氯吡格雷与质子泵抑制剂的相互作用

氯吡格雷能够降低冠心病患者再次发生心肌梗死的风险,故广泛用于急性冠脉综合征和经皮冠脉介入术后的患者。临床相关指南建议,氯吡格雷应与质子泵抑制剂（proton pump inhibitor,PPI）合用以减少氯吡格雷的胃肠道不良反应。但是,氯吡格雷需经肝脏细胞色素P450酶的同功酶CYP2C19代谢才能转化为活性产物发挥作用,而PPI同样主要由CYP2C19代谢。药代动力学研究显示,氯吡格雷与奥美拉唑合用会发生药物相互作用、由此降低氯吡格雷的抗血小板作用,而泮托拉唑与氯吡格雷的相互作用不明显。发表于2009年的系列回顾性病例对照研究表明,氯吡格雷与PPI合用会增加心血管不良事件的发生风险。但这一研究结果并未得到前瞻性的随机、对照研究和荟萃分析的证实。因此,目前仍需进行大规模的前瞻性的随机、对照试验来分析氯吡格雷和PPI合用与心血管不良事件风险间的相关性。鉴于临床上有大量服用氯吡格雷的患者需合用PPI来降低胃肠道出血风险,建议现最好选用与氯吡格雷相互作用较小的泮托拉唑。     

氯吡格雷与质子泵抑制剂相互作用的研究进展

急性冠状动脉综合征患者被推荐服用氯吡格雷时合用质子泵抑制剂(PPIs),以降低患者胃肠道出血的发生率。近年来有些学者关注氯吡格雷与PPIs之间的相互作用,众多研究的结论也是矛盾的,因此给服用氯吡格雷的患者开PPIs处方之前,强化消化道出血风险及心血管风险的个体化危险评估仍是非常必要的。     

分析氯吡格雷与质子泵抑制剂的相互作用

目的总结氯吡格雷与质子泵抑制剂的相互作用。方法分析并总结相关研究文献,对氯吡格雷与质子泵抑制剂的相互作用进行阐述。结果与结论氯吡格雷联合阿司匹林能强化抗血小板作用,降低心血管事件发生率,是目前冠状动脉介入术(PCI)后标准的抗血小板治疗方案[1]。但双联抗血小板治疗常引起胃肠道不适,甚至可能增加出血风险。临床常通过合用质子泵抑制剂来预防上消化道出血的发生。近年来,关于质子泵抑制剂对抗血小板治疗的拮抗作用,以及这种拮抗作用能否明显增加PCI后不良心血管事件的发生,成为心血管医师研究的热点。     

质子泵抑制剂与氯吡格雷的药物相互作用解析

近年来,临床研究发现氯吡格雷合用质子泵抑制剂（proton pump inhibitors,PPI）可能会增加急性冠脉综合征（acute coronary syndrome,ACS）或经皮冠状动脉介入（percutaneous coronary intervention,PCI）术后患者心血管不良事件发生的风险,因此,联合用药存在争议。本文从氯吡格雷与CYP2C19多态性、PPI与氯吡格雷在药理及临床作用上的相互影响、相关临床研究来深入解析药物相互作用。药代动力学研究的Meta分析结果显示,PPI可能削弱了氯吡格雷抗血小板的效应。10个临床观察性研究都体现了这个观点,但文献质量偏低,而其余3篇低质量的观察性研究、5篇中等质量的观察性研究和1篇高质量的RCT均未发现氯吡格雷合用PPI会显著增加患者心血管不良事件的发生风险。     

氯吡格雷与质子泵抑制剂相互作用探讨

在第58届美国心脏学会2009科学年会（ACC2009）上公布了一项名为“ACTIVE-A”的研究结果，该主要研究者之一Salim Yusuf教授认为“对华法林禁忌的房颤患者，阿司匹林加上氯吡格雷能够在可接受风险的基础上提供益处，因此可作为华法林安全的替代治疗”。另外，目前临床上联合应用阿司匹林和氯吡格雷已经写入指南，     

