凝血酶受体拮抗剂在抗血栓方面的研究进展

20世纪90年代初克隆和发现的凝血酶受体(PAR-1)为研制抗血栓药物提供了一个新靶点,引起学术界和制药业的广泛关注。由于凝血酶受体的特殊活化机制,其自身相连的活化氮端与活化中心近在咫尺,只有结合力很高的小分子化合物才能有效地拮抗凝血酶受体。因此,多年来,只有少数化合物被发现具有较好的凝血酶受体拮抗活性,其中vorapaxar和atopaxar进入了临床试验。vorapaxar在Ⅲ期临床试验发现有显著疗效,但也有出血不良反应,尤其不适用于有中风史的患者。最近,vorapaxar与PAR-1结合的晶体结构已经发表。这些结果为设计和研制新一代凝血酶受体拮抗剂指出了优化的方向,提供了分子水平的结构信息。本文从药物化学角度综述近年来凝血酶受体拮抗剂的研究进展和现状,重点描述vorapaxar、atopaxar以及相关化合物和最新发表的PAR-1拮抗剂。     

Emerging antiplatelet therapy for coronary artery disease and acute coronary syndrome

Antiplatelet therapy is used widely with proven benefit for the prevention of further ischemic cardiac complications in patients with known coronary artery disease (CAD) and a history of acute coronary syndrome (ACS). The limitations of conventional antiplatelet therapy with aspirin, clopidogrel, or prasugrel, as well as the fact that rates of recurrent ischemic events still remain high with use of these agents, underscore the need to investigate alternate agents that may further reduce event rates while limiting bleeding risk. The selection of antiplatelet therapy is further influenced by the following: ticagrelor was approved in July 2011 by the United States Food and Drug Administration (FDA), and clopidogrel is slated to become available as a generic productin 2012. We provide an overview of emerging agents for the treatment of CAD and ACS, including the reversible P2Y(12) antagonists ticagrelor, cangrelor, and elinogrel, and a new class of oral protease-activated receptor-1 (PAR-1) inhibitors, vorapaxar and atopaxar.The recently approved P2Y(12) antagonists prasugrel and ticagrelor demonstrate enhanced ability to prevent adverse cardiac outcomes. However, this comes at a cost of a potential increased risk of bleeding. New adverse effects have also emerged, including dyspnea for all of the reversible P2Y(12) antagonists (ticagrelor, cangrelor, and elinogrel) and ventricular pauses for ticagrelor. In addition, the newer P2Y(12) antagonists have a faster onset and offset. Two of these agents, cangrelor and elinogrel, are available as intravenous formulations, which may provide additional benefits in patients who undergo coronary artery bypass graft (CABG) surgery. Trials with the PAR-1 inhibitors have also shown trends toward reductions in cardiac events, but not without the possibility of increased bleeding. More than ever, as the arsenal of antiplatelet therapy expands, health care providers need to understand the pharmacologic and pharmacodynamic differences between conventional and emerging antiplatelet therapies for patients with ACS and CAD. Health care providers must also carefully assess patient-specific factors such as risk of thrombosis, concomitant disease states, age, drug adherence, and aspirin dose, and plan for those patients who will be undergoing CABG when selecting antiplatelet therapy in order to optimally balance bleeding and thrombosis risk.     

Antiplatelet therapy: thrombin receptor antagonists

Activated platelets stimulate thrombus formation in response to rupture of an atherosclerotic plaque or endothelial cell erosion, promoting atherothrombotic disease. Multiple pathways contribute to platelet activation. Aspirin, an irreversible inhibitor of thromboxane A2 synthesis, in combination with clopidogrel, an inhibitor of P2Y(12) adenosine diphosphate platelet receptors, represent the current standard-of-care of antiplatelet therapy for patients with acute coronary syndrome and for those undergoing percutaneous coronary intervention. Although these agents have demonstrated significant clinical benefit, the increased risk of bleeding and the recurrence of thrombotic events represent substantial limitations. Thrombin is one of the most important platelet activators. The inhibition of protease-activated receptor 1 showed a good safety profile in preclinical studies. In fact, phase II studies with vorapaxar (SCH530348) and atopaxar (E5555) showed no increase of bleeding events in addition to the current standard-of-care of antiplatelet therapy. Although the results of phase III trials for both drugs are awaited, this family is a promising new addition to the current clinical practice for patients with atherothrombotic disease, not only as an alternative, but also as additional therapy.     

