ORALLY EFFECTIVE CVS-1123 PREVENTS CORONARY-ARTERY THROMBOSIS IN THE CONSCIOUS DOG

Background We examined the oral efficacy of a direct thrombin inhibito r, CVS-1123 [(CH3CH2CH2)(2)-CH-CO-Asp (OCH3)-Pro-Arg-CHO; MW, 575]. Th e object was to determine whether thrombin inhibition could reduce the incidence of occlusive coronary artery thrombosis in response to arte rial wall injury. Methods and Results Arterial wall injury was induced in conscious dogs by a 150-mu A anodal current applied to the intimal surface of the circumflex coronary artery 30 minutes after oral CVS-1 123 (20 mg/kg every 8 hours for three doses; n=11) or placebo containi ng diluent (n=10). Dogs were monitored for 8 hours and at 24 hours. Th e coronary artery remained patent for 24 hours in 8 of 11 CVS-1123-tre ated dogs. All dogs (n=10) in the placebo group developed a sustained, occlusive arterial thrombus. Two hours after the initial oral dose, t he plasma CVS-1123 concentration was 13+/-1 mu g/mL, reaching a maximu m of 15+/-1 mu g/mL after the second dose and 4.4+/-0.5 mu g/mL at 24 hours. Ex vivo platelet aggregation to gamma-thrombin was inhibited an d activated partial thromboplastin time was increased after treatment with CVS-1123 (P<.05). Conclusions The direct thrombin inhibitor CVS-1 123 is effective after oral administration in reducing the incidence o f primary thrombus formation in an experimental model of arterial wall injury. Thrombin-specific inhibitors, such as CVS-1123, may be altern ative antithrombotic agents in clinical settings in which heparin-asso ciated thrombosis is a complicating factor or when long-term anticoagu lation is required.