108d057dc090881a6478c986ecb28

High-level resistance to quinolones was frequently observed ( 21 % ) , but resistance to erythromycin ( 3 % ) and tetracycline ( 5 % ) was rare .

Campylobacter infections in HIV-infected patients: clinical and bacteriological features. To study the clinical and bacteriological features of Campylobacter infections in HIV-infected patients. ### design A retrospective analysis (1989-1992), followed by a prospective analysis (1992-1994). ### setting Hospital HIV inpatient unit. ### Patients And Methods All patients with Campylobacter spp. identified by the laboratory of microbiology at Saint-Louis Hospital, Paris were studied, and their clinical features as well as their response to therapy recorded. ### results During the study period, Campylobacter infection was documented in 38 HIV-infected patients, 76% of whom had AIDS. Campylobacter spp. was isolated from stools in 36 cases and from blood cultures in four cases. Species identification yielded C. jejuni (84%) and C. coli (16%). High-level resistance to quinolones was frequently observed ( 21 % ) , but resistance to erythromycin ( 3 % ) and tetracycline ( 5 % ) was rare . Diarrhoea, fever and abdominal pain were the main clinical features of infection. Other intestinal pathogens were found in 42% of patients. Most patients had an acute illness with rapid resolution under appropriate antimicrobial therapy. However, eight patients (21%), experienced chronic diarrhoea with persistent isolation of Campylobacter and in vivo selection of resistant strains, requiring multiple courses of antibiotics. ### conclusions Campylobacter usually cause acute diarrhoea in patients with HIV infection. Antimicrobial therapy should be guided on in vitro susceptibility testing because of the prevalence of antibiotic resistance. Despite appropriate therapy, some patients will present with prolonged diarrhoea and in vivo selection of multiresistant isolates.

https://pubmed.ncbi.nlm.nih.gov/7576322/

4c60c779d2cfef9da2574018640095c5

The addition of tamoxifen did not worsen the known side effects of gefitinib , or induce additional side effects .

Gefitinib in combination with tamoxifen in patients with ovarian cancer refractory or resistant to platinum-taxane based therapy--a phase II trial of the AGO Ovarian Cancer Study Group (AGO-OVAR 2.6). tamoxifen and gefitinib (IRESSA) combination therapy was studied in patients with ovarian cancer refractory or resistant to platinum- and taxane-based therapy. ### Patients And Methods In this phase II study, 56 patients with epithelial ovarian carcinoma or cancer of the fallopian tube or peritoneum received oral tamoxifen 40 mg/day and gefitinib 500 mg/day until progression or unacceptable toxicity. ### results Seventeen patients (mean age: 59.6 years) had previously received first-line platinum/taxane treatment only, while 39 had received 2-8 (median 2) prior chemotherapy regimens. gefitinib dose reduction to 250 mg/day was performed in 10 patients (14.9%), predominantly due to diarrhea (6 patients [10.7%]). Trial medication was discontinued in 6 patients (10.7%) due to adverse events (AEs). The most frequent drug-related AEs were diarrhea and acne-like skin rash. There were no tumor responses, but 16 patients had stable disease. Median time-to-progression was 58 days (95% CI, 55-71 days) and median survival was 253 days (95% CI, 137-355 days). ### conclusion gefitinib plus tamoxifen did not appear to be efficacious in the treatment of patients with refractory/resistant ovarian cancer. The addition of tamoxifen did not worsen the known side effects of gefitinib , or induce additional side effects .

https://pubmed.ncbi.nlm.nih.gov/17161453/

72fd0bfc3ea97cb4d9ed0ee4850e2bd3

A topical combination of 0.25 % finasteride and 3 % minoxidil may be a promising option in the treatment of FPHL with an additional benefit of increasing hair diameter .

Efficacy of Topical Combination of 0.25% Finasteride and 3% Minoxidil Versus 3% Minoxidil Solution in Female Pattern Hair Loss: A Randomized, Double-Blind, Controlled Study. The relationship between female pattern hair loss (FPHL) and androgenic hormones is not well established, but some evidence indicates oral finasteride may be efficacious in FPHL. Use of a topical formulation has been proposed to minimize unwanted effects. ### objectives Our objective was to compare the efficacy and safety of topical 0.25% finasteride combined with 3% minoxidil solution and 3% minoxidil solution as monotherapy in the treatment of FPHL. ### methods This was a prospective, randomized, double-blind study in 30 postmenopausal women with FPHL. Each participant was randomized to receive either topical 0.25% finasteride combined with topical 3% minoxidil or topical 3% minoxidil solution as monotherapy for 24 weeks. To determine efficacy, the hair density and diameter was measured and global photographic assessment was conducted at baseline and 8, 16, and 24 weeks. Side effects and serum dihydrotestosterone levels were also evaluated. ### results By 24 weeks, hair density and diameter had increased in both groups, and finasteride/minoxidil was significantly superior to minoxidil solution in terms of hair diameter (p = 0.039). No systemic side effects were reported. However, serum dihydrotestosterone levels in the finasteride/minoxidil group significantly decreased from baseline (p = 0.016). ### conclusion A topical combination of 0.25 % finasteride and 3 % minoxidil may be a promising option in the treatment of FPHL with an additional benefit of increasing hair diameter . Nevertheless, as it may be absorbed percutaneously, it should be reserved for postmenopausal women. ### Trial Registration clinicaltrials.in.th; identifier TCTR20160912002.

https://pubmed.ncbi.nlm.nih.gov/30206824/

4d71f06710452ec611d9616f759b359f

This report is the first about the long-term use of dasatinib in patients with Ph+ all and mrd elevation but hematologic remission during imatinib chemotherapy .

Dasatinib for a child with Philadelphia chromosome-positive acute lymphoblastic leukemia and persistently elevated minimal residual disease during imatinib therapy. imatinib has improved outcomes in patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (all). Minimal residual disease (mrd) is a useful tool for predicting leukemia relapse. However, there is no consensus on how to treat children with elevation of BCR-ABL transcripts but no evidence of hematologic relapse during chemotherapy combined with imatinib. Here, we report the case of a child with Ph+ all who had persistent elevation of mrd, but no evidence of hematologic relapse while receiving imatinib plus intensive chemotherapy. dasatinib was substituted for imatinib because no suitable donor for allogeneic hematopoietic stem-cell transplantation (hsct) was available. Less-intensive chemotherapy with methotrexate and 6-mercaptopurine was administered concomitantly. No serious adverse events were encountered. With continuous dasatinib combined with chemotherapy, but no allogeneic hsct, our patient reached complete molecular remission and has been in complete molecular remission for more than 13 months. This report is the first about the long-term use of dasatinib in patients with Ph+ all and mrd elevation but hematologic remission during imatinib chemotherapy . In a similar situation, chemotherapy combined with dasatinib instead of allogeneic hsct could be considered to avoid hsct-related mortality and morbidity. Clinical trials are needed.

https://pubmed.ncbi.nlm.nih.gov/26300669/

7e0de118f601e9e5d0fca43b872b1a77

Acute verapamil toxicity in a patient with chronic toxicity : possible interaction with ceftriaxone and clindamycin .

