Ueno Masafumi, Ferreiro José Luis, Angiolillo Dominick J
Division of Cardiology, Department of Medicine, University of Florida College of Medicine-Jacksonville, Shands Jacksonville, 655 West 8th Street, Jacksonville, FL 32209, USA.
Expert Rev Cardiovasc Ther. 2010 Aug;8(8):1191-200. doi: 10.1586/erc.10.49.
Atherothrombotic disease is the leading cause of death worldwide. Currently, dual antiplatelet therapy with aspirin and ADP receptor antagonists has shown improved short- and long-term clinical outcomes but is associated with increased bleeding risk, and the rates of recurrent ischemic events still remain high. Selective inhibition of the principal protease-activated receptor (PAR)-1 for thrombin, the most potent platelet activator, represents a promising novel strategy to reduce ischemic events without increasing the risk of bleeding. Two PAR-1 antagonists are currently being tested in clinical trials: SCH 530348 and E5555. Both have demonstrated an antiplatelet effect without increasing bleeding time in preclinical trials. Results of Phase II trials showed that SCH 530348, in addition to standard antiplatelet therapy, was well tolerated and not associated with increased bleeding risk. The safety and tolerability of E5555 is being evaluated in patients with coronary artery disease and non-ST-segment elevation acute coronary syndrome in four Phase II clinical trials. Two large-scale Phase III trials assessing the efficacy of SCH 530348 in addition to the standard of care are currently ongoing. This article provides an overview of the current status of knowledge on platelet thrombin receptor antagonists, focusing on pharmacologic properties and clinical development.
动脉粥样硬化血栓形成性疾病是全球主要的死亡原因。目前，阿司匹林和ADP受体拮抗剂的双重抗血小板治疗已显示出改善短期和长期临床结局，但与出血风险增加相关，且复发性缺血事件的发生率仍然很高。选择性抑制凝血酶的主要蛋白酶激活受体（PAR）-1（最有效的血小板激活剂）是一种有前景的新策略，可降低缺血事件风险而不增加出血风险。目前有两种PAR-1拮抗剂正在进行临床试验：SCH 530348和E5555。两者在临床前试验中均已证明具有抗血小板作用且不增加出血时间。II期试验结果表明，除标准抗血小板治疗外，SCH 530348耐受性良好且不增加出血风险。E5555的安全性和耐受性正在四项II期临床试验中对冠心病和非ST段抬高急性冠脉综合征患者进行评估。目前正在进行两项大规模III期试验，评估除标准治疗外SCH 530348的疗效。本文概述了血小板凝血酶受体拮抗剂的当前知识状况，重点关注其药理特性和临床开发情况。
