Cox D, Smith R, Quinn M, Theroux P, Crean P, Fitzgerald D J
Centre for Cardiovascular Science, Royal College of Surgeons in Ireland, Dublin.
J Am Coll Cardiol. 2000 Nov 1;36(5):1514-9. doi: 10.1016/s0735-1097(00)00919-0.
The study was done to determine the role of partial agonist activity in the lack of effectiveness of the oral GPIIb/IIIa antagonist orbofiban.
Orbofiban, an oral GPIIb/IIIa antagonist, was found to increase the mortality of patients with acute coronary syndromes (ACS) in the OPUS-TIMI-16 trial, despite the fact that it is a very potent anti-platelet agent and that IV agents have proven very effective.
Patients (n = 520) with ACS were randomized to orbofiban 30 mg, 40 mg or 50 mg twice daily or 50 mg once daily or placebo. Platelet activity was assessed in 175 patients by examining GPIIb/IIIa receptor conformation, expression of CD63 antigen, and platelet aggregation.
Plasma concentrations of orbofiban at the highest dose (74 +/- 6 ng/ml peak, 61 +/- 5 ng/ml trough) exceeded the IC50 for platelet aggregation to adenosine diphosphate (ADP) (29 +/- 6 ng/ml) and thrombin-activating peptide (61 +/- 18 ng/ml). Orbofiban induced a conformational change in GPIIb/IIIa detected as the displacement of the monoclonal antibody mAb2; such conformational changes have been linked to partial agonist activity. Consistent with this, platelet expression of CD63 ex vivo was significantly increased at five time points during the study. In vitro, orbofiban increased platelet aggregation to a submaximal concentration of epinephrine (67 +/- 19% vs. 27 +/- 9%, n = 5) and increased thromboxane formation when the platelet GPIIb/IIIa were clustered using monoclonal antibodies to the receptor.
Orbofiban is both an antagonist and a partial agonist of platelet GPIIb/IIIa. At low concentrations of the drug, this partial agonist activity may enhance platelet aggregation. Along with suboptimal plasma drug levels, these findings may help explain the lack of efficacy seen with orbofiban in patients with ACS.
本研究旨在确定部分激动剂活性在口服糖蛋白IIb/IIIa拮抗剂 orbofiban 疗效不佳中所起的作用。
尽管 orbofiban 是一种强效抗血小板药物，且静脉用药已被证明非常有效，但在 OPUS-TIMI-16 试验中发现，口服糖蛋白IIb/IIIa拮抗剂 orbofiban 会增加急性冠状动脉综合征（ACS）患者的死亡率。
将520例ACS患者随机分为每日两次服用30mg、40mg或50mg orbofiban组，或每日一次服用50mg orbofiban组或安慰剂组。通过检测糖蛋白IIb/IIIa受体构象、CD63抗原表达和血小板聚集情况，对175例患者的血小板活性进行评估。
最高剂量（峰浓度74±6ng/ml，谷浓度61±5ng/ml）的 orbofiban 血浆浓度超过了血小板对二磷酸腺苷（ADP）（29±6ng/ml）和凝血酶激活肽（61±18ng/ml）聚集的半数抑制浓度（IC50）。Orbofiban 诱导糖蛋白IIb/IIIa构象发生变化，表现为单克隆抗体mAb2的位移；这种构象变化与部分激动剂活性有关。与此一致的是，在研究期间的五个时间点，离体血小板CD63的表达显著增加。在体外，当使用针对该受体的单克隆抗体使血小板糖蛋白IIb/IIIa聚集时，orbofiban 可使血小板对肾上腺素的聚集增加至亚最大浓度（67±19%对27±9%，n = 5），并增加血栓素的形成。
Orbofiban 既是血小板糖蛋白IIb/IIIa的拮抗剂又是部分激动剂。在低药物浓度时，这种部分激动剂活性可能会增强血小板聚集。连同血浆药物水平不理想一起，这些发现可能有助于解释在ACS患者中观察到的 orbofiban 疗效不佳的原因。