Acute verapamil toxicity in a patient with chronic toxicity : possible interaction with ceftriaxone and clindamycin . To report a case of acute toxicity in a patient with chronic verapamil toxicity, possibly precipitated by intravenous administration of the highly protein-bound drugs ceftriaxone and clindamycin. ### Data Sources Case reports, review articles, and relevant laboratory and clinical studies identified by MEDLINE (1984-forward), and relevant cross references from those articles. ### Data Extraction Data were abstracted from pertinent sources by one author and reviewed by the remaining authors. ### Case Summary A 59-year-old man who had been receiving sustained-release verapamil 240 mg q12h for more than two years for hypertension, and phenytoin 300 mg/d for many years for prophylaxis against seizures, was noted to be in junctional rhythm when he presented to the emergency room with bilateral pneumonia. Administration of intravenous ceftriaxone 1 g and clindamycin 900 mg precipitated symptoms of acute verapamil toxicity in this patient. The toxicity led to complete heart block requiring cardiopulmonary resuscitation and insertion of a temporary pacemaker. He spontaneously reverted to normal sinus rhythm after 16 hours. Subsequent cardiac evaluation, including echocardiogram, 48-hour dynamic electrocardiographic recording (Holter), and exercise stress test were normal. The patient has remained in sinus rhythm for more than one year after this episode. ### conclusions We believe that junctional rhythm on admission was a result of chronic verapamil toxicity. This may have been because of increased bioavailability of the drug or increased sensitivity of the receptors. Administration of ceftriaxone, clindamycin, or both agents might have precipitated acute verapamil toxicity by displacing verapamil from its protein-binding sites. Extreme caution is necessary when a highly protein-bound drug is given to a patient already receiving verapamil.

https://pubmed.ncbi.nlm.nih.gov/8364267/

06dac7461e1acaebd6a082e3d469f6da

Eighty-three patients were treated with rituximab , cyclophosphamide , doxorubicin , vincristine , prednisone ( R-CHOP ) , 7 with rituximab , etoposide , cyclophosphamide , doxorubicin , vincristine , prednisone ( R-EPOCH ) , and 6 with R-CHOP with methotrexate , 3 g/m(2 ) .

De novo CD5+ diffuse large B-cell lymphoma: Adverse outcomes with and without stem cell transplantation in a large, multicenter, rituximab treated cohort. De novo CD5+ diffuse large B-cell lymphomas (DLBCL) are a distinct subgroup of DLBCL with poor prognosis. However the role of rituximab-containing therapy and salvage stem cell transplantation in this patients' population remain to be defined. We retrospectively reviewed clinical features and outcomes of 102 patients with de novo CD5+ DLBCL treated with rituximab-containing therapy at nine different institutions. By Hans' criteria, 64 patients had activated B-cell (ABC) subtype, 24 germinal center B-cell (GCB) subtype, and 14 were not evaluated. No patients had a myc translocation. Eighty-three patients were treated with rituximab , cyclophosphamide , doxorubicin , vincristine , prednisone ( R-CHOP ) , 7 with rituximab , etoposide , cyclophosphamide , doxorubicin , vincristine , prednisone ( R-EPOCH ) , and 6 with R-CHOP with methotrexate , 3 g/m(2 ) . The overall response rate to front-line therapy was 85%. The 3-year progression free survival (PFS) and overall survival (OS) for all patients were 40 and 65%, respectively. The 3-year PFS for ABC- and GCB-subtypes was 34 and 45%, respectively. The 3-year OS for ABC- and GCB-subtypes was 62 and 67%, respectively. The median time to second treatment failure was 3 months and 1 month for ABC- and GCB-subtypes, respectively. Twenty of 28 (71%) transplanted patients with autologous, allogeneic, or both, relapsed. This study confirms the poor prognosis of de novo CD5+ DLBCL in a large multi-center cohort despite initial rituximab-containing chemotherapy and suggests that stem cell transplantation fails to salvage the majority of these patients. Approaches to prevent recurrence and/or novel therapies for relapsed disease are needed for this subgroup of DLBCL patients.

https://pubmed.ncbi.nlm.nih.gov/26800311/

a48033035346a4791fd19c2ed770d582

More active therapies are needed for older and unfit patients with chronic lymphocytic leukemia ( CLL ) who are not eligible for chemoimmunotherapy with fludarabine , cyclophosphamide , and rituximab .

Outcomes of patients with chronic lymphocytic leukemia treated with first-line idelalisib plus rituximab after cessation of treatment for toxicity. More active therapies are needed for older and unfit patients with chronic lymphocytic leukemia ( CLL ) who are not eligible for chemoimmunotherapy with fludarabine , cyclophosphamide , and rituximab . The phosphyotidylinositol-3-kinase δ inhibitor idelalisib is effective in patients with treatment-naive and relapsed/refractory CLL as monotherapy and in combination with rituximab, but it can be associated with treatment-limiting adverse events, particularly diarrhea/colitis. The outcomes for patients who cease treatment for adverse events have not been previously described. ### methods The authors analyzed long-term follow-up data from 40 treatment-naïve patients aged ≥65 years who received treatment at The University of Texas MD Anderson Cancer Center on a phase 2 study of idelalisib plus rituximab for CLL. ### results In patients who permanently ceased treatment because of toxicity, the time to subsequent disease progression was analyzed according to baseline characteristics. Fifteen patients permanently ceased therapy (PCT) because of toxicity (PCTTOX ), most commonly diarrhea/colitis (n = 7), at a median of 11 months after commencing treatment. PCTTOX was associated with a higher risk of subsequent disease progression (hazard ratio, 6.61; 95% confidence interval, 1.77-16.15) relative to that observed in patients who remained on therapy. Ten patients subsequently progressed, and 7 required salvage therapy; 5 patients remained progression-free at a median of 23.3 months (range, 8.5-28.6 months). Patients who were positive for ζ-associated protein-70 had more rapid disease progression after treatment cessation (P = .048). There were no CLL-related deaths. ### conclusions PCTTOX is the major determinant of PFS in patients who receive first-line idelalisib-based treatment. However, a subgroup of patients with favorable biologic characteristics has prolonged PFS, even after PCTTOX . The absence of CLL-related deaths indicates that salvage treatment is generally successful after PCTTOX . Cancer 2016;122:2505-11. © 2016 American Cancer Society.

https://pubmed.ncbi.nlm.nih.gov/27182988/

5b7841090a61ffbb76316003d172ae52

Among them , 18 ( 85.7 % ) patients had disease control with gefitinib and 12 ( 57.1 % ) patients with salvage erlotinib .

Erlotinib as salvage treatment after failure to first-line gefitinib in non-small cell lung cancer. Chemotherapy is the mainstay treatment for advanced non-small cell lung cancer (NSCLC). gefitinib, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), has been recently shown to be effective as a first-line treatment in Asian patients with advanced NSCLC, especially for those with favourable clinical features such as female, non-smoker and adenocarcinoma. However, resistance to gefitinib ensues invariably and there is little evidence as for the effectiveness of subsequent salvage treatment. The purpose of this study is to evaluate the efficacy of erlotinib, another EGFR-TKI, after failed first-line use of gefitinib. ### method Retrospective review of NSCLC patients with favourable clinical features who received gefitinib as first-line treatment and subsequent salvage treatment with erlotinib. ### results A total of 21 patients with NSCLC were included in the study. Among them , 18 ( 85.7 % ) patients had disease control with gefitinib and 12 ( 57.1 % ) patients with salvage erlotinib . There was an association between the disease control with gefitinib and erlotinib (p = 0.031). The disease control rate of erlotinib was independent of the chemotherapy use between the two EGFR-TKIs. ### conclusion For NSCLC patients with favourable clinical features, erlotinib was effective in those who had prior disease control with first-line gefitinib.

https://pubmed.ncbi.nlm.nih.gov/19680652/

3f238468374dde345c8746618ac78e38

In addition to its reproductive function , kisspeptin signalling is also involved in extra-hypothalamic-pituitary-gonadal ( HPG ) axis systems , including oxytocin and arginine vasopressin ( AVP ) secretion .

