新型噻吩吡啶类抗血小板药——普拉格雷

普拉格雷（prasugrel,CS-747,LY-640315）是继噻氯匹定（tielopidine）和氯吡格雷（clopidogrel）之后的第3代噻吩吡啶类的抗血小板药。我们对普拉格雷的研究现状作一综述。     

噻吩并四氢吡啶衍生物的合成及其抗血小板聚集活性研究

为了寻找新型的ADP受体拮抗剂类抗血栓药物, 合成了18个未见文献报道的噻吩并四氢吡啶衍生物, 化合物结构经¹H NMR和MS确证。大鼠体内抗血小板聚集活性研究表明, 化合物C1的活性优于阳性对照药噻氯匹定, 值得进一步深入研究; 化合物A4、B2、C4和C7均有不同程度的抑制血小板聚集的活性。     

ADP受体阻滞剂的临床研究进展

阿斯匹林（Asp)通过单一的途径影响血小板的作用，几十年来一直是抗血小板治疗的主要药物，对心血管有不完全的保护作用，但阿斯匹林影响了血管紧张素转换酶抑制剂的血液动力学。双嘧达莫（潘生丁）有辅助的治疗作用，但没有迹象表明单用双嘧达莫或与阿斯匹林一起用比单独服用标准剂量的阿斯匹林更有效。口服血小板糖蛋白Ⅱb/Ⅲa受体阻滞剂，最初被认为很有希望，但在最近的临床试验中的结果却令人失望。新一代药物一噻吩并吡啶，通过阻滞5’－二磷酸腺苷（ADP）受体，抑制了血小板的活性。本文讨论了该类药物的药理作用、临床研究和应用价值，包括噻氯吡啶和氯吡格雷。5’－二磷酸腺苷受体阻滞剂通过另外的途径抑制了血小板的活性，在防治心血管疾病方面比阿斯匹林更有效。     

抗血小板药物的合理应用(二)

心、脑血管疾病是导致人类死亡的主要病因,动脉粥样硬化血栓形成是心、脑血管疾病的病理基础,其中血小板激活和聚集在其形成过程中起核心作用。抗血小板治疗有助于减少心、脑血管不良事件的发生。根据循证医学的要求,重点介绍目前临床应用较多的5类抗血小板药物中的4个代表性药物,包括其适应证、用法用量、注意事项和联合用药等。     

抗血小板药物的合理应用(一)

心、脑血管疾病是导致人类死亡的主要病因,动脉粥样硬化血栓形成是心、脑血管疾病的病理基础,其中血小板激活和聚集在其形成过程中起核心作用。抗血小板治疗有助于减少心、脑血管不良事件的发生。根据循证医学的要求,重点介绍目前临床应用较多的5类抗血小板药物中的4个代表性药物,包括其适应证、用法用量、注意事项和联合用药等。     

二磷酸腺苷诱导的血小板聚集率测定方法研究

目的：研究二磷酸腺苷（ADP）诱导的血小板聚集率的测定方法。方法：收集30例急性冠脉综合征（ACS）患者的血样,选择5,10,20μmol·L＾-1不同浓度的ADP测定血小板1,3,5min的聚集率和最大聚集率。结果：5μmol·L^-1ADP组不同时间点的血小板聚集率与10,20μmol·L^-1ADP组差异显著（P〈0．01）,10μmol·L^-1ADP组不同时间点的血小板聚集率与20μmol·L。ADP组差异无统计学意义。研究发现血小板聚集率有直方双曲线和波形图两组有代表性的图形。结论：对于普利生公司的LBY—NJ4四通道血小板聚集仪,10μmol·L^-1为最适ADP诱导剂浓度。初步推断患者的血小板聚集率的图形为直方双曲线,可能对氯吡格雷的反应较高,氯吡格雷能起到较好的抗血小板作用。     

噻氯吡定和氯吡格雷的药理学特性与临床应用评价

目的 :为临床合理使用噻氯吡定和氯吡格雷提供参考。方法 :通过查阅文献 ,对噻氯吡定和氯吡格雷的作用机制、药代动力学、不良反应 (ADR)、药物相互作用和临床研究进行分析和讨论。结果与结论 :由于噻氯吡定和氯吡格雷的结构类似 ,作用模式类似 ,因此它们存在类似的药理作用和ADR。噻氯吡定和氯吡格雷为有效的抗血小板药 ,能有效预防患血管疾病者的中风、心肌梗死和血管性死亡。但在使用时一定要警惕其严重ADR。     

