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.