Mapping of Kisspeptin Receptor mRNA in the Whole Rat Brain and its Co-Localisation with Oxytocin in the Paraventricular Nucleus. The neuropeptide kisspeptin and its receptor play an essential role in reproduction as a potent modulator of the gonadotrophin-releasing hormone (GnRH) neurone. In addition to its reproductive function , kisspeptin signalling is also involved in extra-hypothalamic-pituitary-gonadal ( HPG ) axis systems , including oxytocin and arginine vasopressin ( AVP ) secretion . By contrast to the accumulating information for kisspeptin neurones and kisspeptin fibres, the histological distribution and function of the kisspeptin receptor in the rat brain remain poorly characterised. Using in situ hybridisation combined with immunofluorescence, the present study aimed to determine the whole brain map of Kiss1r mRNA (encoding the kisspeptin receptor), and to examine whether oxytocin or AVP neurones express Kiss1r. Neurones with strong Kiss1r expression were observed in several rostral brain areas, including the olfactory bulb, medial septum, diagonal band of Broca and throughout the preoptic area, with the most concentrated population being around 0.5 mm rostral to the bregma. Co-immunofluorescence staining revealed that, in these rostral brain areas, the vast majority of the Kiss1r-expressing neurones co-expressed GnRH. Moderate levels of Kiss1r mRNA were also noted in the rostral periventricular area, paraventricular nucleus (PVN), and throughout the arcuate nucleus. Relatively weak Kiss1r expression was observed in the supraoptic nucleus and supramammillary nuclei. Moderate to weak expression of Kiss1r was also observed in several regions in the midbrain, including the periaqueductal gray and dorsal raphe nucleus. We also examined whether oxytocin and AVP neurones in the PVN co-express Kiss1r. Immunofluorescence revealed the co-expression of Kiss1r in a subset of the oxytocin neurones but not in the AVP neurones in the PVN. The present study provides a fundamental anatomical basis for further examination of the kisspeptin signalling system in the extra-HPG axis, as well as in reproductive function.

https://pubmed.ncbi.nlm.nih.gov/26709462/

e5a7cebcf893355e7a916810c41d4fd6

The combination of volasertib with pemetrexed did not improve efficacy compared with pemetrexed monotherapy .

A Randomized, Open-Label Phase II Trial of Volasertib as Monotherapy and in Combination With Standard-Dose Pemetrexed Compared With Pemetrexed Monotherapy in Second-Line Treatment for Non-Small-Cell Lung Cancer. Second-line therapy options that improve survival for patients with advanced non-small-cell lung cancer (NSCLC) are needed. This randomized, phase II trial (n [ 143) investigated volasertib monotherapy or in combination with pemetrexed compared with pemetrexed monotherapy in patients with NSCLC whose disease had progressed after previous platinum-based chemotherapy. The combination of volasertib with pemetrexed did not improve efficacy compared with pemetrexed monotherapy . ### introduction volasertib is a potent, selective, cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase. In this study we compared volasertib, volasertib with pemetrexed, and pemetrexed alone in patients with advanced non-small-cell lung cancer (NSCLC) whose disease progressed after first-line platinum-based chemotherapy. ### Patients And Methods A run-in phase (n = 12) was used to determine whether volasertib could be combined in full dose with pemetrexed 500 mg/m(2). Subsequent patients were randomized to volasertib (n = 37), volasertib with pemetrexed (n = 47), or pemetrexed (n = 47) administered on day 1 every 21 days. The primary end point was progression-free survival (PFS); secondary end points included objective response rate and pharmacokinetics. ### results volasertib 300 mg was chosen for the randomized phase. Recruitment to single-agent volasertib was stopped early because of lack of efficacy. Median PFS was 5.3 months with pemetrexed compared with 3.3 months with volasertib with pemetrexed (hazard ratio [HR], 1.141; 95% confidence interval [CI], 0.73-1.771) and 1.4 months with volasertib (HR, 2.045; 95% CI, 1.27-3.292). ORRs were 10.6% with pemetrexed, 21.3% for volasertib with pemetrexed, and 8.1% with volasertib. The most common all-grade related adverse events (pemetrexed/volasertib with pemetrexed/volasertib) were: fatigue (28 [61%]/27 [59%]/11 [31%]), nausea (21 [46%]/19 [41%]/0 [0%]), decreased apetite (14 [31%]/13 [28%]/2 [6%]), neutropenia (4 [9%]/8 [17%]/9 [25%]), rash (9 [20%]/8 [17%]/2 [6%]), vomiting (6 [13%]/13 [28%]/0 [0%]), and diarrhea (8 [17%]/11 [24%]/0 [0%]). Pharmacokinetics analyses showed no drug-drug interactions between volasertib and pemetrexed. ### conclusion For treatment in the second-line for advanced or metastatic NSCLC, the combination of volasertib with standard pemetrexed did not increase toxicity significantly but also did not improve efficacy compared with single-agent pemetrexed.

https://pubmed.ncbi.nlm.nih.gov/26100229/

2203a64a832c5f247dd8231046b2e400

A phase I/II study was carried out to determine the maximum tolerated dose of paclitaxel ( Taxol ; Bristol-Myers Squibb Company , Princeton , NJ ) in combination with a fixed dose of carboplatin ( area under the concentration-time curve = 6 by Calvert method ) given on an every-3-week schedule to patients with non-small cell lung cancer ( NSCLC ) .

Preliminary results of a phase I/II clinical trial of paclitaxel and carboplatin in non-small cell lung cancer. A phase I/II study was carried out to determine the maximum tolerated dose of paclitaxel ( Taxol ; Bristol-Myers Squibb Company , Princeton , NJ ) in combination with a fixed dose of carboplatin ( area under the concentration-time curve = 6 by Calvert method ) given on an every-3-week schedule to patients with non-small cell lung cancer ( NSCLC ) . Cohorts of patients were entered at increasing dose levels of paclitaxel: six at dose level I (paclitaxel 150 mg/m2), six at dose level 2 (paclitaxel 175 mg/m2), 11 at dose level 3 (paclitaxel 200 mg/ m2), 21 at dose level 4 (paclitaxel 225 mg/m2), and five at dose level 5 (paclitaxel 250 mg/m2). The patients comprised 31 men and 18 women with a median age of 62 years (age range, 46 to 81 years) and a median Southwest Oncology Group performance status of I (range, 0 to 2). Twenty-three patients had unresectable stage III NSCLC and 26 had stage IV NSCLC. Fortynine patients and 176 treatment courses are evaluable for toxicity. Grade 4 neutropenia or grade 3 arthralgias/ myalgias or sensory neuropathy were the most significant toxicities of therapy. In addition, two patients (dose levels 2 and 3) experienced acute chest pain, flushing, and hypotension, and had electrocardiogram changes during the paclitaxel infusion; one had mild creatine phosphokidnase MB elevation. Both recovered uneventfully, were not re-treated with paclitaxel, and account for two of only four hospitalizations for toxicity management in this trial. At this time, 42 patients with objectively measurable disease are evaluable for responses: two complete responses and 24 partial responses (62% objective response rate) have been observed. These data imply that the maximum tolerated dose of paclitaxel is 250 mg/m2 with dose-limiting toxicity consisting primarily of grade 3 osteo/arthralgias-myalgias or cumulative sensory neuropathy; paclitaxel at a dose of 225 mg/m2 given by 3-hour infusion combined with carboplatin at a calculated target area under the concentration-time curve of 6 is a well-tolerated outpatient treatment regimen and highly active in NSCLC; myelosuppression is mild and rarely dose limiting. Most notably, paclitaxel appears to decrease carboplatin's pharmacodynamic effects on thrombopoiesis.