氯吡格雷与质子泵抑制剂的相互作用研究

<正>基础及临床研究表明,血小板的激活与聚集在急性冠脉综合征(ACS)及经皮冠状动脉介入(PCI)术后动脉血栓的形成过程中起着重要作用,故抗血小板药已广泛应用于ACS以及PCI的抗血栓治疗。业已证实,阿司匹林、氯吡格雷对心脑血管疾病有抗血栓治疗效果。与阿司匹林单药治疗相比,阿司匹林联合氯吡格雷能明显降低急性心肌梗死后冠脉事件的     

质子泵抑制剂药物的不良反应与药物相互作用

目的：了解质子泵抑制剂（PPI）不良反应及与其他药物相互作用,掌握配伍禁忌,促进临床合理用药。方法：检索2010年1月～2012年1月国内外医学期刊公开发表的PPI不良反应报道,对不良反应类型进行统计分析,最后对合并用药中与PPI具有相互作用药物进行研究分析。结果：PPI不良反应主要集中在消化系统,其次是神经内分泌系统、过敏反应、感染、视力伤害等。结论：质子泵抑制剂作为胃酸分泌抑制剂在临床应用广泛,但长期应用潜在不良反应。临床应加强对PPI不良反应的监测研究,尤其是与合用药间的配伍使用研究,以促进合理用药,减少不良反应。     

北京医院老年患者质子泵抑制剂与氯吡格雷合用情况调查分析

目的 :调查并评价北京医院老年患者氯吡格雷与质子泵抑制剂合用现状。方法:检索北京医院治疗药物监测系统,查阅2012年1月至2016年12月的合用氯吡格雷和质子泵抑制剂的老年住院患者(≥65岁),对病例进行系统的回顾性分析,并对调查结果进行统计分析。结果:共纳入患者6 376例,其中男性3 619例(56.8%),女性2 757例(43.2%);平均年龄(77.2±6.8)岁。患者分布在33个科室,主要集中在心血管科(包括心内科,心外科和心血管重症监护室),占49.5%。氯吡格雷与5种质子泵抑制剂均有联用,合用例数排序为艾司奥美拉唑>泮托拉唑>奥美拉唑>兰索拉唑>雷贝拉唑;合理联用的总比例为39.2%。结论:尽管北京医院老年患者氯吡格雷与质子泵抑制剂合理联用的比例呈上升趋势,但总合理联用率仍偏低,且各科室差异较大,需要进一步规范。     

从氯吡格雷的代谢看与质子泵抑制剂相互作用的必然性和重要性

对抗血小板凝集,降低血栓形成的骨架,成为心血管事件一、二级预防"基石"。但抗血小板药在对抗血小板聚集酶和血小板膜受体的同时,也导致胃肠黏膜损伤和出血,由此所带来的消化道损伤需要平衡患者的血栓和出血风险,也带来与质子泵抑制剂联合应用的相互作用和肝酶抑制的权衡。近期报道,氯吡格雷与质子泵抑制剂长期合用会增加心脏突发事件及死亡率,直接挑战了正在临床广泛施行的多个重要用药指南,甚至涉及是否需要修订经皮冠脉介入(PCI)的治疗指南,为学术界争论的热点。为此,诸多循证研究证实,以奥美拉唑为代表的质子泵抑制剂通过抑制CYP2C19等,对氯吡格雷的代谢和抗血小板作用产生影响,不但减效而且增加心血管事件的风险,提示应重视两类药的相互作用,对患者综合评估收益与风险个体化处理。     

中国六城市质子泵抑制剂与氯吡格雷联合应用处方现状研究

目的了解我国质子泵抑制剂(PPI)与氯吡格雷联合应用处方现状。方法数据来自《医院处方分析合作项目》2010-2013年全国六城市88家医院门诊和住院数据,每家医院每年随机抽取40 d门诊处方和住院医嘱,包括患者基本信息、用药情况、诊断和用药金额等项目,从中提取PPI与氯吡格雷联合使用的数据,用Foxpro 8.0数据库软件进行统计分析。结果使用氯吡格雷的患者中,氯吡格雷联合PPI所占比例:门诊患者为2.1%~3.6%,住院患者为16.1%~31.6%;奥美拉唑、埃索美拉唑联合氯吡格雷的比例,由2010年的第1位和第2位,下降到2013年的第3位或第4位,而泮托拉唑、雷贝拉唑与氯吡格雷联合的比例逐渐上升到第1位或第2位;心内科、老干科、普通内科及神经内科4个科室,奥美拉唑、埃索美拉唑联合氯吡格雷的比例较高。结论临床医生已随着相关治疗指南的更迭调整用药行为,关注到PPI与氯吡格雷药物相互作用会引发的心脏病风险,对重点科室应加强宣传教育,为患者优先选择相互作用影响小的药物,以保证治疗效果及兼顾规避用药风险。     

