Validation of a liquid chromatographic method for the pharmaceutical quality control of products containing elacridar

Many anticancer drugs have an impaired bioavailability and poor brain penetration because they are substrates to drug efflux pumps such as P-glycoprotein and Breast Cancer Resistance Protein.Elacridar is a strong inhibitor of these two drug efflux pumps and therefore has great potential to improve oral absorption and brain penetration of many anticancer drugs.Currently,a clinical formulation of elacridar is unavailable and therefore the pharmaceutical development of a drug product is highly warranted.This also necessitates the availability of an analytical method for its quality control.A reverse-phase high-performance liquid chromatographic method with ultraviolet detection was developed for the pharmaceutical quality control of products containing elacridar as the active pharmaceutical ingredient.The analytical method was validated for linearity,accuracy,precision,selectivity,carry-over,stability of stock and reference solutions,stability of the final extract,stability-indicating capability and impurity testing.We found that elacridar is unstable in aqueous solutions that are exposed to light because a hydroxylation product of elacridar is formed.Therefore,sample solutions with elacridar must be protected from light.

性格、生活方式与心血管疾病和癌症风险的关系:基于人群的队列随访研究

目的:在大样本队列中研究性格测试指标与心血管疾病和癌症风险的关系。设计:基于人群的队列随访研究。地点:德国海德堡。参与者:1992—1995年间5114例年龄在40～65岁的男性和女性。

口服红霉素与心源性猝死的风险

BACKGROUND: Oral erythromycin prolongs cardiac repolarization and is associated with case reports of torsades de pointes. Because erythromycin is extensively metabolized by cytochrome P-450 3A(CYP3A) isozymes, commonly used medications that inhibit the effects of CYP3A may increase plasma erythromycin concentrations, thereby increasing the risk of ventricular arrhythmias and sudden death. We studied the association between the use of erythromycin and the risk of sudden death from cardiac causes and whether this risk was increased with the concurrent use of strong inhibitors of CYP3A. METHODS: We studied a previously identified Tennessee Medicaid cohort that included 1,249,943 person-years of follow-up and 1476 cases of confirmed sudden death fromcardiac causes. The CYP3A inhibitors used in the study were nitroimidazole antifungal agents, diltiazem, verapamil, and troleandomycin; each doubles, at least, the area under the time-concentration curve for a CYP3A substrate. Amoxicillin, an antimicrobial agent with similar indications but which does not prolong cardiac repolarization, and former use of erythromycin also were studied, to assess possible confounding by indication. RESULTS: The multivariate adjusted rate of sudden death fromcardiac causes among patients currently using erythromycinwas twice as high (incidence-rate ratio, 2.01; 95 percent confidence interval, 1.08 to 3.75; P=0.03) as that among those who had not used any of the study antibiotic medications. There was no significant increase in the risk of sudden death among former users of erythromycin(incidence-rate ratio, 0.89; 95 percent confidence interval, 0.72 to 1.09; P=0.26) or among those who were currently using amoxicillin (incidence-rate ratio, 1.18; 95 percent confidence interval, 0.59 to 2.36; P=0.65). The adjusted rate of sudden death from cardiac causes was five times as high (incidence-rate ratio, 5.35; 95 percent confidence interval, 1.72 to 16.64; P=0.004) among those who concurrently used CYP3A inhibitors and erythromycin as that among those who had used neither CYP3A inhibitors nor any of the study antibiotic medications. In contrast, there was no increase in the risk of sudden death among those who concurrently used amoxicillin and CYP3A inhibitors or those currently using any of the study antibiotic medications who had formerly used CYP3A inhibitors. CONCLUSIONS: The concurrent use of erythromycin and strong inhibitors of CYP3A should be avoided.

药物治疗帕金森病患者与突发难治性嗜睡

Background: Episodes of sudden uncontrollable somnolence have been reported in patients with Parkinson disease (PD) receiving dopamine agonists, including pramipexole and ropinirole, but controversy persists concerning their nature, severity, and frequency. Abstract:Objectives: To quantify the risk of sudden uncontrollable somnolence in patients taking specific PD medications and to define its predictors. Methods: We contacted 929 patients with PD and administered a 45-to 60-minute interview addressing medication use, adverse events, and the patient’s clinical status in the preceding 6 months. Their physicians completed record reviews detailing their clinical histories and drug regimens. The outcome of interest in this case-control study was an episode of somnolence that was uncontrollable, severe, and inappropriate, such as while driving or engaged in social activity. For multiple events, the first was chosen as the index event. For each case, we sampled control time from all respondents who had no event as of the index time for that case. Multiple logistic regression was used to adjust for potential confounders. Results: Episodes of uncontrollable somnolence were reported by 22%of all respondents. After controlling for age, sex, PD duration and severity, frailty, and other medication use, we found that patients receiving a dopamine agonist (pramipexole, ropinirole, or pergolide) were nearly 3-fold as likely to have episodes of sudden uncontrollable somnolence (odds ratio, 2.8; 95%confidence interval, 1.8-4.2) compared with all other PD medication users. Similar risks were seen for the 3 agents, pramipexole, ropinirole, and pergolide, each compared with levodopa alone (odds ratio, 2.2, 1.8, and 2.1, respectively), with a clear dose-response relationship for each. No increase in risk was seen with any other drugs studied. Conclusions: Dopamine agonists widely used for the management of PD significantly increase the risk of sudden uncontrollable somnolence in a dose-related manner. Greater attention to this potentially serious adverse effect will be necessary to improve the safety of use of this important category of PD drugs.

