Interaction between warfarin and cannabis

Delta‐9‐tetrahydrocannabinol (THC), the main psychoactive cannabinoid in cannabis, may inhibit the cytochrome P450 enzyme CYP2C9. Consequently, cannabis use might infer a risk of drug‐drug interaction with substrates for this enzyme, which includes drugs known to have a narrow therapeutic window. In this study, we describe a case report of a 27‐year‐old man treated with warfarin due to mechanical heart valve replacement who presented with elevated international normalized ratio (INR) value (INR = 4.6) following recreational cannabis use. We conducted a review of the available literature, using the PubMed and EMBASE databases while following PRISMA guidelines. Following screening of 85 articles, three eligible articles were identified, including one in vitro study and two case reports. The in vitro study indicated that THC inhibits the CYP2C9‐mediated metabolism of warfarin. One case study reported of a man who on two occasions of increased marijuana use experienced INR values above 10 as well as bleeding. The other case study reported of a patient who initiated treatment with a liquid formulation of cannabidiol for the management of epilepsy, ultimately necessitating a 30% reduction in warfarin dose to maintain therapeutic INR values. The available, although sparse, data suggest that use of cannabinoids increases INR values in patients receiving warfarin. Until further data are available, we suggest patients receiving warfarin be warned against cannabis use.     

Interaction between midazolam and clarithromycin in the elderly

AIM

To assess the relative contribution of intestinal and hepatic CYP3A inhibition to the interaction between the prototypic CYP3A substrate midazolam and clarithromycin in the elderly.

METHODS

On day 1, 16 volunteers (eight male, eight female) aged 65–75 years weighing 59–112 kg received simultaneous doses of midazolam intravenously (i.v.) (0.05 mg kg⁻¹ over 30 min) and orally (p.o.) (3.5 mg of a stable isotope, ¹⁵N₃-midazolam). Starting on day 2, clarithromycin 500 mg was administered orally twice daily for 7 days. On day eight, i.v. and p.o. doses of midazolam were administered 2 h after the final clarithromycin dose. Serum and urine samples were assayed for midazolam, ¹⁵N₃-midazolam and metabolites by gas chromatography/mass spectometry.

RESULTS

Men and women exhibited similar i.v. (30.4 vs. 36.0 l h⁻¹) and p.o. (119 vs. 124 l h⁻¹) clearances of midazolam. Midazolam hepatic availability was significantly (P = 0.006) greater in men [0.79, 95% confidence interval (CI) 0.75, 0.84] than in women (0.66, 95% CI 0.59, 0.73), but midazolam intestinal availability (0.39 vs. 0.55) was not different. Following clarithromycin dosing, a significant decrease in systemic (33.2 l h⁻¹ to 11.5 l h⁻¹) and oral (121 l h⁻¹ to 17.4 l h⁻¹) midazolam clearance occurred. Oral, hepatic and intestinal availability was significantly increased after clarithromycin dosing from 0.34 to 0.72, 0.73 to 0.91 and 0.47 to 0.79, respectively. Clarithromycin administration led to an increase in the AUC of midazolam by 3.2-fold following i.v. dosing and 8.0-fold following p.o. dosing. Similar effects were observed for males and females.

CONCLUSIONS

Intestinal and hepatic CYP3A inhibition by clarithromycin significantly reduces the clearance of midazolam in the elderly.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Clarithromycin is a mechanism-based inhibitor of CYP3A that has been shown to inhibit midazolam hydroxylation in young, healthy subjects.
• Elderly persons exhibit altered metabolism of a variety of drugs, including clarithromycin.
• However, the consequences of increased exposure to an inhibitor drug on CYP3A activity have not been addressed.

WHAT THIS STUDY ADDS

• This study utilized intravenous and oral midazolam as in vivo probes to examine the effect of clarithromycin on intestinal and hepatic CYP3A activity.
• Although clarithromycin concentrations are greater in elderly individuals than in young, healthy volunteers, intestinal and hepatic CYP3A enzymes are inhibited to a similar extent as in the young.

