Co-administration Of Pump Inhibitors Research Articles

The Tetrahydroisoquinoline Scaffold in ABC Transporter Inhibitors that Act as Multidrug Resistance (MDR) Reversers.

The failure of anticancer chemotherapy is often due to the development of resistance to a variety of anticancer drugs. This phenomenon is called multidrug resistance (MDR) and is related to the overexpression of ABC transporters, such as P-glycoprotein, multidrug resistance- associated protein 1 and breast cancer resistance protein. Over the past few decades, several ABC protein modulators have been discovered and studied as a possible approach to evade MDR and increase the success of anticancer chemotherapy. Nevertheless, the co-administration of pump inhibitors with cytotoxic drugs, which are substrates of the transporters, does not appear to be associated with an improvement in the therapeutic efficacy of antitumor agents. However, more recently discovered MDR reversing agents, such as the two tetrahydroisoquinoline derivatives tariquidar and elacridar, are characterized by high affinity towards the ABC proteins and by reduced negative properties. Consequently, many analogs of these two derivatives have been synthesized, with the aim of optimizing their MDR reversal properties. This review aims to describe the MDR modulators carrying the tetraidroisoquinoline scaffold reported in the literature in the period 2009-2021, highlighting the structural characteristics that confer potency and/or selectivity towards the three ABC transport proteins. Many compounds have been synthesized in the last twelve years showing interesting properties, both in terms of potency and selectivity. Although clear structure-activity relationships can be drawn only by considering strictly related compounds, some of the compounds reviewed could be promising starting points for the design of new ABC protein inhibitors.

Abstract 2: Co-administration of Proton-Pump Inhibitors with Thienopyridines Increases Risk of Adverse Cerebrovascular Outcomes

Background: Pharmacokinetic and prior interaction studies on thienopyridine-proton pump inhibitors (PPI) provide conflicting data for cardiovascular outcomes. There is no established evidence on the association of concomitant use of PPI-thienopyridine with adverse cerebrovascular outcomes. Methods: We conducted a systematic review and meta-analysis of randomized controlled trials (RCT) and cohort studies from inception to December 2016, reporting following outcomes among patients treated with thienopyridine + PPI vs. thienopyridine alone: 1. ischemic stroke (IS), 2. combined ischemic and hemorrhagic stroke, 3. composite outcome of stroke, myocardial infarction (MI) and cardiovascular (CV) death, 4. MI, 5. all-cause mortality, and 6. major or minor bleeding events. We performed subgroup analyses to assess IS recurrence rates for eligible studies, and assess outcomes amongst the two study designs. We calculated pooled relative risk (RR) ratios and 95% CI using random-effects models. Results: We identified 22 studies (12 RCTs and 10 cohort studies) with 131,714 participants. Concomitant use of PPI and thienopyridines was associated with increased risk of IS [RR=1.75 (95%CI: 1.41-2.16), I 2 =0%], composite stroke/MI/CV death [RR=1.14 (95%CI 1.01-1.29), I 2 =74%], and MI [RR=1.19 (95%CI: 1.0-1.4), I 2 =80%]. The co-administration of PPI and thienopyridines was not associated with the risk of combined ischemic and hemorrhagic stroke, cardiovascular death, major or minor bleeding, and all-cause mortality. Subgroup analyses demonstrated increased risk of IS [RR=1.6 (95%CI: 1.1-2.3), I 2 =33%] and combined ischemic and hemorrhagic stroke [RR=1.34 (95%CI: 1.1-1.63), I 2 =0%] in cohort studies, while RCTs demonstrated significant risk for composite stroke/MI/CV death [RR=1.17 (95%CI: 1.04-1.32), I 2 =72%]. PPI-thienopyridine co-prescription did not increase the risk of stroke recurrence in patients with prior IS. Conclusions: PPI-thienopyridine co-prescription increases the risk of IS and composite stroke/MI/CV death. Our findings highlight the need for pharmacovigilance and corroborate with current guidelines for PPI deprescription, especially in patients treated with thienopyridines for the prevention of cerebrovascular events.

Tranexamic acid for upper gastrointestinal bleeding.

