Combined effects of a factor Xa inhibitor YM466 and a GPIIb/IIIa antagonist YM128 on thrombosis and neointima formation in mice

Yoshiyuki Iwatsuki; Tomihisa Kawasaki; Kazumi Hayashi; Yumiko Moritani; Tomoko Nii; Keiji Miyata

doi:10.1160/TH04-04-0206

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2004; 92(06): 1221-1228
DOI: 10.1160/TH04-04-0206

Theme Issue Article

Schattauer GmbH

Combined effects of a factor Xa inhibitor YM466 and a GPIIb/IIIa antagonist YM128 on thrombosis and neointima formation in mice

Authors

Yoshiyuki Iwatsuki

¹Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan
Tomihisa Kawasaki

¹Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan
Kazumi Hayashi

¹Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan
Yumiko Moritani

¹Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan
Tomoko Nii

²International Clinical Development Department, Yamanouchi Pharmaceutical Co., Ltd.,Tokyo, Japan
Keiji Miyata

¹Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan

Abstract

Summary

Thrombosis and neointima formation limit the efficacy of coronary angioplasty. Factor Xa inhibitors and GPIIb/IIIa antagonists have shown to be effective on acute thrombosis and late neointima formation, however, their combined effects remain to be elucidated. Vascular injury was induced by FeCl₃ in the carotid artery in mice. For thrombosis studies, the test drug was orally administered 1 hour before vascular injury. For neointima studies, the test drug was orally administered 1 hour before and twice daily for 1 week after vascular injury, and then histological analysis was performed 3 weeks after vascular injury. YM466 inhibited thrombotic occlusion at 30 mg/kg with prolongation of prothrombin time (PT), and tail transection bleeding time (BT) was affected at 100 mg/kg. YM466 also inhibited neointima formation at 10 mg/kg. YM128 inhibited thrombotic occlusion and neointima formation at 10 and 30 mg/kg, respectively, with inhibition of platelet aggregation and prolongation of BT. In contrast, the combination of 10 mg/kg YM466 and 3 mg/kg YM128 inhibited thrombotic occlusion and neointima formation without affecting PT, platelet aggregation and BT. Concomitant inhibition of factor Xa and GPIIb/IIIa may provide a safer and more effective therapeutic regimen for treatment of coronary angioplasty.

Keywords

Combination - factor Xa inhibitor - GPIIb/IIIa antagonist - thrombosis - neointima formation

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