Interaction between clopidogrel and proton-pump inhibitors

The American Heart Association/American College of Cardiology guidelines recommend initiating a proton-pump inhibitor (PPI) to prevent gastrointestinal bleeding if patients are receiving concomitant therapy with clopidogrel and aspirin. Recently, concern has been raised regarding the ability of PPIs to decrease the antiplatelet activity of clopidogrel. To date, there are 16 studies that evaluated the outcomes of using clopidogrel with a PPI. One of the studies has shown that adding lansoprazole to clopidogrel has no effect on the concentration of clopidogrel’s inactive metabolite. The eight clinical trials that studied the effect of using PPIs and clopidogrel together on platelet function testing have shown differing effects between PPIs. Concurrent omeprazole and clopidogrel use was shown to decrease the antiplatelet effects of clopidogrel in three studies; whereas pantoprazole, lansoprazole and esomeprazole have been shown to have no significant effect on the antiplatelet response to clopidogrel. Six other studies showed that using PPIs and clopidogrel together led to adverse clinical outcomes; however, one study that did a separate analysis on pantoprazole, showed that using pantoprazole with clopidogrel had no significant impact on clinical outcomes. Post hoc analysis from a large randomized trial comparing prasugrel with clopidogrel indicated no clinically significant effects of PPIs in patients treated with either prasugrel or clopidogrel. Preliminary results from a prospective, randomized trial comparing cardiovascular clinical outcomes between omeprazole and placebo in clopidogrel-treated patients have been reported and suggest no interaction. However, the study was stopped prematurely secondary to loss of funding and follow-up limited to a median of 133 days so no firm conclusions were drawn. The data currently available regarding concurrent clopidogrel and PPI use are limited, so further studies are needed to provide a definite conclusion. Until additional prospective studies are available, the use of clopidogrel with a PPI should be avoided, if possible, and a H₂-receptor antagonist be selected instead. Prasugrel may be administered safely with a PPI as there is currently no evidence of a pharmacokinetic, pharmacodynamic or adverse clinical effects.     

Impact of proton pump inhibitors on efficacy of clopidogrel: Review of evidence

Clopidogrel is a prodrug which requires cytochrome P450 2C19 (CYP 2C19) enzyme for its conversion to an active thiol metabolite. Proton pump inhibitors (PPIs) inhibits enzyme CYP 2C19 interfering with the conversion of clopidogrel into its active metabolite. Studies document the possible interaction of clopidogrel and PPIs leading to a decrease in the antiplatelet efficacy of clopidogrel. A PubMed/MEDLINE database literature search was carried out and the bibliographies of found articles were checked for other relevant literature. Most retrospective cohort studies and studies using platelet markers found a significant association between PPI use especially omeprazole and decreased efficacy of clopidogrel while few comparative trials using clinical outcomes found no association between the same. Pantoprazole was not associated with the decrease in the antiplatelet efficacy of clopidogrel. Patients on dual antiplatelet therapy and/or with a history of gastrointestinal bleed will require gastroprotection in the form of PPIs. In such cases, pantoprazole should be the preferred PPI. Rabeprazole can be used as an alternative.     