五类抗血小板聚集药的安全应用

目前,噻氯匹定、氯吡格雷、双嘧达莫、曲克芦丁、阿司匹林这五类抗血小板聚集药已为临床广泛应用,因此这五类药物所引发的头晕、腹泻、肝功能异常等不良反应更应引起人们的重视。     

氯吡格雷对二磷酸腺苷诱导的血小板聚集的影响

目的 :探讨氯吡格雷对血小板聚集率的影响。方法 :血小板聚集率增高病人 2 4例 ,男性 1 4例 ,女性 1 0例 ,年龄 (5 9±s 1 0 )a。给予氯吡格雷5 0mg ,po,qd×4wk。在服药后 8d,4wk后用光学法测定血小板聚集率 (ADP诱导法 ) ,Duke法测定出、凝血时间 ,凝血因子Ⅰ及血小板计数。结果 :高血小板聚集率的病人使用氯吡格雷后血小板聚集率明显下降 ,治疗后 8d,4wk分别下降 (3 1±2 5 ) % ,(3 2± 2 1 ) % ,(P <0 .0 1 )。但出、凝血时间 ,血小板计数及凝血因子Ⅰ含量在使用氯吡格雷后无明显变化。结论 :氯吡格雷可有效拮抗ADP诱导的血小板聚集作用     

抗血小板聚集药——噻氯匹定

抗血小板聚集药──噻氯匹定高家荣（安徽中医学院附属医院合肥２３００３１）汤秀兰（安徽医科大学附属医院）噻氯匹定（Ｔｉｃｌｏｐｉｄｉｎｅ）是噻氯吡啶的衍生物。临床上主要用于脑血管栓塞性卒中的预防、不稳定性心绞痛的治疗等，其疗效比阿司匹林显著［１］。现将...     

Effects of ADP-receptor antagonism beyond traditional inhibition of platelet aggregation

Atherothrombosis, or thrombus formation, at the site of a disrupted atherosclerotic plaque is the common pathophysiology related to myocardial infarction, ischaemic stroke and peripheral arterial disease. A growing body of evidence demonstrates an important role for vascular inflammation in the pathophysiology of atherosclerosis/atherothrombosis and the importance of the platelet as a mediator of inflammation. Clopidogrel is an ADP receptor antagonist that is superior to acetylsalicylic acid (ASA) for the prevention of ischaemic stroke, myocardial infarction and vascular death in patients with symptomatic atherosclerosis. The use of clopidogrel as well as ASA provides sustained, incremental benefit in patients with coronary manifestations of atherothrombosis. Recent evidence indicates that clopidogrel reduces markers of vascular inflammation across the cerebrovascular, coronary and peripheral circulations. These effects are not observed after treatment with ASA alone. Further studies have revealed that clopidogrel may have potential anticoagulant effects and may inhibit arterial vasoconstriction. These broader effects may contribute to the protective benefits of clopidogrel and should be considered when evaluating antiplatelet agents and optimising antiplatelet regimens.     

Squalene synthase inhibitors

Hypercholesterolaemia (defined as elevated levels [> 200 mg/dl] of plasma total cholesterol [TC]) is a significant risk factor for the development of atherosclerosis. The discovery and development of new hypocholesterolaemic agents has been a high priority for both pharmaceutical and academic researchers because of the devastating nature of the illness and the potentially huge patient population. Until recently, therapies for the treatment of hypercholesterolaemia suffered from a poor side-effect profile and lingering concerns over long-term toxicity. All of this changed with the introduction of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (HMGRIs), the most effective therapy to date in terms of lipid-lowering and side-effect profile. These compounds inhibit the enzyme, HMG CoA reductase, in the rate-limiting step of cholesterol biosynthesis and this results in significant decreases of plasma cholesterol at relatively low doses of HMGRI. The success of these agents has stimulated the search for other inhibitors of the multistep cholesterol biosynthetic pathway. Probably the most desirable enzyme to inhibit in this pathway is squalene synthase (SS). This is the only enzyme in the whole pathway that is solely committed to the synthesis of the sterol nucleus of cholesterol, and therefore inhibition would not affect the biosynthesis of other biologically important molecules. It is hoped that this would lead to an even better side-effect profile than the HMGRIs. Researchers have used substrate-based drug design, natural product screening and archival screening in their efforts to discover novel squalene synthase inhibitors. Whether the efficacy and safety of these agents in man will be superior to currently available therapies remains to be determined.     

