Beneficial effects of combined thromboxane synthase inhibition/receptor blockade with CGS 22652 in a canine model of coronary thrombosis.
Various antiplatelet agents were examined for their effectiveness as adjuncts to thrombolytic therapy in a canine model of thrombin-induced coronary thrombosis. Aspirin (5 mg/kg i.v. bolus), CGS 15435A (thromboxane synthase inhibitor (TxSI), 0.1 mg/kg i.v. bolus +0.04 mg/kg per h) and BM 13.505 (thromboxane receptor antagonist (TxRA), 0.5 mg/kg i.v. bolus +0.2 mg/kg per h) administered concurrently with streptokinase (750,000 units/h) were examined for their effects on reperfusion and reocclusion, as were a combination therapy with CGS 15435A + BM 13.505 or the dual TxRA/TxSI inhibitor, CGS 22652 (1 mg/kg i.v. bolus +0.4 mg/kg per h). All dogs received heparin (150 U/kg bolus + 50 U/kg per h) throughout the experimental protocol. Survival analysis at reperfusion indicated that thrombolysis was significantly improved in dogs treated with CGS 15435A, BM 13.505, CGS 15435A+BM 13.505 or CGS 22652 over that of vehicle-treated animals. Both dual inhibitor groups and the BM 13.505 group were significantly different from aspirin. Aspirin-treated dogs were not different from vehicle. Otherwise, all treatments differed from the vehicle-treated group at reocclusion. Time and incidence of reocclusion for CGS 22652 was significantly improved over that of BM 13.505. Residual thrombus weight was significantly reduced in the CGS 22652-treated and BM 13.505 + CGS 15435A-treated animals. These findings demonstrate that streptokinase-induced thrombolysis is accompanied by TxA2/prostaglandin H2 synthesis and platelet activation and suggest a role for platelet activation during reocclusion following clot lysis. These studies also show it is possible to combine the beneficial effects of both a TxRA and TxSI into a single chemical entity, CGS 22652, which, when administered as adjunctive therapy to streptokinase, results in an apparent synergistic antithrombotic effect.
Olson
R W
RW
Research Department, Ciba-Geigy Corporation, Summit, NJ 07901.
Dotson
R
R
Mathis
J
J
Cohen
D S
DS
Webb
R L
RL
D015121:6-Ketoprostaglandin F1 alpha / Q000494:pharmacology; D000818:Animals; D001241:Aspirin / Q000627:therapeutic use; D002210:Caprylates / Q000627:therapeutic use*; D003326:Coronary Circulation / Q000187:drug effects; D003328:Coronary Thrombosis / Q000188:drug therapy* / Q000503:physiopathology; D015232:Dinoprostone / Q000378:metabolism; D004285:Dogs; D006439:Hemodynamics / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology; D008297:Male; D015425:Myocardial Reperfusion; D010648:Phenylacetates / Q000627:therapeutic use; D015539:Platelet Activation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use*; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013300:Streptokinase / Q000627:therapeutic use; D013449:Sulfonamides / Q000627:therapeutic use*; D013929:Thromboxane B2 / Q000494:pharmacology; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D013931:Thromboxanes / Q000037:antagonists & inhibitors
D002210:Caprylates; D007211:Indoles; D010648:Phenylacetates; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D017482:Receptors, Thromboxane; D013449:Sulfonamides; D013931:Thromboxanes; C051984:5-chloro-1-methyl-2-(3-pyridyl)-3-indolehexanoic acid; C078274:CGS 22652; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D013300:Streptokinase; D013930:Thromboxane-A Synthase; D015232:Dinoprostone; D001241:Aspirin; C051762:daltroban