Potent inhibition of thrombin with a monoclonal antibody against tissue factor (Sunol-cH36): results of the PROXIMATE-TIMI 27 trial
Potent inhibition of thrombin with a monoclonal antibody against tissue factor (Sunol-cH36): results of the PROXIMATE-TIMI 27 trial
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DOI：
10.1093/eurheartj/ehi094
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发表时间：
2005-04-01
影响因子：
39.3
通讯作者：
Antman, EM
中科院分区：
文献类型：
--
作者：
Morrow, DA;Murphy, SA;Antman, EM
组织因子（TF）的暴露是急性冠状动脉综合征发病机制中的关键步骤。Sunol-cH 36，一种针对TF的嵌合单克隆抗体，阻断因子X与TF：VIIa复合物的结合。本报告介绍了第一个完成的试验Sunol-CH 36在human.Methods和结果我们评估了Sunol-CH 36的安全性和药代动力学在一个开放标签，剂量递增的试验中受试者稳定的冠状动脉疾病。安全性分析包括所有不良事件，重点是显性或隐性出血。将五个剂量的Sunol-cH 36（0.03、0.06、0.08、0.1、0.3mg/kg）作为单次静脉推注给予26名受试者（每个剂量层三至八名受试者）。未发生大出血（血红蛋白下降>= 2 g/dL）。观察到自发性轻微出血，具有剂量相关模式。值得注意的是，大多数自发性出血事件在临床上与血小板介导的出血（例如牙龈、舌）一致，无血小板减少症。中位终末半衰期为72.2（25 th，75 th：28.4，72.5）h。结论Sunol-cH 36具有剂量依赖性抗凝作用。我们推测，使用这种凝血酶生成的强效抑制剂观察到的粘膜出血可能反映了凝血级联反应和血小板途径之间的网络连接导致的抗血小板作用，这可能证明与这种新型抗凝剂具有临床相关性。
Aims Exposure of tissue factor (TF) is a critical proximal step in the pathogenesis of acute coronary syndromes. Sunol-cH36, a chimaeric monoclonal antibody to TF, blocks binding of factor X to the TF:Vlla complex. This report describes the first completed trial of Sunol-cH36 in humans.Methods and results We assessed the safety and pharmacokinetics of Sunol-cH36 in an open-label, dose-escalating trial among subjects with stable coronary artery disease. The safety analysis included all adverse events with a focus on overt or occult bleeding. Five doses of Sunol-cH36 (0.03, 0.06, 0.08, 0.1, 0.3 mg/kg) were administered as a single intravenous bolus to 26 subjects (three to eight subjects per dose tier). No major bleeding (>= 2 g/dL haemoglobin decline) occurred. Spontaneous minor bleeding was observed with a dose-related pattern. Notably, the majority of spontaneous bleeding episodes were clinically consistent with platelet-mediated bleeding (e.g. gum, tongue) without thrombocytopenia. The median terminal half-life was 72.2 (25th, 75th: 28.4, 72.5) h.Conclusion Sunol-cH36 exhibited dose-dependent anticoagulant effects. We postulate that the mucosal bleeding observed with this potent inhibitor of thrombin generation may reflect antiplatelet effects resulting from networking between the coagulation cascade and platelet pathways that could prove clinically relevant with this novel class of anticoagulants.