国产硫酸氯吡格雷片降低血小板聚集率的临床观察

目的：比较国产氯吡格雷片（CPG）和噻氯吡啶片（TCP）降低血小板聚集率的疗效和安全性。方法：240例高血小板聚集率的患者随机分为CPG组（CPG50mg）和TCP组（TCP250mg）进行双盲、对照治疗4wk,观察治疗前后血小板聚集率的变化和不良反应。结果：CPG组和TCP组降低血小板聚集率的疗效相同[二磷酸腺苷（ADP）0.5μmol/L诱导,CPG组降低28.8％,TCP组降低32.8％,P＝0.23;ADP1.0μmol/L诱导,CPG组降低34.3％,TCP组降低37.2％,P＝0.42]。CPG组的不良反应较少。结论：国产CPG（50mg）与TCP（250mg）有等效的抗血小板聚集作用,而且安全性较好。     

Review of pharmacoeconomic evaluation of genotype-guided antiplatelet therapy

Introduction: Clopidogrel is an antiplatelet agent widely prescribed for acute coronary syndrome (ACS), and it is activated by the CYP enzyme system to active metabolite. CYP2C19 loss-of-function (LOF) allele(s) affect the responsiveness of clopidogrel, but not the new antiplatelet agents (prasugrel and ticagrelor). We reviewed the pharmacoeconomic studies on genotype-guided use of new antiplatelet agents.

Areas covered: A literature search was conducted between the period of 2000 and 2014. Seven studies including cost-effectiveness and risk-benefit analyses of CYP2C19 genotype-guided antiplatelet therapy in ACS patients were reviewed. Genotype-guided prasugrel was found to be cost-effective when compared with universal antiplatelet therapy in four studies. Three studies showed genotype-guided ticagrelor to be cost-effective in ACS patients with percutaneous coronary intervention (PCI), and universal ticagrelor to be cost-effective in ACS patients. Drug cost of antiplatelet agents and relative risk of the new antiplatelet versus clopidogrel for clinical events were common influential factors of cost-effectiveness analyses.

Expert opinion: All studies in the present review focused on selecting antiplatelet agents for carriers of CYP2C19 LOF allele(s). Cost-effectiveness of genotype-guided use of antiplatelets was demonstrated in high-risk ACS patients.     

Differential inhibitory effects of proton pump inhibitors on the metabolism and antiplatelet activities of clopidogrel and prasugrel

The interaction between proton pump inhibitors (PPIs) and clopidogrel/prasugrel was investigated. The IC50 values of omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole on the metabolic ratios of 2-oxo-clopidogrel/clopidogrel, H4 (the active metabolite of clopidogrel)/2-oxo-clopidogrel and R-138727 (the active metabolite of prasugrel)/prasugrel thiolactone in human liver microsomes were determined. The antiplatelet activities of clopidogrel and prasugrel were measured with or without PPIs. As a result, most PPIs (except for pantoprazole) inhibited the formation of 2-oxo-clopidogrel with IC50 values of 20-32 μm and inhibited the formation of H4 with IC50 values of 6-20 μm. PPIs inhibited the formation of R-138727 with IC50 values of 9-25 μm. Among the tested PPIs, omeprazole exhibited the highest inhibitory potency on the formation of H4. Omeprazole, esomeprazole and rabeprazole exhibited the highest inhibitory potencies on the formation of R-138727. For platelet aggregation, omeprazole and lansoprazole show higher inhibitory effects on the antiplatelet activity of clopidogrel. On the other hand, omeprazole, esomeprazole and rabeprazole significantly decreased the antiplatelet activity of prasugrel thiolactone. These data indicate that PPIs differ in their effects of inhibiting the metabolism and antiplatelet activities of clopidogrel and prasugrel.     

InforMatrix: ADP antagonists in acute coronary syndromes

Introduction: InforMatrix is an interactive matrix model, in which pharmacotherapeutic strategies are supported in a rational manner, by means of a transparent selection methodology.

Areas covered: In this paper, InforMatrix is applied to ADP antagonists, including clopidogrel, prasugrel and ticagrelor. These drugs are important additions to the treatment of acute coronary syndromes. The drugs are compared using the following selection criteria: efficacy, safety, tolerability, ease of use, applicability and cost. All direct comparative studies, as well as placebo-controlled or double-blind comparisons with other drugs, were used in the assessment.