https://pubmed.ncbi.nlm.nih.gov/8941402/

50f8baf7b85a4496d160a40dbd68f5f3

These results suggest that therapy with insulin plus dexamethasone but not therapy with leptin is beneficial for diabetics .

The relationship between nitric oxide and leptin in the lung of rat with streptozotocin-induced diabetes. Lung structural changes and immunoreactivity of endothelial (eNOS)- and inducible nitric oxide synthase (iNOS) were investigated by light microscopy in lungs of treated and untreated diabetic rats. Diabetes was induced by a single intraperitoneal (i.p.) injection of 65 mg kg(-1) streptozotocin (STZ) in Wistar albino male rats. Diabetic rats received daily i.p. doses of dexamethasone (2 mg kg(-1)), leptin (0.5 microg kg(-1)) and intramuscular insulin (20 U kg(-1)) or a combination of these drugs for 1 week starting 4 weeks after the STZ injections. After treatment, the blood levels of glucose, leptin, insulin and nitrate/nitrite (NO(3) (-)/NO(2) (-)) were measured. Dilatation of alveoli and alveolar ducts, partial alveolar wall thickening and increased eNOS- and iNOS characterized the diabetic rat lungs. High blood glucose and nitrate/nitrite levels as well as low insulin and leptin levels were also present. Treatment with insulin, dexamethasone and a combination of these drugs resulted in improvement of the structural and immunohistochemical abnormalities. The most effective treatment was insulin therapy. leptin administration resulted in increased relative amounts of extracellular material, which led to noticeable respiratory efficiency in the diabetic rat lungs. All treatments except leptin lowered blood glucose levels. The combination of insulin and dexamethasone increased blood leptin and insulin, while the remaining diabetic rats had blood with low leptin and insulin concentrations. These results suggest that therapy with insulin plus dexamethasone but not therapy with leptin is beneficial for diabetics .

https://pubmed.ncbi.nlm.nih.gov/17542037/

cda1528c8e375d23ab4a92907786db43

After the first course of treatment , a statistically significant improvement ( p = 0.002 ) in the psychological subscale scores was observed after ondansetron compared with metoclopramide .

Ondansetron compared with metoclopramide in the control of emesis and quality of life during repeated chemotherapy for breast cancer. This was a multicentre, randomised, double-blind, parallel-group study which included female breast cancer patients, receiving their first of 6 scheduled courses of chemotherapy (cyclophosphamide greater than or equal to 500 mg/m2). Patients received an intravenous dose of 16 mg dexamethasone with either 8 mg ondansetron or 60 mg metoclopramide before chemotherapy, followed by oral dosing with 8 mg ondansetron or 20 mg metoclopramide 3 times daily for 5 days. A total of 93 patients were treated with ondansetron and 94 patients with metoclopramide. On day 1 of their first course of treatment 91 and 60% of patients in the ondansetron and metoclopramide groups respectively were free of emesis (p less than 0.001). Over the 5-day treatment period, the corresponding figures were 81 and 48% (p less than 0.001). The results for nausea also revealed highly statistically significant treatment differences (p less than 0.001) in favour of ondansetron for both day 1 and day 1-5 analyses of the first treatment course. Over the series of courses, 67% of patients receiving ondansetron completed all 6 courses with a maximum of 2 emetic episodes on their worst day, compared with 28% of patients receiving metoclopramide (p less than 0.001). A similar analysis for nausea revealed that 49% of patients receiving ondansetron completed all 6 courses with 'none' or 'mild' nausea compared with 27% of patients receiving metoclopramide (p less than 0.001). These differences were reflected in quality of life data (Rotterdam Symptom Checklist). After the first course of treatment , a statistically significant improvement ( p = 0.002 ) in the psychological subscale scores was observed after ondansetron compared with metoclopramide . No differences were observed in the physical or functional activity subscales after the first course. However, the quality of life results over the series of courses revealed a more pronounced difference in favour of ondansetron in the psychological subscale scores (p less than 0.001) as well as trends in favour of ondansetron in the physical (p = 0.096) and functional activity (p = 0.056) subscales. Extrapyramidal symptoms were reported in 19% of patients in the metoclopramide group and resulted in 15% of patients withdrawing from their randomised anti-emetic schedule, either during or between treatment courses. Other adverse events were generally minor in nature and did not necessitate withdrawal from treatment. In conclusion, this study shows that ondansetron is significantly superior to metoclopramide (each with a single pre-treatment dose of dexamethasone) in the control of emesis over 6 courses of chemotherapy for breast cancer.(ABSTRACT TRUNCATED AT 400 WORDS)

https://pubmed.ncbi.nlm.nih.gov/1387929/

8394cbf1a7ef9d49fdf46ec0121b08db

The rate of grade 3 or 4 neutropenia was higher in the venetoclax-rituximab group than in the bendamustine-rituximab group , but the rates of grade 3 or 4 febrile neutropenia and infections or infestations were lower with venetoclax than with bendamustine .

Venetoclax-Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. venetoclax inhibits BCL2, an antiapoptotic protein that is pathologically overexpressed and that is central to the survival of chronic lymphocytic leukemia cells. We evaluated the efficacy of venetoclax in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia. ### methods In this randomized, open-label, phase 3 trial, we randomly assigned 389 patients to receive venetoclax for up to 2 years (from day 1 of cycle 1) plus rituximab for the first 6 months (venetoclax-rituximab group) or bendamustine plus rituximab for 6 months (bendamustine-rituximab group). The trial design did not include crossover to venetoclax plus rituximab for patients in the bendamustine-rituximab group in whom progression occurred. The primary end point was investigator-assessed progression-free survival. ### results After a median follow-up period of 23.8 months, the rate of investigator-assessed progression-free survival was significantly higher in the venetoclax-rituximab group (32 events of progression or death in 194 patients) than in the bendamustine-rituximab group (114 events in 195 patients); the 2-year rates of progression-free survival were 84.9% and 36.3%, respectively (hazard ratio for progression or death, 0.17; 95% confidence interval [CI], 0.11 to 0.25; P<0.001 by the stratified log-rank test). The benefit was maintained across all clinical and biologic subgroups, including the subgroup of patients with chromosome 17p deletion; the 2-year rate of progression-free survival among patients with chromosome 17p deletion was 81.5% in the venetoclax-rituximab group versus 27.8% in the bendamustine-rituximab group (hazard ratio, 0.13; 95% CI, 0.05 to 0.29), and the 2-year rate among those without chromosome 17p deletion was 85.9% versus 41.0% (hazard ratio, 0.19; 95% CI, 0.12 to 0.32). The benefit of venetoclax plus rituximab over bendamustine plus rituximab was confirmed by an independent review committee assessment of progression-free survival and other secondary efficacy end points. The rate of grade 3 or 4 neutropenia was higher in the venetoclax-rituximab group than in the bendamustine-rituximab group , but the rates of grade 3 or 4 febrile neutropenia and infections or infestations were lower with venetoclax than with bendamustine . The rate of grade 3 or 4 tumor lysis syndrome in the venetoclax-rituximab group was 3.1% (6 of 194 patients). ### conclusions Among patients with relapsed or refractory chronic lymphocytic leukemia, venetoclax plus rituximab resulted in significantly higher rates of progression-free survival than bendamustine plus rituximab. (Funded by Genentech and AbbVie; ClinicalTrials.gov number, NCT02005471 .).

