Lapchak Paul A, Araujo Dalia M
Department of Neuroscience, University of California San Diego, La Jolla, California 92093-0624, USA.
Am J Cardiovasc Drugs. 2003;3(2):87-94. doi: 10.2165/00129784-200303020-00002.
The only drug approved by the US FDA for use in patients with acute ischemic stroke is the thrombolytic, alteplase. Whereas alteplase rapidly restores blood flow, the drug has to be administered within 6 hours after symptom onset and is associated with an increased incidence of intracerebral hemorrhage (ICH). Moreover, transient and permanent re-occlusions associated with increased mortality continue to occur after thrombolysis with alteplase. Platelets are believed to play a pivotal role in the pathogenesis of atherothrombosis and the binding of the platelet glycoprotein (GP) IIb/IIIa receptor to fibrinogen is the final common pathway leading to platelet aggregation and thrombus formation. Antiplatelet agents such as platelet GP IIb/IIIa receptor antagonists have been studied in numerous multicenter, randomized clinical trials in patients with acute coronary symptoms (ACS). The intravenous GP IIb/IIIa receptor antagonists abciximab, eptifibatide and tirofiban are approved by the FDA for use in patients with ACS, and intravenous tirofiban is also approved for use during coronary intervention. Oral GP IIb/IIIa receptor antagonists such as lotrafiban, xemilofiban, sibrafiban and orbofiban have failed to provide myocardial protection in patients with ACS. Compared with ACS, few trials have evaluated the efficacy and tolerability of platelet GP IIb/IIIa receptor antagonists in patients with cerebrovascular syndromes. Agents such as SM-20302, TP201, ME3277, murine 7E3 F(ab')(2 )and SDZ-GPI 562 have been reported to preserve microvascular patency in different animal models of acute ischemic stroke and they may have neuroprotective properties. Platelet GP IIb/IIIa receptor antagonists may be suitable as a single therapeutic or as an adjunct therapeutic to thrombolysis with alteplase for the treatment of stroke. Platelet GP IIb/IIIa receptor antagonists may enhance the efficacy of thrombolytics and reduce potentially fatal adverse effects such as ICH. Preliminary results from the Abciximab in Emergent Stroke Treatment Trial (AbESTT) indicate that abciximab, administered as a bolus dose 0.25 mg/kg followed by 12-hour infusion, was associated with significant improvement in clinical rating scores and no significant increase in bleeding episodes in patients with acute stroke. The tolerability of argatroban in patients with acute stroke is currently being assessed in the multicenter Argatroban in Ischemic Stroke (ARGIS-1) trial.
美国食品药品监督管理局（US FDA）批准用于急性缺血性中风患者的唯一药物是溶栓剂阿替普酶。虽然阿替普酶能迅速恢复血流，但该药物必须在症状出现后的6小时内给药，且与脑出血（ICH）发病率增加有关。此外，在使用阿替普酶进行溶栓后，与死亡率增加相关的短暂性和永久性再闭塞仍会发生。血小板被认为在动脉粥样硬化血栓形成的发病机制中起关键作用，血小板糖蛋白（GP）IIb/IIIa受体与纤维蛋白原的结合是导致血小板聚集和血栓形成的最终共同途径。抗血小板药物，如血小板GP IIb/IIIa受体拮抗剂，已在众多针对急性冠状动脉症状（ACS）患者的多中心随机临床试验中进行了研究。静脉注射的GP IIb/IIIa受体拮抗剂阿昔单抗、依替巴肽和替罗非班已获美国食品药品监督管理局批准用于ACS患者，静脉注射替罗非班也被批准用于冠状动脉介入治疗期间。口服的GP IIb/IIIa受体拮抗剂，如洛曲非班、西美洛非班、西拉非班和奥波非班，未能为ACS患者提供心肌保护。与ACS相比，很少有试验评估血小板GP IIb/IIIa受体拮抗剂在脑血管综合征患者中的疗效和耐受性。据报道，诸如SM - 20302、TP201、ME3277（鼠源7E3 F(ab')(2)）和SDZ - GPI 562等药物在急性缺血性中风的不同动物模型中可保持微血管通畅，并且可能具有神经保护特性。血小板GP IIb/IIIa受体拮抗剂可能适合作为单一治疗药物或作为阿替普酶溶栓治疗中风的辅助治疗药物。血小板GP IIb/IIIa受体拮抗剂可能会增强溶栓药物的疗效，并减少诸如脑出血等潜在致命的不良反应。阿昔单抗用于紧急中风治疗试验（AbESTT）的初步结果表明，以0.25 mg/kg的推注剂量给药，随后进行12小时输注的阿昔单抗，与急性中风患者的临床评分显著改善相关，且出血事件无显著增加。目前正在多中心缺血性中风阿加曲班试验（ARGIS - 1）中评估阿加曲班在急性中风患者中的耐受性。