Inhibiting PAR-1 in the prevention and treatment of atherothrombotic events

Importance of the field: Aspirin, an irreversible inhibitor of thromboxane A₂ production, in combination with clopidogrel, an inhibitor of PY₁₂ ADP platelet receptors, represents the current standard-of-care of antiplatelet therapy for patients with acute coronary syndrome and those undergoing percutaneous coronary intervention. Although these agents have demonstrated significant clinical benefit, the increased risk of bleeding and the recurrence of thrombotic events represent substantial limitations.

Areas covered in this review: The inhibition of protease-activated receptors (PAR)-1, is the target for novel antiplatelet drugs, which showed a good safety profile in preclinical studies. The drugs most developed are vorapaxar (SCH530348) and atopaxar (E5555), which will be further evaluated in ongoing Phase III and II clinical trials respectively.

What the reader will gain: This review is focused on the current knowledge of PAR-1 antagonists, analyzing the pharmacological and early phase clinical investigation findings on these new drugs.

Take home message: The PAR-1 receptor offers a new target for the inhibition of platelet activation and aggregation. Preliminary results showed the good safety profile of these new agents. The results of the Phase III ongoing trials will provide important clinical insight into the blockade of thrombin-induced platelet activation.     

Resistance to antiplatelet drugs: what progress has been made?

Introduction: Despite well-documented efficacy, recurrent thrombotic event occurrences, particularly stent thrombosis, have been repeatedly demonstrated in stented patients treated with aspirin and clopidogrel. The latter observation stimulated the close scrutiny of the pharmacodynamic effects of clopidogrel and revealed the ‘wide variability’ and the phenomenon of ‘antiplatelet resistance’. High on-treatment platelet reactivity to ADP (HPR) during clopidogrel therapy is an independent risk factor for ischemic event occurrences in post-percutaneous coronary intervention (post-PCI) patients. Recent observational studies demonstrated a link between low on-treatment platelet reactivity to bleeding. The concept of a ‘therapeutic window’ of P2Y₁₂ receptor reactivity associated with both ischemic event occurrence (upper threshold) and bleeding risk (lower threshold) has been proposed.

Areas covered: An update on and a brief review of the current knowledge on antiplatelet resistance were presented. Evidence available from studies evaluating aspirin resistance and high and low on-treatment platelet reactivity to ADP during P2Y₁₂ receptor blocker therapy was collected from a selective literature search.

Expert opinion: The available evidence indicates that HPR is an independent risk factor for post-PCI ischemic event occurrences. The therapeutic window concept for the P2Y₁₂ receptor blocker therapy may facilitate the balance between reducing ischemic events and avoiding bleeding events, thereby improving net clinical outcome.     

Platelets in atherothrombosis--diagnostic and prognostic value of platelet activation in patients with atherosclerotic diseases

Platelets and their activation have a pivotal role in the development of atherosclerotic diseases such as acute myocardial infarction (AMI), stroke and peripheral arterial occlusion. Biomarkers of platelet activation are making inroads into clinical studies and may serve as promising agents upstream to established downstream markers of myocardial necrosis such as troponin and creatin kinase. Targeting the degree of platelet activation assessed by the key collagen receptor of platelet activation, glycoprotein VI (GPVI), may have diagnostic and prognostic value for the assessement of high-risk groups of patients with symptomatic coronary artery disease and ischemic stroke and may be worthwhile to help to facilitate clinical decision-making and to rapidly initiate adequate therapy. The concert of platelet count, platelet activation, platelet aggregation and subsequent inflammation has had a significant impact on the clinical outcome in patients with atherosclerotic diseases. For a therapeutical approach to ameliorate prognosis, the use of antiplatelet treatment in particular in AMI patients with low response to clopidogrel has partly been overcome by novel second antiplatelet drugs on top of aspirin such as prasugrel and ticagrelor. Antiplatelet therapy may be adapted according to a GPVI-based platelet activity monitoring along with aggregometry of residual platelet aggregation. Other approaches using protease-activated receptor- 1 antagonists vorapaxar or atopaxar, which inhibit the platelet thrombin receptor, soluble GPVI called Revacept?, which blocks the collagen binding sites at the vascular lesion and anopheline saliva protein derived from the malaria vector mosquito, a platelet adhesion inhibitor independent of a GPVI mechanism, still wait for their breakthrough.     

