This Article Full Text Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cousins, G. R. Articles by Lucchesi, B. R. Search for Related Content PubMed PubMed Citation Articles by Cousins, G. R. Articles by Lucchesi, B. R.

(Circulation. 1996;94:1705-1712.)
© 1996 American Heart Association, Inc.

Articles

Orally Effective CVS-1123 Prevents Coronary Artery Thrombosis in the Conscious Dog

Geoffrey R. Cousins, BS; Gregory S. Friedrichs, PhD; Yuji Sudo, DVM, PhD; Sam S. Rebello, PhD; William E. Rote, PhD; George P. Vlasuk, PhD; Thomas G. Nolan, PhD; Christine Mendoza, PhD; Benedict R. Lucchesi, PhD, MD

the Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, Mich, and Corvas International, San Diego, Calif (W.E.R., G.P.V., T.G.N., C.M.).

Correspondence to Benedict R. Lucchesi, PhD, MD, University of Michigan Medical School, Department of Pharmacology, 1301C Medical Science Research Bldg III, Ann Arbor, MI 48109-0632. E-mail benluc@umich.edu.

Background We examined the oral efficacy of a direct thrombin inhibitor, CVS-1123 [(CH₃CH₂CH₂)₂-CH-CO-Asp(OCH₃)-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-µA 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 µg/mL, reaching a maximum of 15±1 µg/mL after the second dose and 4.4±0.5 µg/mL at 24 hours. Ex vivo platelet aggregation to -thrombin was inhibited and activated partial thromboplastin time was increased after treatment with CVS-1123 (P<.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.

Key Words: thrombosis • platelets • electrical stimulation • ischemia • myocardial infarction

This article has been cited by other articles:

				J. I. Weitz and J. Hirsh New Anticoagulant Drugs Chest, January 1, 2001; 119(1_suppl): 95S - 107S. [Full Text] [PDF]

				J. Mitchel, D. Waters, T. Lai, M. White, T. Alberghini, A. Salloum, D. Knibbs, D. Li, and G. V. Heller Identification of Coronary Thrombus With a IIb/IIIa Platelet Inhibitor Radiopharmaceutical, Technetium-99m DMP-444 : A Canine Model Circulation, April 11, 2000; 101(14): 1643 - 1646. [Abstract] [Full Text] [PDF]

				J. J. Cook, S. J. Gardell, M. A. Holahan, G. R. Sitko, G. L. Stump, A. A. Wallace, D. B. Gilberto, T. R. Hare, J. A. Krueger, D. L. Dyer, et al. Antithrombotic Efficacy of Thrombin Inhibitor L-374,087: Intravenous Activity in a Primate Model of Venous Thrombus Extension and Oral Activity in a Canine Model of Primary Venous and Coronary Artery Thrombosis J. Pharmacol. Exp. Ther., April 1, 1999; 289(1): 503 - 510. [Abstract] [Full Text]