Combined effects of a factor Xa inhibitor YM466 and a GPIIb/IIIa antagonist YM128 on thrombosis and neointima formation in mice.
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 FeCl(3) 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.
Iwatsuki
Yoshiyuki
Y
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan.
Kawasaki
Tomihisa
T
Hayashi
Kazumi
K
Moritani
Yumiko
Y
Nii
Tomoko
T
Miyata
Keiji
K
D017130:Angioplasty; D000818:Animals; D001760:Bleeding Time; D001777:Blood Coagulation / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D002341:Carotid Artery Thrombosis / Q000188:drug therapy*; D002712:Chlorides; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors; D005290:Ferric Compounds / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D009281:Naphthalenes / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D010974:Platelet Aggregation; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011517:Prothrombin Time; D013927:Thrombosis / Q000188:drug therapy*; D013997:Time Factors
D002712:Chlorides; D065427:Factor Xa Inhibitors; D005290:Ferric Compounds; D009281:Naphthalenes; D010879:Piperazines; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C111032:YM 60828; C501989:YM128; D015951:Factor Xa; C024555:ferric chloride