Orally effective CVS-1123 prevents coronary artery thrombosis in the conscious dog
Cousins, G.R.; Friedrichs, G.S.; Sudo, Y.; Rebello, S.S.; Rote, W.E.; Vlasuk, G.P.; Nolan, T.G.; Mendoza, C.; Lucchesi, B.R.
Circulation 94(7): 1705-1712
1996
ISSN/ISBN: 0009-7322 PMID: 8840864 Document Number: 459243
Background: We examined the oral efficacy of a direct thrombin inhibitor, CVS-1123 ((CH-3CH-2CH-2)-2-CH-CO-Asp(OCH-3)-Pro-Arg-CHO; MW, 575). The object was to determine whether thrombin inhibition could reduce the incidence of occlusive coronary artery thrombosis in response to arterial 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-1123 (20 mg/kg every 8 hours for three doses; n= 11) or placebo containing diluent (n =10). Dogs were monitored for 8 hours and at 24 hours. The coronary artery remained patent for 24 hours in 8 of 11 CVS-1123-treated dogs. All dogs (n= 10) in the placebo group developed a sustained, occlusive arterial thrombus. Two hours after the initial oral dose, the plasma CVS-1123 concentration was 13+-1 mu-g/mL, reaching a maximum 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 y-thrombin was inhibited and activated partial thromboplastin time was increased after treatment with CVS-1123 (P lt .05). Conclusions: The direct thrombin inhibitor CVS-1123 is effective after oral administration in reducing the incidence of primary thrombus formation in an experimental model of arterial wall injury. Thrombin-specific inhibitors, such as CVS-1123, may be alternative antithrombotic agents in clinical settings in which heparin-associated thrombosis is a complicating factor or when long-term anticoagulation is required.