kw-3635 and Arterial-Occlusive-Diseases

Antithrombotic effects of KW-3635, a newly synthesized thromboxane (TX) A2-receptor antagonist, were studied in guinea pigs. In the extracorporeal circulation thrombosis model, the shunt was filled with thrombi, and reduction of platelet count and increase in plasma TXA2 concentration were observed. KW-3635 (30 and 100 mg/kg, p.o.) inhibited the thrombus formation in the shunt and prevented the decrease in platelet count in the circulating blood without affecting the red blood cell count. BM13,505 (30, 100 mg/kg, p.o.), another TXA2-receptor antagonist, and ticlopidine (300 mg/kg, p.o.), an antiplatelet drug, also inhibited the thrombus formation, while aspirin (10, 300 mg/kg, p.o.) did not. Peripheral arterial occlusive disease was induced by injection of sodium laurate into the femoral artery in guinea pigs. Daily oral administration of KW-3635 (3-30 mg/kg) significantly prevented the progression of vascular lesions. BM13,505 (3-30 mg/kg, p.o.) and ticlopidine (100 mg/kg, p.o.) also ameliorated the vascular lesions, whereas aspirin (10, 100 mg/kg, p.o.) did not. KW-3635 at concentrations up to 10(-4) M did not affect coagulation parameters in vitro. These results suggest that TXA2 is involved in the pathogenesis of arterial thrombotic and ischemic disorders. KW-3635 may be useful for the treatment of thrombotic disease and peripheral arterial occlusive diseases.

Topics: Animals; Arterial Occlusive Diseases; Aspirin; Benzimidazoles; Benzoxepins; Blood Coagulation; Blood Platelets; Disease Models, Animal; Erythrocyte Count; Femoral Artery; Guinea Pigs; Lauric Acids; Male; Phenylacetates; Platelet Count; Sulfonamides; Thrombosis; Thromboxane A2; Thromboxanes; Ticlopidine

The purpose of this study was to examine whether the blockade of thromboxane A2 (TxA2)/prostaglandin H2 (PGH2) receptor by the selective TxA2/PGH2 receptor antagonist KW-3635 (sodium (E)-11-[2-(5,6-dimethyl-1-benzimidazolyl)ethylidene]-6,11- dihydrodibenz[b,e]oxepine-2-carboxylate monohydrate, CAS 127166-41-0) is effective in enhancing tissue-type plasminogen activator (tPA)-induced thrombolysis and preventing reocclusion in a model of femoral artery thrombosis in anesthetized dogs. The thrombus was formed by inserting a copper coil into the femoral artery. Sodium heparin (100 U/kg i.v.) was administered shortly after the formation of thrombus. All dogs received i.v. tPA at a dose of 20 micrograms/kg/min starting 60 min after the formation of the occlusive thrombus for up to 60 min if necessary, to achieve reperfusion. After 30 min of thrombotic occlusion, the animals received vehicle (Group I, controls, n = 9) or KW-3635 (Group II, 0.3 mg/kg bolus i.v. + 0.3 mg/kg/h infusion, n = 9; Group III, 1 mg/kg bolus i.v. + 1 mg/kg/h infusion, n = 9) and the infusion of either vehicle or KW-3635 was continued thereafter throughout the experiment. The time to reperfusion in Group I was 37.3 +/- 5.2 min, while those in Group II and Group III were 25.3 +/- 6.2 min (p greater than 0.05) and 17.3 +/- 3.1 min (p less than 0.05), respectively. Reocclusion occurred within 4 h in 100% of Group I, whereas the incidence of reocclusion was reduced to 67% in Group II and to 0% in Group III. These data suggest that endogenous TxA2 generation is involved in lysis and rethrombosis during thrombolytic therapy by tPA.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Arterial Occlusive Diseases; Benzimidazoles; Benzoxepins; Dogs; Female; Femoral Artery; Fibrinolytic Agents; Male; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic; Recurrence; Thrombosis; Thromboxane A2; Tissue Plasminogen Activator