反复住院预示社区心力衰竭人群的死亡率

背景:识别具有高死亡风险的患者对于适当处置患者和卫生保健资源至关重要。因心力衰竭(HF)反复住院对死亡率的影响尚未在大样本的社区HF人群中进行研究。本研究旨在依据患者因HF住院次数确定其生存特点。方法:通过卫生保健利用数据库,识别2000—2004年英属哥伦比亚所有居民中首次因HF住院的患者队列。

Carboxylesterase 1 family knockout alters drug disposition and lipid metabolism

The mammalian carboxylesterase 1(Ces1/CES1)family comprises several enzymes that hydrolyze many xenobiotic chemicals and endogenous lipids.To investigate the pharmacological and physiological roles of Ces1/CES1,we generated Ces1 cluster knockout(Ces1^(-/-))mice,and a hepatic human CES1 transgenic model in the Ces1^(-/-)background(TgCES1).Ces1^(-/-)mice displayed profoundly decreased conversion of the anticancer prodrug irinotecan to SN-38 in plasma and tissues.TgCES1 mice exhibited enhanced metabolism of irinotecan to SN-38 in liver and kidney.Ces1 and hCES1 activity increased irinotecan toxicity,likely by enhancing the formation of pharmacodynamically active SN-38.Ces1^(-/-)mice also showed markedly increased capecitabine plasma exposure,which was moderately decreased in TgCES1 mice.Ces1^(-/-)mice were overweight with increased adipose tissue,white adipose tissue inflammation(in males),a higher lipid load in brown adipose tissue,and impaired blood glucose tolerance(in males).These phenotypes were mostly reversed in TgCES1 mice.TgCES1 mice displayed increased triglyceride secretion from liver to plasma,together with higher triglyceride levels in the male liver.These results indicate that the carboxylesterase 1 family plays essential roles in drug and lipid metabolism and detoxification.Ces1^(-/-)and TgCES1 mice will provide excellent tools for further study of the in vivo functions of Ces1/CES1 enzymes.

SGLT2抑制剂上市后的新风险——药品监管机构的及时性与透明度

随着钠-葡萄糖共转运蛋白2(SGLT2)抑制剂新风险的陆续出现,药品监管机构应该如何应对?Alice Bhasale和同事比较了各主要药品监管机构公共安全信息传达的数量、及时性、力度和透明度。

Linking the Paul Coverdell National Acute Stroke Program to commercial claims to establish a framework for real-world longitudinal stroke research

Background Non-interventional large-scale research on real-world patients who had a stroke requires the use of multiple data sources ensuring access to longitudinal data from large populations with clinically-detailed information.We sought to establish a framework for longitudinal research on patients hospitalised with stroke by linking information-rich,deidentified inpatient data from the Paul Coverdell National Acute Stroke Program(PCNASP)to commercial and Medicare Advantage longitudinal claims data.Methods All stroke admissions in PCNASP between 2008 and 2015 were evaluated for linkage to longitudinal claims from a commercial insurer using an algorithm based on six available common data fields(patient age,gender,admission date,discharge date,discharge diagnosis and state)and a hospital match.We evaluated the linkage quality(via the percentage of unique records in the linked dataset)and the representativeness of the linked population.We also described medical history,stroke severity and patterns of medication use among the PCNASP-claims linked cohort.Results The linkage produced uniqueness equal to 99.1%.We identified 5644 linked and 98896 unlinked patients who had an ischaemic stroke hospitalisation in claims data.Linked patients were younger than unlinked(69.7 vs 72.5 years),but otherwise similar by medical history,prestroke medication use or lab values.Stroke severity was mild and most patients were discharged home.Prestroke and discharge use of antihypertensive and statins in the PCNASP were greater than their use as measured by filled prescriptions in claims.Conclusions High-quality linkage between the PCNASP and commercial claims data is feasible.This linkage identified differences between reported or recommended versus actual out-of-hospital medication utilisation,highlighting the importance of longitudinal data availability for research aimed to improve the care of patients who had a stroke.