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 Frederick, L. G. Articles by Feigen, L. P. Search for Related Content PubMed PubMed Citation Articles by Frederick, L. G. Articles by Feigen, L. P. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB ACETYLSALICYLIC ACID HEPARIN Medline Plus Health Information Blood Thinners

(Circulation. 1996;93:129-134.)
© 1996 American Heart Association, Inc.

Articles

The Protective Dose of the Potent GPIIb/IIIa Antagonist SC-54701A Is Reduced When Used in Combination With Aspirin and Heparin in a Canine Model of Coronary Artery Thrombosis

Leo G. Frederick, MS; Osman D. Suleymanov, MS; Lucy W. King, BS; Anita K. Salyers, BS; Nancy S. Nicholson, MBA, MS; Larry P. Feigen, PhD

From the Department of Cardiovascular Diseases Research, Searle, Skokie, Ill.

Correspondence to Leo G. Frederick, Searle, 4901 Searle Pkwy, Skokie, IL 60077.

Background Fibrinogen receptor antagonists block the fibrinogen-platelet interaction at the GPIIb/IIIa receptors and inhibit thrombus formation. SC-54701 is the active metabolite of SC-54684A, an orally active fibrinogen receptor antagonist. We compared the efficacy of SC-54701A (SCa, hydrochloride salt) with that of aspirin (ASA) or heparin and with combination therapy in a canine model of continuous current injury.

Methods and Results Sixty-six dogs were used (6 per treatment). SCa (15-minute loading dose followed by [//] infusion [µg/kg per minute]: (0.87//0.39=1xSCa; 0.52//0.23=0.6xSCa; and 0.425//0.20=0.5xSCa), ASA (2.8 mg/kg), heparin (200 U/kg plus 1000 U/h), or saline (0.1 mL/kg) was administered intravenously. Experimental time was 180 minutes of current. Time to occlusion was increased (P<.05) by SCa (T=incidence of thrombosis) (1xSCa, >180 minutes [T=0]; 0.6xSCa, 158±15 minutes [T=2]; 0.5xSCa, 130±22 minutes [T=4]), heparin (114±16 minutes [T=5]), and ASA plus heparin (130±11 minutes [T=5]) relative to saline (58±7 minutes [T=6]). Time to occlusion for the SCa treatments was increased compared with ASA (64±7 minutes [T=6]). When 0.5xSCa was administered with ASA plus heparin, time to occlusion was >180 minutes [T=0]. SCa provided complete protection at 90% inhibition of ex vivo collagen-induced platelet aggregation. Cyclic flow variations were minimal with SCa or any treatment involving 0.5xSCa and ASA.

Conclusions SCa has dose-dependent antithrombotic efficacy and inhibits ex vivo platelet aggregation. ASA, heparin, or saline was ineffective in this model. SCa (0.5x) plus ASA and heparin maximized the antithrombotic effect of this lower dose of SCa.

Key Words: platelets • aggregation • antithrombotic agents • thrombosis

This article has been cited by other articles:

				J. K. Hennan, J. Huang, T. D. Barrett, E. M. Driscoll, D. E. Willens, A. M. Park, L. J. Crofford, and B. R. Lucchesi Effects of Selective Cyclooxygenase-2 Inhibition on Vascular Responses and Thrombosis in Canine Coronary Arteries Circulation, August 14, 2001; 104(7): 820 - 825. [Abstract] [Full Text] [PDF]

				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]

				S. Honda, Y. Tomiyama, T. Aoki, M. Shiraga, Y. Kurata, J. Seki, and Y. Matsuzawa Association Between Ligand-Induced Conformational Changes of Integrin alpha IIbbeta 3 and alpha IIbbeta 3-Mediated Intracellular Ca2+ Signaling Blood, November 15, 1998; 92(10): 3675 - 3683. [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]

				P. Hoffmann, A. Bernat, P. Savi, and J. M. Herbert Prevention of Thrombosis and Enhancement of Thrombolysis in Rabbits by SR 121787, a Glycoprotein II/III Antagonist J. Pharmacol. Exp. Ther., August 1, 1998; 286(2): 670 - 675. [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]