https://pubmed.ncbi.nlm.nih.gov/29562156/

fb834baa1bb0f848711c6b8bd0faecd0

This study investigated the efficacy and toxicity associated with consolidation chemotherapy using paclitaxel and carboplatin after concurrent chemoradiation ( CCR ) in cervical cancer patients .

Phase II Study of Consolidation Chemotherapy after Adjuvant or Primary Concurrent Chemoradiation Using Paclitaxel and Carboplatin to Treat High-Risk Early-Stage or Locally Advanced Cervical Cancer. This study investigated the efficacy and toxicity associated with consolidation chemotherapy using paclitaxel and carboplatin after concurrent chemoradiation ( CCR ) in cervical cancer patients . ### Materials And Methods From a total of 37 patients, 19 with International Federation of Gynecology and Obstetrics (FIGO) stage IB1-IIA cervical cancer (group 1) underwent surgery followed by consolidation chemotherapy after CCR, and 18 with stage IIB-IVA disease (group 2) received consolidation chemotherapy after primary CCR. Three cycles of chemotherapy using paclitaxel (135 mg/m(2)) and carboplatin (AUC 5.0) were administered every 3 weeks for CCR therapy, and three cycles of consolidation chemotherapy using paclitaxel (175 mg/m(2)) and carboplatin (AUC 5.0) were used every 3 weeks after CCR. ### results The complete and partial response rates were 77.8% and 22.2% in group 2. Moreover, the 3-year progression-free and overall survival rates were 62.7% and 90.9% in group 1, and 51.9% and 60% in group 2, respectively. The most common grade 3 or 4 hematologic toxicities observed were leukopenia (group 1, 10.5%; group 2, 13.0%) and neutropenia (group 1, 7.0%; group 2, 14.8%), and grade 3 or 4 diarrhea (group 1, 1.8%) and febrile illness (group 2, 1.9%) were the most frequently observed non-hematologic toxicities. When we compared these results with previous reports, consolidation chemotherapy after CCR using paclitaxel and carboplatin revealed a relatively lower complete response rate (77.8% vs. 87-100%, respectively) and shorter progression-free survival (51.9-62.7% vs. 81-86%, respectively) and overall survival (60-90.9% vs. 81-95%, respectively) in spite of similar toxicity findings. ### conclusion Due to low efficacy results, consolidation chemotherapy using paclitaxel and carboplatin after CCR is not a feasible treatment regimen for high-risk early-stage or locally advanced cervical cancer.

https://pubmed.ncbi.nlm.nih.gov/22802747/

b523382f44b1db749bb1508120a819b6

These secondary leukemias associated with topoisomerase II inhibitors ( most commonly teniposide , etoposide , or doxorubicin ) have distinct clinical and biologic features which have led to the speculation that they are induced by treatment with topoisomerase II inhibitors .

Site-specific DNA cleavage within the MLL breakpoint cluster region induced by topoisomerase II inhibitors. The MLL gene located at 11q23 is frequently disrupted by chromosomal translocation in a wide spectrum of newly diagnosed acute leukemias. Recently, it has become apparent that the MLL gene is very frequently disrupted by chromosomal translocations in patients with secondary leukemias associated with chemotherapeutic regimens incorporating topoisomerase II inhibitors. These secondary leukemias associated with topoisomerase II inhibitors ( most commonly teniposide , etoposide , or doxorubicin ) have distinct clinical and biologic features which have led to the speculation that they are induced by treatment with topoisomerase II inhibitors . We have identified a site within the MLL breakpoint cluster region (bcr) that is highly sensitive to double-strand DNA cleavage induced by topoisomerase II inhibitors. This finding is quite specific and highly reproducible. Although it was initially discovered in malignant lymphoblasts isolated from a patient receiving multiagent chemotherapy, this site-specific double-strand DNA cleavage can be induced in tissue culture using malignant cell lines as well as peripheral blood from normal individuals. Site-specific cleavage occurs in a significant fraction of cells using a variety of model systems, is both time and dose dependent, and can be induced with either doxorubicin or etoposide. This site-specific cleavage maps to the same region as a consensus topoisomerase II cleavage site within the MLL bcr. These results suggest that site specific cleavage within the MLL bcr induced by topoisomerase II inhibitors may be an early step leading to MLL translocations and secondary leukemia.

https://pubmed.ncbi.nlm.nih.gov/8639880/

142b4a6fe75ee059396d3428fc9b4f40

In the intention to treat analysis , 14 patients receiving praziquantel were cured compared with none with mefloquine , one with artesunate ( odds ratio 0·03 , 95 % CI 0·004 - 0·29 ) , one with mefloquine-artesunate ( 0·03 , 0·004 - 0·29 ) , and 19 with tribendimidine ( 1·87 , 0·60 - 5·85 ) .

Efficacy and safety of mefloquine, artesunate, mefloquine-artesunate, tribendimidine, and praziquantel in patients with Opisthorchis viverrini: a randomised, exploratory, open-label, phase 2 trial. praziquantel is the only drug available for treatment of Opisthorchis viverrini, although in-vivo studies point to activity of mefloquine, artesunate, and tribendimidine against this liver fluke. We aimed to assess the efficacy and safety of these drugs compared with that of praziquantel in patients with O viverrini infection. ### methods We did a randomised open-label trial between February and April, 2010, in the Saysetha district, Attapeu Province, Laos. Eligible patients were school children aged 10-15 years who had O viverrini infections. Patients were randomly assigned to one of five different treatment groups by use of a computer-generated randomisation code. We assessed efficacy as cure rate and egg reduction rate in intention-to-treat and per-protocol analyses. The trial was registered with Current Controlled Trials, ISRCTN23425032. ### results 125 children were randomly assigned: 25 received mefloquine, 24 artesunate, 24 mefloquine-artesunate, 27 tribendimidine, and 25 praziquantel. 19 patients were lost to follow-up. In the intention to treat analysis , 14 patients receiving praziquantel were cured compared with none with mefloquine , one with artesunate ( odds ratio 0·03 , 95 % CI 0·004 - 0·29 ) , one with mefloquine-artesunate ( 0·03 , 0·004 - 0·29 ) , and 19 with tribendimidine ( 1·87 , 0·60 - 5·85 ) . Egg reduction rate was 98·4% for praziquantel, 30·2% for mefloquine (egg reduction-rate ratio 1·61, 95% CI 0·21-0·72), 31·5% for artesunate (0·43, 0·23-0·80), 41·3% for mefloquine-artesunate (0·60, 0·31-1·10), and 99·3% for tribendimidine (1·00, 0·44-2·30). Most adverse events were mild or moderate and affected all treatment groups; serious adverse events--vertigo, nausea, vomiting, and anxiety--were reported only by patients taking mefloquine or mefloquine-artesunate. ### interpretation Tribendimidine seems to be at least as efficacious as the drug of choice, praziquantel, for the treatment of O viverrini infections; both drugs were well tolerated. mefloquine, artesunate, and mefloquine-artesunate did not show an effect. Tribendimidine should be further investigated with large clinical trials. ### funding Swiss National Science Foundation, University of Basel.