New perspectives in antiplatelet therapy

Platelet activation is a complex mechanism of response to vascular injury and atherothrombotic disease, leading to thrombus formation. A wide variety of surface receptors -integrins, leucine-rich family receptors, G protein coupled receptors, tyrosine kinase receptors- and intraplatelet molecules support and regulate platelet activation. They are potential targets of antiplatelet therapy for the prevention and treatment of arterial thrombosis. Despite the overall clinical benefit of established antiplatelet drugs targeting cyclooxigenase-1 (COX-1), glycoprotein integrin αIIbβ3, and the purinergic P2Y(12) receptor of adenosine diphosphate, a significant proportion of treated patients continue to experience recurrent ischaemic events. This may be in partly attributed to insufficient inhibition of platelet activation. In addition, it should not be underestimated that these drugs are not immune from bleeding complications. The substantial progress in understating the regulation of platelet activation has played a key role in the development of novel antiplatelet agents. Current examples of drug under development and evaluation include: novel P2Y(12) receptor inhibitors (prasugrel, ticagrelor, cangrelor, and elinogrel), thrombin receptor PAR-1 antagonists (vorapaxar, atopaxar), new integrin glycoprotein IIb/IIIa inhibitors, and inhibitors targeting the thromboxane receptor (TP), phosphodiesterases, the collagen receptor glycoprotein VI, and intraplatelet signalling molecules. This review summarizes the mechanisms of action and current clinical evaluation of these novel antiplatelet agents.     

Combination oral antithrombotic therapy for the treatment of myocardial infarction: recent developments

Introduction: There have been significant new developments in the treatment of patients with myocardial infarction with respect to oral antithrombotic agents over the past decade. Recent studies have explored the potential utility of targeting the dual pathway inhibition of platelet function with single or dual antiplatelet agents and the thrombin pathway with direct thrombin inhibitors or factor Xa inhibitors.

Areas covered: In this review, the authors focus on the recent developments of oral antithrombotic agents including antiplatelet and antithrombin agents. It is based on literature covering: aspirin, P2Y₁₂ receptor blockers, PAR-1 inhibitors, direct thrombin inhibitors and factor Xa inhibitors from PubMed since 2008.

Expert opinion: Since thrombus formation involves multiple pathways including platelet activation and aggregation and coagulation, simultaneous and optimal blockade of these pathways is essential to prevent thrombotic complications and to avoid excessive bleeding in the myocardial infraction setting. Despite an improved anti-ischemic effect associated with potent P2Y₁₂ inhibitors plus aspirin, the degree of adverse event reduction compared to clopidogrel therapy in large scale trials is modest along with significantly greater bleeding. Recent studies suggest that targeting the thrombin pathway in addition to antiplatelet agents in high risk patients may further mitigate the risk of ischemic event occurrences with improved safety profiles.     

