Correlation between the in vivo efficacy of GPIIb/IIIa receptor antagonists (m7E3, MK-383 and DMP-728) and ex vivo platelet inhibition

In vivo antithrombotic efficacy of GPIIb/IIIa receptor antagonists (m7E3, M K-383 and DMP-728) was studied with respect to their ex vivo platelet inhib ition in heparinized platelet-rich plasma (hPRP) and citrated platelet-rich plasma (cPRP) using a canine model of carotid artery thrombosis. For each drug group (n = 6), the right carotid artery was used as control vessel and resulting occlusive thrombus was kept in situ to examine the direct thromb olytic efficacy of the antagonists. Thirty minutes after occlusion of contr ol vessel, a low or high dose of each antagonist was administered and the l eft carotid artery was used as test vessel. All control vessels occluded wi thin 86-96 min in response to electrolytic injury. The incidence of occlusi on with lower doses of m7E3, DMP-728, and MK-383 was 100, 33 and 100%, resp ectively; corresponding times to occlusion were 174, 220 and 118 min. Lower doses inhibited ADP- or AA-induced platelet aggregation in cPRP (>80%). In cidence of occlusion with high doses of m7E3, DMP-728 and MK-383 was 33, 0 and 100%, respectively; corresponding times to occlusion were 209, >240 and >240 min. Higher doses inhibited aggregation in cPRP (>80%), but only part ially in hPRP (45-66%). Dose-dependent prolongation of bleeding time occurr ed with all antagonists, None of the antagonists lyzed preformed thrombi in control vessels. The results indicate that ex vivo platelet aggregation co nducted in hPRP, as opposed to conventional cPRP, provides a better assessm ent of the in vivo efficacy of GPIIb/IIIa receptor antagonists.