Expert opinion: By means of the interactive program, users may assign their own individual weight to each criterion and to the properties of the individual drugs, which stimulates concrete discussions on the relative importance of the various aspects of the drugs. When applied to ADP antagonists, the discussion focuses on the documentation of relative efficacy, safety and acquisition cost. The extensive clinical experience with clopidogrel must be balanced against the potential advantages of the other two compounds concerning efficacy. In those countries where generic clopidogrel is available, there are also major differences in acquisition cost between generic clopidogrel and patented prasugrel and ticagrelor. The interactive program provides the opportunity to quantify existing differences in opinion on the (importance of) various properties of the drugs, which greatly facilitates concrete discussions and rational formulary decision making.     

新药替卡格雷与普拉格雷及其克服氯吡格雷抵抗的研究进展

目的对新型抗血小板凝集药普拉格雷和替卡格雷及它们与原有抗血小板聚集药氯吡格雷的异同及克服氯吡格雷抵抗作用进行综述。方法参阅最新国内外公开发表的相关文献,阐述新药普拉格雷和替卡格雷的研发思路及作用特点,比较它们与原有抗血小板聚集药氯吡格雷的异同,论述其克服氯吡格雷抵抗的作用机制所在。结果相对于氯吡格雷,新型抗血小板聚集药普拉格雷和替卡格雷更加强力有效,并可明显降低甚至避免氯吡格雷抵抗事件的发生。结论国际知名制药公司对普拉格雷和替卡格雷的研发理念可带给我们新启示,这些新型抗血小板聚集药为临床医师提供了新的用药选择。     

P2Y12 receptor inhibitors for secondary prevention of ischemic stroke

Introduction: Ischemic stroke (IS) is a major cause of death and disability worldwide. The P2Y₁₂ receptor plays a critical role in the formation of a stable thrombus leading to ischemic complications. Therefore, P2Y₁₂ receptor inhibitors constitute a major antiplatelet strategy in the secondary prevention of IS.

Areas covered: We searched articles about P2Y₁₂ receptor inhibitors and stroke in PubMed published until December 2014. This is a comprehensive review of the role of P2Y₁₂ receptor inhibitors alone and in combination with aspirin in the secondary prevention of noncardioembolic stroke.

Expert opinion: The potential benefit of more potent antiplatelet therapy for secondary stroke prevention must be weighed against the risk of bleeding in patients with IS. Short-term (≤ 3 months) dual antiplatelet therapy with clopidogrel and aspirin that is initiated early after IS or transient ischemic attack due to large artery atherosclerosis appears most efficient.     

A multiple dose study of prasugrel (CS-747), a novel thienopyridine P2Y12 inhibitor, compared with clopidogrel in healthy humans

AIMS: This double-blind, placebo-controlled trial was designed to evaluate the pharmacodynamics, pharmacokinetics, safety, and tolerability of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y(12) ADP receptor antagonist compared with clopidogrel, during multiple oral dosing in healthy subjects. METHODS: Thirty subjects received placebo, prasugrel 5 mg, 10 mg, or 20 mg, or clopidogrel 75 mg orally, daily for 10 days. Platelet aggregation, bleeding time, and prasugrel metabolites were measured and adverse events were recorded. RESULTS: Inhibition of ADP-induced platelet aggregation reached steady state by day 3 following prasugrel 10 and 20 mg compared with 5 days for clopidogrel 75 mg or prasugrel 5 mg. Compared with placebo, at 24 h after the last dose of study drug, inhibition of platelet aggregation using (20 microm) ADP was significantly higher in the prasugrel 10 mg group (58.2 +/- 4.9% vs. 9.2 +/- 4.0%, P < 0.001) with no difference in the clopidogrel group (15.7 +/- 6.8% vs. 9.2 +/- 4.0%, P = 0.78). With 5 microm ADP, inhibition of platelet aggregation with prasugrel 10 mg and clopidogrel 75 mg was significantly higher than with placebo (prasugrel 10 mg, 70.5 +/- 4.7%; clopidogrel 75 mg, 36.5 +/- 9.0%; vs. placebo, 11.3 +/- 5.1%; P < 0.0001 and P = 0.02). On day 10 at 4 h postdose, bleeding time was prolonged with prasugrel 10 mg (prasugrel 10 mg, 706 +/- 252 s vs. placebo, 221 +/- 38 s, P = 0.05) but not with clopidogrel (283 +/- 56 s, P = 0.98). There were no clinically significant bleeding events, serious adverse events, or discontinuations of the study drug. CONCLUSIONS: Compared with clopidogrel 75 mg, prasugrel 10 mg and 20 mg daily for 10 days resulted in more rapid, more consistent, and higher levels of platelet inhibition.