Prasugrel versus Clopidogrel Antiplatelet Therapy after Acute Coronary Syndrome

Antithrombotic therapy is imperative in the management of patients presenting with an acute coronary syndrome (ACS). The combination of antiplatelet therapy in conjunction with antithrombotic therapy has become the standard of care in improving the morbidity and mortality of patients with an ACS and in reducing ischemic complications of percutaneous coronary intervention. Patients with an ACS are at increased risk for a recurrent event, both in-hospital and for several months afterward. Secondary prevention to reduce these events is accomplished through the establishment of appropriate medical therapy. Dual antiplatelet therapy with aspirin and adenosine 5'-diphosphate P2Y(12) receptor blockers such as ticlopidine or clopidogrel are integral components of this regimen; however, both of these thienopyridines have a relatively slow onset of action and variable bioavailability. Prasugrel, a third-generation thienopyridine approved by the US FDA in 2009, has a more rapid onset of platelet inhibition than clopidogrel and ticlopidine because of increased efficiency of prodrug-to-active metabolite conversion. The result is higher and less variable concentration of the active metabolite within 60 minutes following oral dosing. Phase II and III trials assessing the safety and efficacy of prasugrel have been completed, including JUMBO-TIMI 26, PRINCIPLE-TIMI 44, and TRITON-TIMI 38. These trials demonstrated greater inhibition of platelet aggregation and lower rates of the composite endpoint of death, non-fatal myocardial infarction, and stroke compared with clopidogrel. However, major bleeding occurred more frequently with prasugrel treatment than with clopidogrel. This review highlights the current state of evidence-based antiplatelet therapy and provides guidance on appropriate use of prasugrel in cardiovascular medicine.     

Emerging antithrombotic drugs for acute coronary syndrome

Introduction: Acute coronary syndrome (ACS) encompasses acute myocardial infarction (MI) and unstable angina. Activation of platelets and coagulation cascade plays a central role in the development of ACS. Over the past decade, there have been substantial improvements in the strategies for secondary prevention of ACS, including the development of more potent oral antiplatelet agents such as prasugrel and ticagrelor. However, therapies with even better efficacy and safety profiles and more rapid onset and offset of action would be desirable.

Areas covered: This review discusses the advantages and disadvantages of the currently available antithrombotic agents and describes the findings from recent clinical trials of three novel agents; cangrelor (an intravenous P2Y12 receptor antagonist), vorapaxar (protease-activated receptor-1 inhibitor) and rivaroxaban (an oral factor Xa inhibitor).

Expert opinion: Cangrelor appears more promising than clopidogrel when a very rapid onset and reversal of antiplatelet effect is needed. Vorapaxar in addition to standard oral antiplatelet therapy was effective in patients with prior MI, but was not safe in patients with a prior stroke. Low dose rivaroxaban decreased cardiovascular events and mortality in patients post-ACS compared to placebo, although bleeding was increased.     

Ticagrelor: Positive,negative and misunderstood properties as a new antiplatelet agent

相似文献   

Importance of potent P2Y(12) receptor blockade in acute myocardial infarction: focus on prasugrel

INTRODUCTION: Prasugrel therapy is recommended in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI). AREAS COVERED: This article reviews the efficacy and safety profile of prasugrel, cost considerations, and its role in clinical practice based on published data. The authors searched PubMed and Ovid databases for English language clinical trial articles involving the use of prasugrel in human subjects and patients, published through June 2012. The keyword "prasugrel" was used. The review focuses on clinical trials, but other articles including Food and Drug Administration documents are also reviewed. EXPERT OPINION: Prasugrel has a more rapid and greater pharmacodynamic (PD) effect than clopidogrel. No significant drug - drug interactions have been reported. In a large-scale randomized clinical trial, prasugrel was associated with better protection against ischemic event occurrence compared to clopidogrel, but more bleeding in ACS patients undergoing PCI. Adverse outcomes outweighed the benefit of prasugrel in certain subgroups, including patients over the age of 75, those weighing less than 60 kg, and patients with a prior history of stroke or transient ischemic attack. In subsequent PD studies, prasugrel therapy showed suboptimal platelet inhibition in selected patients. In addition, "hyper-responsiveness" to prasugrel may increase the risk of serious bleeding in high-risk patients. More detailed studies are warranted to explore antiplatelet regimens tailored to optimally limit ischemic and bleeding event occurrences. A Phase-III TRILOGY trial (NCT00699998) will indicate the clinical efficacy and safety of prasugrel in patients with non-ST-segment elevation ACS, who are medically managed without coronary revascularization.     

