Phillips D R, Scarborough R M
COR Therapeutics, Inc., South San Francisco, California 94080, USA.
Am J Cardiol. 1997 Aug 18;80(4A):11B-20B. doi: 10.1016/s0002-9149(97)00572-9.
Activation of receptor function of platelet membrane glycoprotein (GP) IIb-IIIa leads to the binding of fibrinogen and is the final common pathway to platelet aggregation. Platelet aggregates provide the structural basis for coronary thrombosis, a major cause of ischemic heart disease. GP IIb-IIIa has a narrow tissue distribution, being found only on platelets and their progenitors, and inhibition of its receptor function has emerged as a promising new therapeutic strategy for management of acute ischemic coronary syndromes and acute ischemic complications of percutaneous coronary interventions. Eptifibatide (INTEGRILIN) is a cyclic heptapeptide inhibitor of GP IIb-IIIa, with an active pharmacophore that is derived from the structure of barbourin, a GP IIb-IIIa inhibitor from the venom of the southeastern pigmy rattlesnake. Like barbourin, eptifibatide is a specific and robust inhibitor of the GP IIb-IIIa receptor function, having a low affinity for other integrins and strongly preventing platelet aggregation. Preclinical pharmacologic studies have established that eptifibatide can inhibit thrombosis effectively, with only modest effects on bleeding time measurements. Pharmacokinetic and pharmacodynamic studies in both animal models and humans have shown that the antiplatelet effect of eptifibatide has a rapid onset of action and that the drug has a short plasma half-life. Furthermore, the rapid reversibility of action of eptifibatide, exemplified by an antihemostatic effect limited to the period of drug administration, was apparent in both healthy volunteers and patients with ischemic heart disease. In clinical trials, eptifibatide has not been found to be immunogenic or to induce thrombocytopenia. These studies have led to the evaluation of eptifibatide in the pivotal Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis (IMPACT II) trial, which enrolled 4,010 patients undergoing coronary angioplasty. The combination of a bolus plus either of 2 infusion doses of eptifibatide reduced the incidence of ischemic complications without increasing the risk of bleeding or other complications. Recent pharmacodynamic studies have established that more aggressive dosing of eptifibatide provides greater inhibition of ex vivo platelet aggregation and more robust antithrombotic activity. Higher doses of eptifibatide were therefore selected for the Platelet GP IIb-IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, which enrolled patients with unstable angina or non-Q-wave myocardial infarction. The available data suggest that eptifibatide may represent a useful clinical alternative to existing antiplatelet therapies.
血小板膜糖蛋白（GP）IIb-IIIa受体功能的激活会导致纤维蛋白原的结合，这是血小板聚集的最终共同途径。血小板聚集体为冠状动脉血栓形成提供了结构基础，而冠状动脉血栓形成是缺血性心脏病的主要原因。GP IIb-IIIa的组织分布狭窄，仅在血小板及其祖细胞上发现，抑制其受体功能已成为治疗急性缺血性冠状动脉综合征和经皮冠状动脉介入治疗急性缺血性并发症的一种有前景的新治疗策略。依替巴肽（INTEGRILIN）是一种GP IIb-IIIa的环七肽抑制剂，其活性药效基团源自巴波林的结构，巴波林是一种来自东南侏儒响尾蛇毒液的GP IIb-IIIa抑制剂。与巴波林一样，依替巴肽是GP IIb-IIIa受体功能的特异性强效抑制剂，对其他整合素亲和力低，能强烈抑制血小板聚集。临床前药理学研究表明，依替巴肽可有效抑制血栓形成，对出血时间测量的影响较小。在动物模型和人类中进行的药代动力学和药效学研究表明，依替巴肽的抗血小板作用起效迅速，且该药物的血浆半衰期较短。此外，依替巴肽作用的快速可逆性，如抗止血作用仅限于给药期间，在健康志愿者和缺血性心脏病患者中均很明显。在临床试验中，未发现依替巴肽具有免疫原性或诱导血小板减少。这些研究促使在关键的依替巴肽最小化血小板聚集和冠状动脉血栓形成（IMPACT II）试验中对依替巴肽进行评估，该试验纳入了4010例接受冠状动脉成形术的患者。依替巴肽静脉推注加两种输注剂量之一的联合用药可降低缺血性并发症的发生率，且不增加出血或其他并发症的风险。最近的药效学研究表明，更积极地使用依替巴肽剂量可对体外血小板聚集产生更大抑制作用，并具有更强的抗血栓活性。因此，在不稳定型心绞痛中血小板GP IIb-IIIa：使用依替巴肽疗法的受体抑制（PURSUIT）试验中选择了更高剂量的依替巴肽，该试验纳入了不稳定型心绞痛或非Q波心肌梗死患者。现有数据表明，依替巴肽可能是现有抗血小板疗法的一种有用的临床替代药物。
