Factor Xa (FXa) is a critical enzyme in the coagulation cascade responsible for thrombin generation, the final enzyme that leads to fibrin clot formation[1]. Darexaban (or YM150) is an oral, direct factor Xa inhibitor, with a Ki for factor Xa of 31 nM. T[2].Darexaban doubled the FXa clotting time and prothrombin time at 2.0 and 1.8 µM, respectively. It also strongly inhibited prothrombin activation induced by free Xa, prothrombinase and whole-blood clots[3].In mice, darexaban inhibited FXa activity in plasma with an ED50 value of 24.8 mg/kg.PT and activated partial thromboplastin time (aPTT) prolonged by darexaban were dose-dependently reversed by intravenously-administered rFVIIa, significantly so at 1 mg/kg. In a FeCl3-induced venous thrombosis (VT) mouse model, darexaban (0.3-10 mg/kg) dose-dependently decreased the thrombus protein content, significantly so at doses of 3 mg/kg or higher. In a tail-transection mouse model, darexaban had no significant effect on the amount of blood loss at doses up to 10 mg/kg, while warfarin showed a dose-dependent increase in blood loss, significantly so from 1 mg/kg/day. Darexaban and its metabolite darexaban glucuronide significantly prolonged PT and aPTT in human plasma in vitro, and while rFVIIa concentration-dependently reversed the prolonged PT in this plasma, ACC dose-dependently reversed both PT and aPTT changes prolonged by darexaban[4].
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