Interactions between clopidogrel and proton pump inhibitors: a review of evidence

Clopidogrel is a thienopyridine, which inhibits the platelet P2Y adenosine diphosphate (ADP) receptor termed P2Y(12). It is taken as a prodrug that requires biotransformation to an active metabolite by cytochrome P450 (CYP) isoenzymes. In addition, esterases shunt the majority of clopidogrel to an inactive pathway, whilst the remaining prodrug requires two separate CYP-dependent oxidative steps. PPIs might diminish the antiplatelet effects and the clinical effectiveness of clopidogrel possibly through inhibition of CYP2C19 and CYP3A4 isoenzymes. Treatment with clopidogrel and aspirin decreases recurrent cardiovascular events after an acute coronary syndrome. However, an inherent increment of major bleeding is also associated with antiplatelet therapy, as well as dyspepsia with aspirin. Also, major bleeding has been associated with high risk for ischemic events and mortality. For this reason, a proton pump inhibitor (PPI) is often co-prescribed to reduce the risk of gastrointestinal tract bleeding, but its concomitant use might reduce the inhibitory effect of clopidogrel on platelet aggregation. Nevertheless, doubts exist about the possible interaction of concomitant PPI use that may reduce the inhibitory effect of clopidogrel on platelet aggregation. Indeed, there is some controversy with regard to the true risk of cardiovascular adverse events arising from a potential drug-drug interaction between clopidogrel and PPI. In this article, we will review the current status and controversies in relation to a possible interaction between clopidogrel and PPIs.     

新型P2Y12受体抑制剂替格瑞洛临床研究进展

抗血小板药物是急性冠脉综合征（Acute Coronary Syndrome,ACS）治疗的基石,对防治心肌缺血和介入并发症是有益的。目前治疗ACS和经皮冠状动脉介入治疗（percutaneous coronary intervention,PCI）指南推荐使用的口服抗血小板药物包括氯吡格雷、替格瑞洛、普拉格雷联合阿司匹林双重抗血小板治疗预防复发性缺血事件。本文对新型P2Y12受体抑制剂替格瑞洛的药代动力学和药效学特点以及在ACS患者中的循证医学证据作一介绍。     

凝血酶受体拮抗剂的研究进展

血栓栓塞性疾病严重威胁人类健康,应用抗血小板药物是当前主要的治疗手段之一。研究证明,凝血酶受体(又称蛋白酶激活受体-1,PAR-1)被凝血酶激活后,可诱导血小板活化。此外,PAR-1主要参与病理性血栓的形成,对人体正常的止血过程影响很小。因此,PAR-1已成为抗血小板药物研发的新兴靶点。目前,已有多个PAR-1拮抗剂如vorapaxar、F16618、F16357、ML161、RWJ-58259、PZ-128已上市或进入临床研究。综述了PAR-1的结构和作用机制以及小分子拮抗剂和多肽类拮抗剂的研究进展。     

PAR-1 Inhibitors: A Novel Class of Antiplatelet Agents for the Treatment of Patients with Atherothrombosis

Stroke and myocardial infarction are leading causes of death and disability worldwide. Typically, these events are triggered by the rupture or erosion of "vulnerable" atherosclerotic plaque, a phenomenon termed atherothrombosis.Three platelet activation pathways are presumed to be particularly important in the genesis of atherothrombosis and are triggered by 1) cyclo-oxygenase (COX)-1 mediated thromboxane A2 (TXA2) synthesis and activation via the TXA2 receptor, 2) adenosine diphosphate (ADP) via the P2Y12 receptor, and 3) thrombin via the protease activated receptor (PAR)-1.Despite the efficacy of aspirin and of a growing family of P2Y12 receptor antagonists on the first 2 pathways, major cardiovascular events continue to occur in patients with coronary and cerebrovascular disease, suggesting that thrombin-mediated platelet activation may contribute to these adverse events.Recently, a novel class of antiplatelet agents able to inhibit thrombin-mediated platelet activation has been developed, PAR-1 inhibitors. In this chapter, we will discuss the rationale underlying the development of this novel class of agents focus on the two drugs in the most advanced stages of development: vorapaxar (SCH530348) and atopaxar (E5555).     

