Antithrombotic effects of DMP 728, a platelet GPIIb/IIIa receptor antagonist, in a canine model of arterial thrombosis.
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)
Rote
W E
WE
Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109-0626.
Davis
J H
JH
Mousa
S A
SA
Reilly
T M
TM
Lucchesi
B R
BR
D000818:Animals; D002341:Carotid Artery Thrombosis / Q000097:blood / Q000188:drug therapy / Q000517:prevention & control; D004195:Disease Models, Animal; D004285:Dogs; D008297:Male; D008698:Mesylates / Q000627:therapeutic use*; D010456:Peptides, Cyclic / Q000627:therapeutic use*; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D010980:Platelet Membrane Glycoproteins / Q000032:analysis / Q000037:antagonists & inhibitors*; D012008:Recurrence; D013927:Thrombosis / Q000188:drug therapy* / Q000517:prevention & control
D008698:Mesylates; D010456:Peptides, Cyclic; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; C085286:DMP 728