Background Tranexamic acid reduces haemorrhage through its antifibrinolytic effects. In a previous version of the present review, we found that tranexamic acid may reduce mortality. This review includes updated searches and new trials.Objectives To assess the effects of tranexamic acid versus no intervention, placebo or other antiulcer drugs for upper gastrointestinal bleeding.Search methods We updated the review by performing electronic database searches (Cochrane Central Register of Controlled Trials (CENTRAL),MEDLINE, EMBASE, Science Citation Index) and manual searches in July 2014.Selection criteriaRandomised controlled trials, irrespective of language or publication status.Data collection and analysis We used the standard methodological procedures of the The Cochrane Collaboration. All-cause mortality, bleeding and adverse events were the primary outcome measures. We performed fixed-effect and random-effects model meta-analyses and presented results as risk ratios (RRs) with 95% confidence intervals (CIs) and used I² as a measure of between-trial heterogeneity. We analysed tranexamic acid versus placebo or no intervention and tranexamic acid versus antiulcer drugs separately. To analyse sources of heterogeneity and robustness of the overall results, we performed subgroup, sensitivity and sequential analyses.Main results We included eight randomised controlled trials on tranexamic acid for upper gastrointestinal bleeding. Additionally, we identified one large ongoing pragmatic randomised controlled trial from which data are not yet available. Control groups were randomly assigned to placebo (seven trials) or no intervention (one trial). Two trials also included a control group randomly assigned to antiulcer drugs(lansoprazole or cimetidine). The included studies were published from 1973 to 2011. The number of participants randomly assigned ranged from 47 to 216 (median 204). All trials reported mortality. In total, 42 of 851 participants randomly assigned to tranexamic acid and 71 of 850 in the control group died (RR 0.60, 95% CI 0.42 to 0.87; P value 0.007; I² = 0%). The analysis was not confirmed when all participants in the intervention group with missing outcome data were included as treatment failures, or when the analysis was limited to trials with low risk of attrition bias. Rebleeding was diagnosed for 117 of 826 participants in the tranexamic acid group and for 146 of 825 participants in the control group (RR 0.80, 95% CI 0.64 to 1.00; P value 0.07; I² = 49%).We were able to evaluate the risk of serious adverse events on the basis of only four trials. Our analyses showed 'no evidence of a difference between tranexamic acid and control interventions regarding the risk of thromboembolic events.’ Tranexamic acid appeared to reduce the risk of surgery ina fixed-effect meta-analysis (RR 0.73, 95% CI 0.56 to 0.95), but this result was no longer statistically significant in a random-effects meta-analysis (RR 0.61, 95% CI 0.35 to 1.04; P value 0.07). No difference was apparent between tranexamic acid and placebo in the assessment of transfusion (RR 1.02, 95% CI 0.94 to 1.11; I² = 0%), and meta-analyses that compared tranexamic acid versus antiulcer drugs did not identify beneficial or detrimental effects of tranexamic acid for any of the outcomes assessed.Authors' conclusions This review found that tranexamic acid appears to have a beneficial effect on mortality, but a high dropout rate in some trials means that we cannot be sure of this until the findings of additional research are published. At the time of this update in 2014, one large study(8000 participants) is in progress, so this review will be much more informative in a few years. Further examination of tranexamic acid would require inclusion of high-quality randomised controlled trials. Timing of randomisation is essential to avoid attrition bias and to limit the number of withdrawals. Future trials may use a pragmatic design and should include all participants with suspected bleeding or with endoscopically verified bleeding, as well as a tranexamic placebo arm and co-administration of pump inhibitors and endoscopic therapy. Assessment of outcome measures in such studies should be clearly defined. Endoscopic examination with appropriate control of severe bleeding should be performed, as should endoscopic verification of clinically significant rebleeding. In addition, clinical measures of rebleeding should be included. Other important outcome measures include mortality (30-day or in-hospital), need for emergency surgery or blood transfusion and adverse events (major or minor).

Taxol-oligoarginine conjugates overcome drug resistance in-vitro in human ovarian carcinoma

ObjectiveMultidrug resistance is the major cause of failure of many chemotherapeutic agents. While resistance can arise from several factors, it is often dominated by drug efflux mediated by P-glycoprotein (P-gp), a membrane-bound polysubstrate export pump expressed at high levels in resistant cells. While co-administration of pump inhibitors and a drug could suppress efflux, this two-drug strategy has not yet advanced to therapy. We recently demonstrated that the reversible attachment of a guanidinium-rich molecular transporter, polyarginine, to a drug provides a conjugate that overcomes efflux-based resistance in cells and animals. This study is to determine whether this strategy for overcoming resistance is effective against human disease. MethodsTumor samples from ovarian cancer patients, both malignant ascites cells and dissociated solid tumor cells, were exposed to Taxol-oligoarginine conjugates designed to release free drug only after cell entry. Cell viability was determined via propidium-iodide uptake by flow cytometry. To analyze bystander effect, toxicity of the drug conjugates was also tested on peripheral blood leucocytes. ResultsHuman ovarian carcinoma specimens resistant to Taxol in vitro demonstrated increased sensitivity to killing by all Taxol-transporter conjugates tested. These studies also show that the drug conjugates were not significantly more toxic to normal human peripheral blood leukocytes than Taxol. ConclusionsThese studies with human tumor indicate that oligoarginine conjugates of known drugs can be used to overcome the efflux-based resistance to the drug, providing a strategy that could improve the treatment outcomes of patients with efflux-based drug-resistance.