Prasugrel during primary percutaneous coronary intervention: evidence from clinical data

Primary percutaneous coronary intervention (PCI) encompassing stent implantation is a mainstay in the management of acute ST-elevation myocardial infarction (STEMI). Despite refinements in techniques and devices, peri- and post-procedural antithrombotic therapy remains pivotal to prevent early and late thrombotic events, without unduly increasing bleeding risk. Concomitant dual antiplatelet therapy with aspirin and clopidogrel has been considered until recently the standard of care in terms of oral antiplatelet agents. However, most recently a novel and more potent thienopyridine, prasugrel, has been tested in randomized trials including patients with STEMI, and subsequently approved for clinical practice in Europe and North America. Despite its potent antithrombotic effect, prasugrel also carries a statistically significant increase in the risk of bleeding, especially in the elderly, those with low body weight, and previous stroke or transient ischemic attack. Thus, the use of prasugrel, as well as that of clopidogrel or ticagrelor, should best be individualized to maximize clinical benefits and minimize hazards.     

一例房颤合并冠心病患者初始抗栓治疗策略及文献复习

目的 探讨房颤伴急性冠脉综合征的抗栓治疗策略。方法 1例46岁房颤合并冠心病的男性患者,房颤卒中风险低危,入院期间未给予抗凝治疗,后出现急性脑梗塞。通过提阅部分指南及文献,分析CHA₂DS₂-VAS_c评分为1分,并伴急性冠脉综合征患者的不同抗栓治疗策略方案及其优劣。结果 文献提示,CHA₂DS₂-VAS_c评分为1分出血低危患者,建议尽早服用抗凝药。双联抗栓（华法林+氯吡格雷）能够有效抗栓并且降低患者出血风险,因此需根据患者的具体情况,尽快将三联调整为双联抗栓（1~3个月内）,保证患者疗效的情况下,降低患者出血风险。结论 临床上遇到相关患者需充分评估患者的出血及血栓风险,制定个体化的抗栓治疗策略。     

缺血性卒中病人CYP2C19基因多态性与个体化抗血小板治疗的临床观察

目的 研究小样本缺血性卒中病人的CYP2C19基因型,根据其CYP2C19基因型指导个体化抗血小板治疗并观察其临床预后.方法 入选急性缺血卒中病人300例,对入选病人采用随机数字表法分为个体化治疗组150例和常规治疗组150例.个体化治疗组在入选后立即检测CYP2C19基因,按照不同的基因型采用个体化的抗血小板治疗方案,即快代谢型按照氯吡格雷负荷量300 mg、维持量50 mg·d-1口服;中间代谢型按照氯吡格雷负荷量300 mg、维持量75 mg·d-1口服;慢代谢型按照氯吡格雷负荷量300 mg、维持量75 mg·d-1,联合阿司匹林100 mg·d-1口服.常规治疗组直接按照氯吡格雷负荷量300 mg、维持量75 mg·d-1口服治疗,不检测CYP2C19基因.通过随访观察两组病人治疗30 d及180 d不良事件发生率之间的差异.结果 随访6个月,再发缺血性卒中的发生率在个体化治疗组显著降低(P<0.05),出血事件的发生率在个体化治疗组明显低于常规治疗组(P<0.05).结论 根据CYP2C19基因型采取不同的治疗方案可以及时发现慢代谢病人,进而调整抗血小板聚集治疗方案,降低不良事件发生率并可以减少药物的不良反应.     

一例联合应用华法林和氯吡格雷导致消化道出血患者的药学监护

目的探讨1例联合抗栓治疗导致消化道出血患者的抗栓治疗方案优化及临床药师的作用。方法临床药师结合患者疾病史、临床特征、实验室检查等多方面因素,通过文献查阅,比较不同抗血小板药物特点,针对患者不同临床疾病进展,合理选用抗栓治疗药物并进行药学监护。结果患者的消化道出血与华法林+氯吡格雷联合抗栓治疗有关,临床药师建议华法林+氯吡格雷调整为华法林+吲哚布芬,监护3个月,患者无出血发生。结论在抗栓治疗过程中,临床药师评估患者出血及栓塞的风险,从药物机制、药物相互作用、患者临床特点等方面进行综合分析,制定最适合的抗栓治疗方案,保证了患者的安全用药。