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 Mousa, S. A. Articles by Reilly, T. M. Search for Related Content PubMed PubMed Citation Articles by Mousa, S. A. Articles by Reilly, T. M. Pubmed/NCBI databases Compound via MeSH Substance via MeSH

(Circulation. 1996;93:537-543.)
© 1996 American Heart Association, Inc.

Articles

Oral Antiplatelet, Antithrombotic Efficacy of DMP 728, a Novel Platelet GPIIb/IIIa Antagonist

Shaker A. Mousa, PhD, FACC; William F. DeGrado, PhD; Dun-Xu Mu, MD; Ram P. Kapil, PhD; Benedict R. Lucchesi, PhD, MD; Thomas M. Reilly, PhD

From The Du Pont Merck Pharmaceutical Co, Wilmington, Del.

Correspondence to Shaker A. Mousa, PhD, The Du Pont Merck Pharmaceutical Co, Exp Station, E400/3456, Wilmington, DE 19880-0400.

Background Currently used antiplatelet drugs, including aspirin and ticlopidine, are effective against certain but not all of the many endogenous platelet activators. Because of their limited efficacy, a significant number of serious thromboembolic complications still occur, highlighting the need for a more effective therapy. DMP 728 has been characterized as a potent and specific platelet glycoprotein IIb/IIIa complex (GPIIb/IIIa) antagonist. The goals of the present study were to determine the oral antiplatelet and antithrombotic efficacies of DMP 728 in various arterial thrombosis models in dogs.

Methods and Results In conscious and anesthetized mongrel dogs, DMP 728 at 0.02 to 1.0 mg/kg PO in gelatin capsules produced dose-dependent antiplatelet effects in inhibiting ex vivo platelet aggregation induced by ADP and prolonging template bleeding time. DMP 728 effects on bleeding time prolongation could be reversed more rapidly than those on platelet aggregation inhibition. A maximal antiplatelet effect for DMP 728 was demonstrated at 1.0 mg/kg PO. DMP 728 demonstrated dose-dependent oral antiplatelet effects with an absolute oral bioavailability of 8% to 12% in dogs. Additionally, the antithrombotic efficacy of DMP 728 was examined after intravenous and oral administration at different doses in various models of arterial thrombosis. In the coronary artery Folts' model in dogs, DMP 728 demonstrated maximal antithrombotic efficacy at 0.01 mg/kg IV and <0.6 mg/kg PO. Additionally, DMP 728 at 0.1 and 1.0 mg/kg IV or PO demonstrated 60% to 100% prevention of primary thrombosis (P<.01) in an electrolytically induced carotid artery thrombosis model in dogs.

Conclusions These data suggest that DMP 728, a low-molecular-weight GPIIb/IIIa receptor antagonist, may have therapeutic potential as an oral antithrombotic agent in coronary and carotid artery thromboembolic disorders.

Key Words: platelet aggregation inhibitors • thrombosis • receptor antagonists

This article has been cited by other articles:

				S. Harder, C. M. Kirchmaier, H. J. Krzywanek, D. Westrup, J.-W. Bae, and H. K. Breddin Pharmacokinetics and Pharmacodynamic Effects of a New Antibody Glycoprotein IIb/IIIa Inhibitor (YM337) in Healthy Subjects Circulation, September 14, 1999; 100(11): 1175 - 1181. [Abstract] [Full Text] [PDF]

				L. G. Frederick, O. D. Suleymanov, J. A. Szalony, B. B. Taite, A. K. Salyers, L. W. King, L. P. Feigen, and N. S. Nicholson Protective Effect of Oral Xemilofiban in Arterial Thrombosis in Dogs : Increased Activity in Combination With Aspirin Circulation, August 25, 1998; 98(8): 813 - 820. [Abstract] [Full Text] [PDF]

				T. H. Muller, H. Weisenberger, R. Brickl, H. Narjes, F. Himmelsbach, and J. Krause Profound and Sustained Inhibition of Platelet Aggregation by Fradafiban, a Nonpeptide Platelet Glycoprotein IIb/IIIa Antagonist, and Its Orally Active Prodrug, Lefradafiban, in Men Circulation, August 19, 1997; 96(4): 1130 - 1138. [Abstract] [Full Text]

				C. Simpfendorfer, K. Kottke-Marchant, M. Lowrie, R. J. Anders, D. M. Burns, D. P. Miller, C. S. Cove, A. C. DeFranco, S. G. Ellis, D. J. Moliterno, et al. First Chronic Platelet Glycoprotein IIb/IIIa Integrin Blockade : A Randomized, Placebo-Controlled Pilot Study of Xemilofiban in Unstable Angina With Percutaneous Coronary Interventions Circulation, July 1, 1997; 96(1): 76 - 81. [Abstract] [Full Text]