Antithrombotic effects of YM466, a synthesized direct inhibitor of factor Xa, in an arterio‐venous shunt thrombosis model in squirrel monkeys

Abstract

The antithrombotic effects of YM466, a synthetic direct inhibitor of human factor Xa (FXa), were evaluated in an arterio-venous shunt thrombosis model in squirrel monkeys. YM466 significantly inhibited thrombus formation after continuous IV zx infusion at doses of 3-30 mg/kg/h. Although prothrombin time (PT) was significantly prolonged at doses of 10 and 30 mg/kg/h, this effect was small (1.2-and 1.4-fold of the control, respectively). Furthermore, YM466 had no effect on template bleeding time and activated partial thromboplastin time at any dose. Plasma anti-FXa activity increased in a dosedependent manner correlating with the antithrombotic effect of YM466. Thrombin-antithrombin III complex levels decreased to less than normal levels at 30 mg/kg/h of YM466. Mean plasma concentrations of YM466 measured by LC/MS/MS were 2.5, 10.5, 27.4, and 75.5 ng/ml at doses of 1, 3, 10, and 30 mg/kg/ h, respectively. These results suggest that YM466 is a safe antithrombotic agent with low bleeding risk, and that plasma anti-FXa activity may be a suitable parameter for monitoring its antithrombotic effect. Drug Dev.

A liquid chromatographic–tandem mass spectrometric method for the determination of YM466, a novel Factor Xa inhibitor, in rat plasma

“…This LOQ value may not be sufficient to determine pharmacologically effective plasma concentrations for YM466 in rats. This is because effective plasma levels of YM466 in squirrel monkeys were 10.5 ng/ml [6], and species differences in the pharmacological response should be considered. Furthermore, the clean-up procedure for the pre-treatment process (e.g.…”

Potential Use of Cyclodextrins to Enhance the Solubility of YM466 in Aqueous Solution

“…1), is a new anticoagulant that inhibits Factor Xa. [1] It was shown to be a safe antithrombotic agent with low bleeding risks in animal models. Therefore, it is expected to prove clinically effective in the treatment of thrombotic disorders, including deep-vein thrombosis and disseminated intravascular coagulation.…”

Aminoalkylmethacrylate copolymer E improves oral bioavailability of YM466 by suppressing drug–bile interaction

“…N‐[4‐[(1‐acetoamidoyl–4–piperidyl) oxy]phenyl]‐N‐[(7‐amidino–2‐naphtyl) methyl] sulfamoyl acetic acid monomesilate (YM466; Fig. 1), a novel anticoagulant with potent antifactor Xa activity,1,2 has been shown to be a safe antithrombotic agent with low risk of bleeding. Therefore, this compound is expected to prove clinically effective in the treatment of thrombotic disorders such as deep vein thrombosis and disseminated intravascular coagulation.…”