THROMBOLYTIC AND ANTITHROMBOTIC EFFICACY OF THE PLATELET GPIIB-IIIA ANTAGONIST DMP728

Objective: This study was undertaken to determine the antithrombotic a nd thrombolytic efficacy of DMP728 alone and in conjunction with throm bolytic agents. Background: Coronary artery reocclusion continues to b e a significant clinical problem after thrombolytic therapy or balloon angioplasty, with incidence rates of 5-20% regardless of thrombolytic intervention. To date, no adjunctive therapy has been shown to elimin ate the incidence of rethrombosis after thrombolysis. DMP728, a novel small-molecular-weight platelet GPIIb-IIIa receptor antagonist, has be en shown to prevent rethrombosis after thrombolysis in various arteria l thrombosis models in dogs. It might therefore have potential utility in optimizing the clinical outcome of currently available thrombolyti c agents. The present investigation was designed to examine the thromb olytic potential of DMP728 alone and in conjunction with different thr ombolytic agents. Methods: The deaggregatory effect of DMP728 in rever sing human platelet aggregation after initiation of platelet aggregati on by 10 mu mol/l adenosine 5'-diphosphate was determined using light- transmittance aggregometry. The in-vitro efficacy of DMP728, alone and in combination with thrombolytic drugs, in dispersing a preformed pla telet-rich clot was determined using a clot-dispersion assay. In addit ion, the in-vivo thrombolytic effects of DMP728, alone and in conjunct ion with streptokinase, were examined in an electrolytically induced f emoral artery thrombosis model in dogs. Results: DMP728 had concentrat ion-dependent deaggregatory and thrombolytic effects in reversing aggr egates and in dispersing a preformed platelet-rich thrombus in vitro. Furthermore, it exhibited significant potentiation (P<0.01) when combi ned with different thrombolytic drugs such as streptokinase, tissue-ty pe plasminogen activator (t-PA) and urokinase in lysing platelet-rich thrombus. DMP728 had significant in-vivo thrombolytic effects along wi th synergy in fully restoring arterial flow upon its concomitant use w ith subeffective to ineffective doses of streptokinase in an electroly tically induced femoral artery thrombosis model in dogs. It also reduc ed the time to reperfusion and prevented the incidence of rethrombosis after streptokinase. Conclusions: These findings suggest the potentia l utility and benefits of DMP728, not only in preventing arterial thro mbosis but also in optimizing the efficacy of thrombolytic drugs.