https://pubmed.ncbi.nlm.nih.gov/21111681/

530b2e275ea93cb02f8d259bdf63376b

Cladribine with Granulocyte Colony-Stimulating Factor , Cytarabine , and Aclarubicin Regimen in Refractory/Relapsed Acute Myeloid Leukemia : A Phase II Multicenter Study .

Cladribine with Granulocyte Colony-Stimulating Factor , Cytarabine , and Aclarubicin Regimen in Refractory/Relapsed Acute Myeloid Leukemia : A Phase II Multicenter Study . Studies targeting cladribine in combination with granulocyte colony-stimulating factor, low-dose cytarabine, and aclarubicin (C-CAG) regimen in relapsed and refractory acute myeloid leukemia (R/R AML) are limited. The complete remission rate after two cycles of C-CAG regimen was 67.6%, and 1-year overall survival and disease-free survival rates were 59.7% and 72.9%, respectively. The C-CAG regimen is significantly effective against R/R AML with a low hematological toxicity and thus serves as an alternative treatment for R/R AML. ### background The optimal salvage chemotherapy regimen for relapsed and refractory acute myeloid leukemia (R/R AML) remains uncertain. Therefore, a phase II study was conducted for the prospective evaluation of the efficacy and safety of the purine analog cladribine in combination with granulocyte colony-stimulating factor (G-CSF), low-dose cytarabine, and aclarubicin (C-CAG) regimen for patients with R/R AML. ### methods A total of 34 patients received C-CAG regimen for salvage treatment as follows: cladribine 5 mg/m ### results All patients received at least two cycles of C-CAG regimen chemotherapy. After two cycles of C-CAG, 23 patients (67.6%) achieved CR, and 5 patients had partial remission (14.7%). At a median follow-up of 15 months (range, 3-38 months), the 1-year overall survival (OS) and disease-free survival (DFS) rates were 59.7% (95% confidence interval [CI], 42.6%-76.8%) and 72.9% (95% CI, 54.3%-91.5%), respectively. The most common adverse effect was myelosuppression. Nonhematological toxicities were mild, and no treatment-related deaths occurred. ### conclusion Preliminary data indicate that the C-CAG regimen chemotherapy is significantly effective against R/R AML with a high remission rate and a low hematological toxicity. Thus, it may serve as an alternative treatment for R/R AML.

https://pubmed.ncbi.nlm.nih.gov/32845551/

ed8e174892bfa279bc6dff6ead1b951f

In guinea pig trachea and human bronchial smooth muscle , SALM was more potent than isoprenaline ( ISO ) , salbutamol ( SALB ) , and clenbuterol ( CLEN ) .

The pharmacology of salmeterol. The pharmacology of salmeterol hydroxynaphthoate (SALM) has been investigated in respiratory tissues in vitro and in animal models in vivo. In guinea pig trachea and human bronchial smooth muscle , SALM was more potent than isoprenaline ( ISO ) , salbutamol ( SALB ) , and clenbuterol ( CLEN ) . The duration of action was greater than 7 h, whereas that for ISO, SALB, and CLEN was 2, 11, and 45 min, respectively. The sustained activity of SALM was reversed by sotalol, but was reestablished when the beta-blocker was removed. SALM was greater than 3000-fold weaker than ISO in cardiac tissues, indicating high beta 2-adrenoceptor selectivity. In the conscious guinea pig, aerosolized SALM, SALB, and CLEN caused dose-related bronchodilatation. The activity of SALM persisted for at least 6 h, compared with less than 2 h for SALB and CLEN. SALM is also a potent inhibitor of mediator release from human lung, this effect being sustained for up to 20 hours. In guinea pig airways in vivo, SALM inhibited histamine-induced plasma protein extravasation for approximately 8 h. salmeterol is a potent and selective beta 2-adrenoceptor agonist with a unique profile of action. It induces persistent bronchodilatation, sustained suppression of mediator release, and long-lasting inhibition of edema formation. This combination of properties may represent an important new advance in the treatment of bronchial asthma.

https://pubmed.ncbi.nlm.nih.gov/1974668/

7e4324b597ca970932933e012a25644d

Combining erlotinib with doxorubicin or docetaxel or SN-38 resulted in additive or even synergistic antiproliferative effects .

Erlotinib induces cell cycle arrest and apoptosis in hepatocellular cancer cells and enhances chemosensitivity towards cytostatics. Hepatocellular carcinoma (HCC) is one of the most common cancer-related causes of death worldwide. In light of the very poor 5-year-survival new therapeutic approaches are urgently needed. Recently, evidence has been accumulated that the epidermal growth factor receptor (EGFR) is a promising target for cancer therapy. Several reports indicate that EGFRs are expressed frequently in HCC, most likely contributing to the aggressive growth characteristics of these tumors. ### methods erlotinib, an inhibitor of EGFR-tyrosine kinase, potently suppresses the growth of various tumors, but its effect on HCC remains to be explored. We therefore studied the antineoplastic potency of erlotinib in human HCC cells (Huh-7 and HepG2 cell lines). ### results We show that erlotinib inhibited HCC growth in a time- and dose-dependent manner. Moreover erlotinib treatment induced apoptosis and resulted in a dose-dependent arrest at the G1/S checkpoint of the cell cycle. Combining erlotinib with doxorubicin or docetaxel or SN-38 resulted in additive or even synergistic antiproliferative effects . ### conclusions Our data demonstrate that in human HCC cells the inhibition of EGFR-tyrosine kinase by erlotinib induces growth inhibition, apoptosis and cell cycle arrest. Additionally, erlotinib enhances the antineoplastic activity of conventional cytostatic drugs. Thus, inhibiting EGFR-tyrosine kinase appears to be a promising treatment strategy in HCC.

https://pubmed.ncbi.nlm.nih.gov/16023762/

8f4e4e227dec85d45c10f67b403c5305

Importantly , the risk of neutropenia 14 days after initiation of treatment with artesunate plus amodiaquine was higher among HIV-infected children than among HIV-uninfected children ( 45 % vs. 6 % ; p < .001 ) .