Lack of drug interaction between omeprazole, lansoprazole, pantoprazole and theophylline

AIMS: Theophylline is a model substrate of cytochrome P4501A2. The ability of the proton pump inhibitors (PPI) omeprazole, lansoprazole and pantoprazole to induce cytochrome P4501A2 has not yet been unequivocally resolved. The aim of this comprehensive study was to compare directly the effect of the three PPI on the absorption and disposition of theophylline. METHODS: Twenty healthy, nonsmoking, male and female volunteers (extensive metabolisers of cytochrome P4502C19 and Helicobacter pylori negative) participated in a randomized, double-blind, four-period, placebo-controlled crossover study. In each of the four periods they received either omeprazole (40 mg), lansoprazole (60 mg), pantoprazole (80 mg) or placebo once daily for 10 days. Sustained release theophylline (350 mg twice daily) was coadministered from day 8-10. Pharmacokinetics of theophylline as well as of all three PPI were determined at steady-state (day 10). RESULTS: In all periods, point estimates and 90% confidence intervals of the area under the concentration-time curves (AUC), maximum steady-state concentrations and peak-trough fluctuations of theophylline were not altered by PPI pretreatment and met the required limits for bioequivalence. Point estimates (90% confidence intervals) of the AUC ratios of theophylline plus PPI to theophylline alone were 0.92 (0.87-0.97), 0.90 (0.85-0.95) and 1.00 (0.95-1.06) for omeprazole, lansoprazole and pantoprazole, respectively. CONCLUSIONS: Concomitant intake of omeprazole, lansoprazole or pantoprazole at high therapeutic doses does not affect the absorption and disposition of theophylline.     

CYP2C19基因多态性对药物代谢影响的研究进展

药物代谢和相互作用的差异与CYP的单核苷酸基因多态性有关。综述CYP2C19基因多态性对质子泵抑制剂、抗真菌药伏立康唑、抗血小板药氯吡格雷的代谢和药物相互作用的影响,以期为个体化用药提供参考。     

我院质子泵抑制剂用药分析及合理使用探讨

目的：通过专项点评了解我院质子泵抑制剂的使用情况,指导临床合理用药。方法：随机抽取2013年7-12月份归档病历共202份,对该类药物的适应证、用法用量、药物相互作用、不良反应等进行专项点评和综合分析。结果：202份病历中,应用质子泵抑制剂的有78份,使用率为38.61%;其中使用合理的病历40份,不合理的病历38份。结论：我院质子泵抑制剂的使用在用药指征、剂型选择、给药途径、药物相互作用等方面尚存在颇多不合理的地方,亟待改进。     

Influences of different proton pump inhibitors on the anti-platelet function of clopidogrel in relation to CYP2C19 genotypes

AIMS

The efficacy of clopidogrel is influenced by CYP2C19 genotypes and substrates of CYP2C19, such as proton pump inhibitors (PPIs). We assessed the influence of three different PPIs on the anti-platelet function of clopidogrel in relation to CYP2C19 genotype status.

METHODS

Thirty-nine healthy volunteers with different CYP2C19 genotypes took clopidogrel 75 mg with or without omeprazole 20 mg, lansoprazole 30 mg or rabeprazole 20 mg in the morning for 7 days. The influence of the three PPIs on the anti-platelet function of clopidogrel was determined. A less than 30% inhibition of platelet aggregation (IPA) during clopidogrel dosing was defined as a ‘low responder’. We also examined whether evening dosing of omeprazole could prevent the interaction with clopidogrel dosed in the morning.

RESULTS

In rapid metabolizers (RMs, *1/*1, n = 15) of CYP2C19, omeprazole and rabeprazole significantly attenuated the anti-platelet function of clopidogrel. In decreased metabolizers (DMs, carriers of *2 and/or *3, n = 24), there was a large variation in IPA and there was a trend but no significant decrease in IPA when placed on a concomitant PPI. Some DMs became ‘low-responders’ when placed on a concomitant PPI. Evening omeprazole dose in RMs did not seem to cause a significant decrease in IPA in contrast to morning dosing, but did so in DMs.

CONCLUSIONS

The three PPIs affected the efficacy of clopidogrel to different degrees. Both omeprazole and rabeprazole significantly decreased IPA in RMs but not DMs, although there was a trend towards lower IPA in DMs. Morning and evening dosing of omeprazole were both associated with lower IPA in DMs.     

质子泵抑制剂的研究进展

本文通过回顾国内外近 2 0a有关质子泵抑制剂的研究及临床应用 ,就奥美拉唑、兰索拉唑、泮托拉唑、雷贝拉唑等新型质子泵抑制剂的作用机制及临床应用进行综述 ,旨在探讨质子泵抑制剂国内外研究进展及临床疗效比较