Sa. Mousa et al., THROMBOLYTIC AND ANTITHROMBOTIC EFFICACY OF THE PLATELET GPIIB-IIIA ANTAGONIST DMP728, Coronary artery disease, 5(11), 1994, pp. 919-927
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.