Antithrombotic effects of DMP 728, a platelet GPIIb/IIIa receptor antagonist, in a canine model of arterial thrombosis.

Abstract

The platelet glycoprotein IIb/IIIa receptor (GPIIb/IIIa, fibrinogen receptor) represents the final common pathway for platelet aggregation. Inhibition of GPIIb/IIIa with antibodies or peptides containing the RGD sequence has been reported to prevent arterial thrombosis. We examined DMP 728 [(cyclic[D-2-amino-butyryl-N2-methyl-L-arginyl-glycyl-L-aspartyl-3-(a min o- methyl-benzoic acid], methanesulfonic acid salt], a cyclic peptidomimetic, GPIIb/IIIa receptor antagonist, for prevention of thrombosis and rethrombosis in a canine model of carotid artery thrombosis. Dogs were anesthetized, and both carotid arteries were instrumented with an electrode, a flow probe, and a stenosis. A 300-microA current was applied to the intimal surface in the right carotid artery (RCA, control) through the electrode; time to occlusive thrombus formation and thrombus mass was noted. The RCA served as the control vessel; the left carotid artery (LCA) served as the test vessel after DMP 728 administration (0.1 or 1. mg/kg, intravenously, i.v.). As compared with controls, occlusive thrombus formation was reduced by both doses of DMP 728 (control 100% n = 12; 0.1 mg/kg i.v. 17%, p < 0.05, n = 6; 1.0 mg/kg i.v. 0%, p < 0.05, n = 6), time to occlusion was increased (p < 0.05), and thrombus weight was reduced (p < 0.05). Ex vivo platelet aggregation was inhibited in all groups. In a second group of animals, a carotid artery thrombus was formed and lysed with anisoylated plasminogen activator complex (APSAC; 0.05 U/kg intraarterially, i.a.) with or without DMP 728.(ABSTRACT TRUNCATED AT 250 WORDS)

• Authors: W E Rote, J H Davis, S A Mousa, T M Reilly, B R Lucchesi
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 23 Issue 4 Pg. 681-9 (Apr 1994) ISSN: 0160-2446 [Print] United States
• PMID: 7516023 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Mesylates
• Peptides, Cyclic
• Platelet Aggregation Inhibitors
• Platelet Membrane Glycoproteins
• DMP 728

Topics

• Animals
• Carotid Artery Thrombosis (blood, drug therapy, prevention & control)
• Disease Models, Animal
• Dogs
• Male
• Mesylates (therapeutic use)
• Peptides, Cyclic (therapeutic use)
• Platelet Aggregation Inhibitors (therapeutic use)
• Platelet Membrane Glycoproteins (analysis, antagonists & inhibitors)
• Recurrence
• Thrombosis (drug therapy, prevention & control)