     

Statins and fracture risk. A systematic review

PURPOSE: To summarize current evidence on statin use and fracture risk and to explore potential sources of heterogeneity among study results. METHODS: A computerized search was conducted on MEDLINE, EMBASE, and the Cochrane databases using the keywords HMG-CoA reductase inhibitor, osteoporosis, and fractures. A meta-analysis was performed to summarize results of studies identified. RESULTS: Statin use was associated with a 23% lower fracture risk (OR = 0.77, 95%CI: 0.66-0.90). An effect of statins was found in case-control (OR = 0.62, 0.45-0.85, n = 6) and cohort (OR = 0.77, 0.59-1.00, n = 8) studies, but not in post hoc analyses of randomized trials (OR = 1.03, 0.91-1.16, n = 4). A reduced risk with statin use was found for fractures of the hip (OR = 0.58, 0.46-0.74, n = 16), spine (OR = 0.65, 0.48-0.88, n = 8) and other sites (OR = 0.77, 0.60-1.00, n = 7), and both in women (OR = 0.80, 0.66-0.96, n = 11) and men (OR = 0.62, 0.36-1.08, n = 3). Among the observational studies that also evaluated the effect of other lipid-lowering drugs, no reduced fracture risk was found for these agents (OR = 0.96, 0.85-1.09, n = 10). The test for heterogeneity was significant for study results of statin use versus no-use (p < 0.01). Meta-regression analyses suggested that study design might partly account for the heterogeneity. There was an indication of publication bias by examining Begg's plot, although Egger's test was not significant (p = 0.13). CONCLUSIONS: Current evidence does not support an effect of statins in preventing fractures given (i) the lack of association in randomized trials, (ii) the heterogeneity among observational studies, (iii) the potential residual confounding, and (iv) the potential publication bias.     

克拉霉素与茜素红的荷移反应及其测定

目的建立测定克拉霉素制剂含量的方法。方法利用克拉霉素与茜素红在水-醇介质中发生电荷转移反应,形成电荷转移络合物,采用可见分光光度法测定。结果荷移反应生成的荷移络合物在526nm处有最大吸收,络合物的组成比是1∶1,表观摩尔吸光系数是7.71×103L.mol-1.cm-1,药物浓度在5~90mg/L范围内服从比耳定律,方法平均回收率在98.0%以上,RSD为1.3%(n=6)。结论方法稳定、准确、灵敏、快速,对样品的测定结果令人满意。     

Synthesis of [N‐methyl‐13C]clarithromycin

We describe a simple synthesis of [N‐methyl‐¹³C]clarithromycin ( 3 ) via the N‐desmethylation of clarithromycin. Copyright © 2004 John Wiley & Sons, Ltd.     

药物制剂中药物与辅料相互作用的研究进展

药物制剂中药物与辅料间的相互作用对药物的溶解度、稳定性、生物利用度等方面具有正向或负向的影响.因此,在药物制剂研发过程中,对药物与辅料间、辅料与辅料间相互作用的考察不可缺少.本文就近年来国内外固体制剂、液体制剂和载体给药系统中的原辅料相互作用以及用于相容性研究的分析方法等研究进展进行综述,为药物制剂研究中的处方筛选及剂...     

依折麦布联合他汀类药物调血脂对主要心血管事件影响的系统评价

目的 系统评价依折麦布联合他汀类药物与单药应用双倍剂量他汀调血脂治疗中对主要心血管事件的影响。方法 检索CENTRAL、PubMed、EMBASE、中国生物医学文献数据库（CBM）、中国学术期刊全文数据库（CNKI）和万方等数据库,收集依折麦布联合他汀类药物与双倍剂量他汀类药物调脂治疗心血管不良事件的随机对照试验（RCT）,检索时限均从建库至2018年4月1日。由2名评价员独立筛选文献、提取资料并评价纳入研究的方法学质量,采用RevMan 5.3和R3.3.1软件进行数据分析。结果 共纳入16个RCTs,共3 534例患者。Meta-分析结果显示与单药应用双倍剂量他汀组相比,依折麦布联合他汀组可降低心绞痛［RR=0.36,95% CI（0.21,0.63）,P=0.000 3］、心肌梗死［RR=0.59,95% CI（0.36,0.95）,P=0.03］和主要心血管不良事件（心源性死亡、心绞痛、心肌梗死、血运重建）［RR=0.58,95% CI（0.38,0.87）,P=0.009］的发生风险,且具有统计学差异;两组血运重建、心源性死亡、卒中和全因死亡风险无统计学差异。结论 现有证据表明依折麦布联合他汀类药物比单药应用双倍剂量他汀能进一步降低不良心血管事件发生风险,但上述结果尚需更多多中心、大样本随机对照试验进一步证实。     

