Nicholson N S, Abood N A, Panzer-Knodle S G, Frederick L G, Page J D, Salyers A K, Suleymanov O D, Szalony J A, Taite B B, Anders R J
Cardiovascular Discovery Research, Pharmacia Corp., 4901 Searle Parkway, Skokie, Illinois 60077, USA.
Med Res Rev. 2001 May;21(3):211-26. doi: 10.1002/med.1007.
A key role has been established for platelet activation and thrombus formation in the pathogenesis of acute coronary syndromes, and restenosis after percutaneous interventions. Antiplatelet agents that have a wider spectrum of activity than aspirin, and clopidogrel would be expected to provide improved antithrombotic protection. Preclinical studies were used to predict clinical efficacy of orally active GPIIb/IIIa antagonists such as xemilofiban, sibrafiban, lefradafiban, and orbofiban. While clinical trials have shown potent and sustained platelet inhibition, outcomes of trials with these first generation GPIIb/IIIa compounds have been disappointing. The active moiety of orbofiban is a potent and specific inhibitor of fibrinogen binding to GPIIb/IIIa, leading to inhibition of platelet aggregation to a wide variety of agonists. Studies comparing inhibition of aggregation and bleeding suggest that chronic inhibition of platelet aggregation can be achieved without major bleeding side effects. Thrombus formation is prevented in canine models of thrombosis. Orbofiban is approximately 28% bioavailable with a t(1/2) of 18 hr. The high bioavailability, long half-life, and potential safety suggest orbofiban would be suitable for chronic oral administration. Clinical data demonstrate that orally administered orbofiban has the desired pharmacodynamic effect of inhibiting platelet aggregation but does not demonstrate clinical benefit when examined in large-scale trials.
血小板活化和血栓形成在急性冠脉综合征的发病机制以及经皮介入治疗后的再狭窄过程中起着关键作用。与阿司匹林和氯吡格雷相比，具有更广泛活性谱的抗血小板药物有望提供更好的抗血栓保护作用。临床前研究被用于预测口服活性糖蛋白IIb/IIIa拮抗剂（如西美罗非班、西拉非班、来氟非班和奥波非班）的临床疗效。虽然临床试验已显示出强效且持续的血小板抑制作用，但这些第一代糖蛋白IIb/IIIa化合物的试验结果却令人失望。奥波非班的活性部分是纤维蛋白原与糖蛋白IIb/IIIa结合的强效特异性抑制剂，可抑制血小板对多种激动剂的聚集。比较聚集抑制和出血情况的研究表明，在无严重出血副作用的情况下可实现血小板聚集的长期抑制。在犬类血栓形成模型中可预防血栓形成。奥波非班的生物利用度约为28%，半衰期为18小时。高生物利用度、长半衰期和潜在安全性表明奥波非班适合长期口服给药。临床数据表明，口服奥波非班具有抑制血小板聚集的预期药效学作用，但在大规模试验中并未显示出临床益处。
