Antithrombotic effects of YM-60828 a newly synthesized factor Xa inhibitor in rat thrombosis models and its effects on bleeding time

摘要

class="enumerated" style="list-style-type:decimal">The effects of YM-60828, a newly synthesized factor Xa inhibitor, were investigated to analyse the relationship between its antithrombotic effects and its prolongation of template bleeding time in rats. YM-60828 was compared with argatroban, heparin and dalteparin. All agents were intravenously administered as a bolus.In ex vivo studies, YM-60828 and argatroban prolonged both prothrombin time and activated partial thromboplastin time in a dose-dependent manner, while heparin and dalteparin prolonged only activated partial thromboplastin time.In a venous thrombosis model, all agents exerted antithrombotic effects in a dose-dependent manner. The ID50 values of YM-60828, argatroban, heparin and dalteparin were 0.0081 mg kg⁻¹, 0.011 mg kg⁻¹, 6.3 iu kg⁻¹ and 4.7 iu kg⁻¹, respectively.In an arterio-venous shunt model, all agents exerted antithrombotic effects in a dose-dependent manner. The ID50 values of YM-60828, argatroban, heparin and dalteparin were 0.010 mg kg⁻¹, 0.011 mg kg⁻¹, 10 iu kg⁻¹ and 4.2  iu  kg⁻¹, respectively.In bleeding time studies, all agents prolonged template bleeding time in a dose-dependent manner. ED2 values, the doses causing a 2 fold prolongation of bleeding time in the saline group, of YM-60828, argatroban, heparin and dalteparin were 0.76 mg kg⁻¹, 0.081 mg kg⁻¹, 18 iu kg⁻¹ and 25 iu kg⁻¹, respectively.The ratio (ED2/ID50) of YM-60828 was more than 30 fold greater than that of heparin and more than 10 fold greater than those of argatroban and dalteparin.These data show that YM-60828 can exert its antithrombotic effects with little prolongation of bleeding time compared with the other currently used anticoagulant agents.