High risk of neutropenia in HIV-infected children following treatment with artesunate plus amodiaquine for uncomplicated malaria in Uganda. artemisinin-based combination therapies are rapidly being adopted for the treatment of malaria in Africa; however, there are limited data on their safety and efficacy among human immunodeficiency virus (HIV)-infected populations. ### methods We compared malaria treatment outcomes between cohorts of HIV-infected and HIV-uninfected children in Uganda who were observed for 18 and 29 months, respectively. Malaria was treated with artesunate plus amodiaquine, and outcomes were assessed using standardized guidelines. HIV-infected children received trimethoprim-sulfamethoxazole prophylaxis and antiretroviral therapy in accordance with current guidelines. ### results Twenty-six HIV-infected participants experiencing 35 episodes of malaria and 134 HIV-uninfected children experiencing 258 episodes of malaria were included in the study. Twelve HIV-infected children were receiving antiretroviral therapy, 11 of whom were receiving zidovudine. Malaria treatment was highly efficacious in both the HIV-infected and HIV-uninfected cohorts (28-day risk of recrudescence, 0% and 3.6%, respectively); however, there was a trend towards increased risk of recurrent malaria among the HIV-uninfected children (2.9% vs. 13.2%; p = .08). Importantly , the risk of neutropenia 14 days after initiation of treatment with artesunate plus amodiaquine was higher among HIV-infected children than among HIV-uninfected children ( 45 % vs. 6 % ; p < .001 ) . The severity of all episodes of neutropenia in HIV-uninfected children was mild to moderate, and 16% of episodes of neutropenia in the HIV-infected cohort were severe or life-threatening (neutrophil count, <750 cells/mm(3)). In the HIV-infected cohort, the risk of neutropenia was significantly higher among children who received antiretroviral therapy than among those who did not receive antiretroviral therapy (75% vs. 26%; p < .001). ### conclusions artesunate plus amodiaquine was highly efficacious for malaria treatment in HIV-infected children but was associated with a high risk of neutropenia, especially in the context of concurrent antiretroviral use. Our findings highlight an urgent need for evaluation of alternative antimalarial therapies for HIV-infected individuals.

https://pubmed.ncbi.nlm.nih.gov/18444813/

c9295160c182a59fb221a758c0844948

During this period , blood pressure ( BP ) was monitored weekly , and daily rhythms of melatonin , corticosterone , leptin and testosterone were evaluated at the end of the experiment .

Endocrine and cardiovascular rhythms differentially adapt to chronic phase-delay shifts in rats. Disturbances in regular circadian oscillations can have negative effects on cardiovascular function, but epidemiological data are inconclusive and new data from animal experiments elucidating critical biological mechanisms are needed. To evaluate the consequences of chronic phase shifts of the light/dark (LD) cycle on hormonal and cardiovascular rhythms, two experiments were performed. In Experiment 1, male rats were exposed to either a regular 12:12 LD cycle (CONT) or rotating 8-h phase-delay shifts of LD every second day (SHIFT) for 10 weeks. During this period , blood pressure ( BP ) was monitored weekly , and daily rhythms of melatonin , corticosterone , leptin and testosterone were evaluated at the end of the experiment . In Experiment 2, female rats were exposed to the identical shifted LD schedule for 12 weeks, and daily rhythms of BP, heart rate (HR) and locomotor activity were recorded using telemetry. Preserved melatonin rhythms were found in the pineal gland, plasma, heart and kidney of SHIFT rats with damped amplitude in the plasma and heart, suggesting that the central oscillator can adapt to chronic phase-delay shifts. In contrast, daily rhythms of corticosterone, testosterone and leptin were eliminated in SHIFT rats. Exposure to phase shifts did not lead to increased body weight and elevated BP. However, a shifted LD schedule substantially decreased the amplitude and suppressed the circadian power of the daily rhythms of BP and HR, implying weakened circadian control of physiological and behavioural processes. The results demonstrate that endocrine and cardiovascular rhythms can differentially adapt to chronic phase-delay shifts, promoting internal desynchronization between central and peripheral oscillators, which in combination with other negative environmental stimuli may result in negative health effects.

https://pubmed.ncbi.nlm.nih.gov/27459109/

e6ef2ab4a8014182fc22a771b631cf26

Offspring whose father filled at least one prescription of the following medications in the three months preceding conception were considered exposed : chloroquine , hydroxychloroquine , losartan , azithromycin , naproxen , dexamethasone and prednisone .

Risk of pre-term births and major birth defects resulting from paternal intake of COVID-19 medications prior to conception. With the ongoing COVID-19 pandemic, large numbers of people will receive one of the several medications proposed to treat COVID-19, including patients of reproductive age. Given that some medications have shown adverse effects on sperm quality, there might be a transgenerational concern. We aim at examining the association between drugs proposed to treat COVID-19 when taken by the father around conception and any pre-term birth or major birth defects in offspring in a nation-wide cohort study using Danish registry data. Offspring whose father filled at least one prescription of the following medications in the three months preceding conception were considered exposed : chloroquine , hydroxychloroquine , losartan , azithromycin , naproxen , dexamethasone and prednisone . ### results For azithromycin and naproxen, large numbers of offspring were exposed (> 1800 offspring), and we found no association with adverse birth outcomes. For chloroquine, losartan and dexamethasone, exposure was intermediate (~ 900 offspring), and there was no statistically significant association with birth defects. For hydroxychloroquine and prednisone, exposure was limited (< 300 offspring). There is strong evidence that azithromycin and naproxen are safe with respect to pre-term birth and birth defects. With some caution, the other drugs investigated can be considered safe.

https://pubmed.ncbi.nlm.nih.gov/32869015/

a61de2c1b9288243838027e81390bf89

The present work is concerned with simultaneous determination of cefepime ( CEF ) and the co-administered drug , levofloxacin ( LEV ) , in spiked human plasma by applying a new approach , Savitzky-Golay differentiation filters , and combined trigonometric Fourier functions to their ratio spectra .

Application of Savitzky-Golay differentiation filters and Fourier functions to simultaneous determination of cefepime and the co-administered drug, levofloxacin, in spiked human plasma. The present work is concerned with simultaneous determination of cefepime ( CEF ) and the co-administered drug , levofloxacin ( LEV ) , in spiked human plasma by applying a new approach , Savitzky-Golay differentiation filters , and combined trigonometric Fourier functions to their ratio spectra . The different parameters associated with the calculation of Savitzky-Golay and Fourier coefficients were optimized. The proposed methods were validated and applied for determination of the two drugs in laboratory prepared mixtures and spiked human plasma. The results were statistically compared with reported HPLC methods and were found accurate and precise.

https://pubmed.ncbi.nlm.nih.gov/25576942/

b78111ab8e6346e4897ac7fb177d87c0

Forthcoming data from phase 3 placebo-controlled trials of everolimus , one focused on monotherapy for pancreatic NET and the other on combination use with octreotide LAR for patients with advanced NET and a history of carcinoid syndrome , will provide insight into its future place in NET therapy .