Interaction between valproate formulation and phenytoin concentrations

Changes in phenytoin concentrations caused by switching valproate formulations with different absorption rates were retrospectively investigated in eleven epileptic patients receiving treatment with both drugs. Total plasma phenytoin concentrations were measured before and after a standard tablet of valproate was replaced by the same dose as a slow-release tablet.The mean plasma phenytoin level rose significantly from 14.4 to 18.7 g·ml^–1. Nine of eleven patients had markedly increased phenytoin levels (by 21 to 72%), and two developed toxic symptoms.The results indicate that changing valproate formulations can cause major alterations in the plasma concentration of co-administered phenytoin.     

异基因造血干细胞移植患者体内环孢素A和伏立康唑的相互作用

目的 分析异基因造血干细胞移植（Allo-HSCT）患者,静脉滴注伏立康唑（VRZ）与环孢素A（CsA）后的药物相互作用（DDI）,为临床精准药物治疗提供依据。方法 进行一项患者自身对照研究,根据纳入排除标准,收集2019年1月—12月在某院进行Allo-HSCT的患者,采用LC-MS/MS法测定术前CsA给药后3～5 d的血药浓度2次,测定术后VRZ给药5～7 d后,CsA和VRZ同一时间的血药浓度2次,分别求其给药前后CsA、VRZ血药浓度的平均值。使用SPSS 20.0对VRZ给药前后CsA标准化血药浓度（C/D）的差异及VRZ血药浓度对CsA的C/D变化进行统计分析。结果 共纳入Allo-HSCT患者15例,用Wilcoxon符号秩和检验比较给药VRZ前后,CsA的C/D中位数变化,有显著性差异（P<0.001）。对VRZ血药浓度与CsA的C/D比值增幅进行Spearman相关性分析,两者无显著相关性（ρ=?0.273,P=0.32）。结论 CsA与VRZ之间存在明显的药物相互作用（DDI）,VRZ使CsA血药浓度显著升高,但VRZ与CsA之间的DDI程度大小与VRZ血药浓度无关,可能与患者个体差异有关。     

非甾体抗炎药物与ACE抑制剂的相互作用

非甾体抗炎药可能通过抑制前列腺素的合成而削弱血管紧张素转换酶抑制剂的有益作用，如对原发性高血压、心肌梗死和充血性心力衰竭的治疗方面。作者对两者相互作用的临床试验研究进行了综述，目前比较肯定的是非甾体抗炎药吲哚美辛对血管紧张素转换酶抑制剂(ACE)降压作用的影响，而阿斯匹林与后者之间的相互作用结果不一，需要进行更多的前瞻性临床试验。     

Australian school-based prevention programs for alcohol and other drugs: A systematic review

Issues. To reduce the occurrence and costs related to substance use and associated harms it is important to intervene early. Although a number of international school-based prevention programs exist, the majority show minimal effects in reducing drug use and related harms. Given the emphasis on early intervention and prevention in Australia, it is timely to review the programs currently trialled in Australian schools. This paper reports the type and efficacy of Australian school-based prevention programs for alcohol and other drugs. Approach. Cochrane, PsychInfo and PubMed databases were searched. Additional materials were obtained from authors, websites and reference lists. Studies were selected if they described programs developed and trialled in Australia that address prevention of alcohol and other drug use in schools. Key Findings. Eight trials of seven intervention programs were identified. The programs targeted alcohol, cannabis and tobacco and most were based on social learning principles. All were universal. Five of the seven intervention programs achieved reductions in alcohol, cannabis and tobacco use at follow up. Conclusion. Existing school-based prevention programs have shown to be efficacious in the Australian context. However, there are only a few programs available, and these require further evaluative research. This is critical, given that substance use is such a significant public health problem. The findings challenge the commonly held view that school-based prevention programs are not effective.[Teesson M, Newton NC, Barrett EL. Australian school-based prevention programs for alcohol and other drugs: A systematic review. Drug Alcohol Rev 2012;31:731-736].