Thrombolytic and antithrombotic efficacy of the platelet GPIIb-IIIa antagonist DMP728.
OBJECTIVE
This study was undertaken to determine the antithrombotic and thrombolytic efficacy of DMP728 alone and in conjunction with thrombolytic agents.


BACKGROUND
Coronary artery reocclusion continues to be 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 eliminate the incidence of rethrombosis after thrombolysis. DMP728, a novel small-molecular-weight platelet GPIIb-IIIa receptor antagonist, has been shown to prevent rethrombosis after thrombolysis in various arterial thrombosis models in dogs. It might therefore have potential utility in optimizing the clinical outcome of currently available thrombolytic agents. The present investigation was designed to examine the thrombolytic potential of DMP728 alone and in conjunction with different thrombolytic agents.


METHODS
The deaggregatory effect of DMP728 in reversing human platelet aggregation after initiation of platelet aggregation by 10 mumol/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 platelet-rich clot was determined using a clot-dispersion assay. In addition, the in-vivo thrombolytic effects of DMP728, alone and in conjunction with streptokinase, were examined in an electrolytically induced femoral artery thrombosis model in dogs.


RESULTS
DMP728 had concentration-dependent deaggregatory and thrombolytic effects in reversing aggregates and in dispersing a preformed platelet-rich thrombus in vitro. Furthermore, it exhibited significant potentiation (P < 0.01) when combined with different thrombolytic drugs such as streptokinase, tissue-type plasminogen activator (t-PA) and urokinase in lysing platelet-rich thrombus. DMP728 had significant in-vivo thrombolytic effects along with synergy in fully restoring arterial flow upon its concomitant use with subeffective to ineffective doses of streptokinase in an electrolytically induced femoral artery thrombosis model in dogs. It also reduced the time to reperfusion and prevented the incidence of rethrombosis after streptokinase.


CONCLUSIONS
These findings suggest the potential utility and benefits of DMP728, not only in preventing arterial thrombosis but also in optimizing the efficacy of thrombolytic drugs.
Mousa
S A
SA
DuPont Merck Pharmaceutical Company, Cardiovascular Disease Division, Wilmington, DE 19880-0400.
Forsythe
M S
MS
Diemer
M
M
Bozarth
J M
JM
Reilly
T M
TM
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D002985:Clinical Protocols; D004285:Dogs; D004359:Drug Therapy, Combination; D005260:Female; D005263:Femoral Artery; D005342:Fibrinolysis / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008297:Male; D008698:Mesylates / Q000494:pharmacology / Q000627:therapeutic use*; D008955:Models, Cardiovascular; D010456:Peptides, Cyclic / Q000494:pharmacology / Q000627:therapeutic use*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011485:Protein Binding / Q000187:drug effects; D012008:Recurrence; D013300:Streptokinase / Q000494:pharmacology / Q000627:therapeutic use*; D013927:Thrombosis / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology
D008698:Mesylates; D010456:Peptides, Cyclic; D010975:Platelet Aggregation Inhibitors; C085286:DMP 728; D000244:Adenosine Diphosphate; D013300:Streptokinase