Everolimus in the treatment of renal cell carcinoma and neuroendocrine tumors. Renal cell carcinoma (RCC) and neuroendocrine tumors (NET) are uncommon malignancies, highly resistant to chemotherapy, that have emerged as attractive platforms for evaluating novel targeted regimens. everolimus is an oral rapamycin derivative within the mammalian target of rapamycin class of agents. Preclinical series have shown that everolimus exhibits anticancer effects in RCC and NET cell lines. A phase 3 placebo-controlled study in advanced clear-cell RCC, known as RECORD-1 (for "REnal Cell cancer treatment with Oral RAD001 given Daily"), documented that everolimus stabilizes tumor progression, prolongs progression-free survival and has acceptable tolerability in patients previously treated with the multikinase inhibitors sunitinib and/or sorafenib. everolimus has been granted regulatory approval for use in sunitinib-pretreated and/or sorafenib-pretreated advanced RCC and incorporated into clinical practice guidelines, and the RECORD-1 safety data are being used to develop recommendations for managing clinically important adverse events in everolimus-treated patients. Ongoing clinical trials are evaluating everolimus as earlier RCC therapy (first-line for advanced disease and as neoadjuvant therapy), in non-clear-cell tumors, and in combination with various other approved or investigational targeted therapies for RCC. Regarding advanced NET, recently published phase 2 data support the ability of everolimus to improve disease control in patients with advanced NET as monotherapy or in combination with somatostatin analogue therapy, octreotide long-acting release (LAR). Forthcoming data from phase 3 placebo-controlled trials of everolimus , one focused on monotherapy for pancreatic NET and the other on combination use with octreotide LAR for patients with advanced NET and a history of carcinoid syndrome , will provide insight into its future place in NET therapy . The results of a number of ongoing phase 3 evaluations of everolimus will determine its broader applicability in treating breast cancer (in combination with chemotherapy and hormonal therapy), several advanced gastrointestinal cancers, hepatocellular carcinoma, and lymphoma (in the adjuvant setting), as well as the various lesions associated with the tuberous sclerosis complex tumor suppressor gene.

https://pubmed.ncbi.nlm.nih.gov/20623346/

2139b0194d74f7931e11395298f4b7b7

The effects of prednisone and azathioprine on circulating immunoglobulin levels and lymphocyte subpopulations in normal dogs .

The effects of prednisone and azathioprine on circulating immunoglobulin levels and lymphocyte subpopulations in normal dogs . This study investigates serum immunoglobulin (SIg) levels and lymphocyte subpopulations in normal dogs in response to putative immunosuppressive doses of prednisone and/or azathioprine. The objectives were to quantify SIg levels and lymphocyte subpopulations, including Thy-1+, CD4+, CD8+ and B cells, in normal dogs both before and after the administration of prednisone and/or azathioprine at 2 mg/kg, PO, each. Eighteen beagles were divided into 3 groups of 6 dogs each. Blood samples for radial immunodiffusion assay of IgG, IgM and IgA, complete blood count (CBC)and flow cytometry were collected prior to the administration of any drugs and again after 14 d of azathioprine, prednisone or azathioprine and prednisone. Peripheral blood mononuclear cells were isolated using density centrifugation and were incubated with monoclonal antibodies reacting with CD4+, CD8+, Thy-1+ and membrane immunoglobulin. Lymphocyte subsets were quantified using flow cytometry. azathioprine-treated dogs had no significant changes in SIg levels or lymphocyte subpopulations. prednisone-treated dogs had significant (P < 0.05) decreases in all SIg levels, all lymphocyte subpopulations and erythrocyte numbers, and had an increase in neutrophil counts. prednisone and azathioprine-treated dogs had significant (P < 0.05) decreases in serum IgG levels and Thy-1+ and CD8+ lymphocyte subpopulations, with an increase in the CD4:CD8. These dogs also had a significant decrease in erythrocyte number and a significant increase in the monocyte count. These findings suggest that azathioprine and prednisone in combination or prednisone alone may be useful for the treatment of T cell-mediated diseases since decreased circulating T cell levels were demonstrated following treatment. The combination of drugs or azathioprine alone may not be appropriate for treatment of acute or autoantibody-mediated immune disease, because SIg levels were minimally affected by treatment.

https://pubmed.ncbi.nlm.nih.gov/9918329/

f879c21487b13e35c833840fda58d3a7

The analytical range for dihydroartemisinin , dihydroartemisinin-glucuronide and artesunate was 10 - 1000 ng/ml and for artemether 90 - 3000 ng/ml with a lower limit of quantification of 10 and 90 ng/ml , respectively .

Development and validation of a liquid chromatography and ion spray tandem mass spectrometry method for the quantification of artesunate, artemether and their major metabolites dihydroartemisinin and dihydroartemisinin-glucuronide in sheep plasma. Recently, promising fasciocidal activities of artesunate and artemether were described in rats and sheep. Therefore, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to quantify artesunate, artemether and their metabolites dihydroartemisinin and dihydroartemisinin-glucuronide in sheep plasma. Protein precipitation with methanol was used for sample workup. Reversed-phase high-performance liquid chromatography (HPLC) was performed using an Atlantis C18 analytical column with a mobile phase gradient system of ammonium formate and acetonitrile. The analytes were detected by MS/MS using selected reaction monitoring (SRM) with electrospray ionisation in the positive mode (transition m/z 267.4 → 163.0). The analytical range for dihydroartemisinin , dihydroartemisinin-glucuronide and artesunate was 10 - 1000 ng/ml and for artemether 90 - 3000 ng/ml with a lower limit of quantification of 10 and 90 ng/ml , respectively . Inter- and intra-day accuracy and precision deviations were < 10%. Consistent relative recoveries (60-80%) were observed over the investigated calibration range for all analytes. All analytes were stable in the autosampler for at least 30 h (6 °C) and after three freeze and thaw cycles. The validation results demonstrated that the LC-MS/MS method is precise, accurate and selective and can be used for the determination of the artemisinins in sheep plasma. The method was applied successfully to determine the pharmacokinetic parameters of artesunate and its metabolites in plasma of intramuscularly treated sheep.

https://pubmed.ncbi.nlm.nih.gov/21259399/

2e2b58482bca022994e3931d9f553e16

Amphotericin B MICs were reduced upon combination with rifabutin from a mean of 0.65 microg/ml to a mean of 0.16 microg/ml against Aspergillus , and from a mean of 0.97 microg/ml to a mean of 0.39 microLg/ml against Fusarium ( P < 0.000001 for both ) .

Inhibition of RNA synthesis as a therapeutic strategy against Aspergillus and Fusarium: demonstration of in vitro synergy between rifabutin and amphotericin B. We investigated the in vitro antifungal activity of amphotericin B, alone and in combination with rifabutin, an inhibitor of bacterial RNA polymerase, against 26 clinical isolates of Aspergillus and 25 clinical isolates of Fusarium. Synergy or additivism between these drugs was demonstrated against all isolates tested. Amphotericin B MICs were reduced upon combination with rifabutin from a mean of 0.65 microg/ml to a mean of 0.16 microg/ml against Aspergillus , and from a mean of 0.97 microg/ml to a mean of 0.39 microLg/ml against Fusarium ( P < 0.000001 for both ) . Similarly, the MICs of rifabutin were reduced upon combination with amphotericin B from a mean of >32 microg/ml to a mean of 1.1 microg/ml against both fungi (P < 0.000001 for both). These positive interactions were corroborated by a colony count study with two Fusarium isolates, for which treatment with the combination of subinhibitory concentrations of amphotericin B (at concentrations 2- and 4-fold less than the MIC) and rifabutin (at concentrations ranging from 4- to 64-fold less than the MIC) resulted in 3.2-log reductions in colony counts compared to those after treatment with either drug alone. Inhibition of RNA synthesis was shown to be the mechanism of antifungal activity. These results suggest that inhibition of fungal RNA synthesis might be a potential target for antifungal therapy.

https://pubmed.ncbi.nlm.nih.gov/9517924/