ym-60828 and ferric-chloride

A simple, quantitative, and reproducible model of lower limb ischemia was developed. Vascular injury was induced by ferric chloride (FeCl(3)) solution to the rat iliac artery, after which blood flow in all of the lower limbs were continuously monitored using a scanning laser Doppler blood flowmeter. After FeCl(3) injury, a distinct decrease in blood flow in the ischemic lower limb was observed and blood flow did not recover during the 30 min after vascular injury. YM466, an oral direct factor Xa inhibitor, dose-dependently inhibited the reduction of peripheral blood flow. The area under the blood flow-time curve during 30 min after vascular injury improved dose-dependently, with significance at doses of 3 and 10 mg/kg. These results suggest that factor Xa inhibitors are effective in patients with peripheral arterial disease, and that this vascular injury model is a useful tool for the screening and evaluation of the efficacy of new antithrombotic agents.

Topics: Administration, Oral; Animals; Blood Vessels; Chlorides; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Ferric Compounds; Fibrinolytic Agents; Ischemia; Lower Extremity; Male; Naphthalenes; Piperidines; Rats; Rats, Sprague-Dawley; Regional Blood Flow

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.

Topics: Angioplasty; Animals; Bleeding Time; Blood Coagulation; Blood Platelets; Carotid Arteries; Carotid Artery Thrombosis; Chlorides; Dose-Response Relationship, Drug; Drug Synergism; Factor Xa; Factor Xa Inhibitors; Ferric Compounds; Mice; Mice, Inbred ICR; Naphthalenes; Piperazines; Piperidines; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Prothrombin Time; Thrombosis; Time Factors