YM-60828, a novel factor Xa inhibitor: Separation of its antithrombotic effects from its prolongation of bleeding time

The antithrombotic effects of intravenous infusions of YM-60828 ([N-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl]-N-[(7-amidino-2- naphthyl)methyl]sulfamoyl]acetic acid dihydrochloride), a novel factor Xa inhibitor, argatroban, heparin and dalteparin in an arterio-venous shunt model were studied in comparison with their effects on template bleeding time. In an arterio-venous shunt model, all agents exerted antithrombotic effects in a dose-dependent manner. ID50 values of YM-60828, argatroban, heparin and dalteparin were 0.0087 mg/kg/h, 0.027 mg/kg/h, 22 IU/kg/h and 11 IU/kg/h, respectively. In bleeding time studies, all agents prolonged bleeding time in a dose-dependent manner. Doses (ED2) of YM-60828, argatroban, heparin and dalteparin, which caused 2-fold prolongation of bleeding time in the saline group, were 3.0 mg/kg/h, 0.25 mg/kg/h, 18 IU/kg/h and 26 IU/kg/h, respectively. The risk-benefit ratio (ED2/ID50) of YM-60828 was much greater than that of the other agents. These data suggest that the antithrombotic effect of YM-60828 oo is separate from its prolongation of bleeding time and that YM-60828 is much safer than conventional anticoagulant agents. (C) 1997 Elsevier Science B.V.