kw-3635 and Disease-Models--Animal

We studied the effect of KW-3635, a selective thromboxane A2 (TXA2)-receptor antagonist, on experimental glomerulonephritis. The glomerulonephritis was induced in mice by the administration of rabbit anti-mouse glomerular basement membrane (GBM) antibody. It was characterized as proteinuria, changes of serum biochemical parameters and glomerular histopathological abnormalities. The administration of KW-3635 (30 mg/kg/day, p.o.) significantly ameliorated the proteinuria, elevation of serum urea nitrogen and the thickening of GBM. These data suggest that TXA2 may play an important pathogenic role in the development and progression of glomerulonephritis.

Topics: Animals; Antibodies, Monoclonal; Basement Membrane; Benzimidazoles; Benzoxepins; Blood Urea Nitrogen; Disease Models, Animal; Glomerulonephritis; Kidney Glomerulus; Male; Mice; Proteinuria; Thromboxane A2

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 antithrombotic effects of the thromboxane (TX) A2-receptor antagonist and aspirin were determined using a photochemically-induced arterial thrombosis model in the femoral arteries of guinea pigs. KW-3635 (sodium (E)-11-[2-(5,6-dimethyl-1-benzimidazolyl)ethylidene]-6,11- dihydrodibenz[b,e]-oxepine-2-carboxylate monohydrate) and BM-13505, both of which are TXA2-receptor antagonists, and aspirin inhibited the thrombus formation at the doses that inhibited the ex vivo platelet aggregation induced by sodium arachidonate (100 microM) or collagen (3 micrograms/ml). These results support the notion that TXA2 is an important mediator in the present model of arterial thrombogenesis.

Topics: Animals; Arachidonic Acid; Aspirin; Benzimidazoles; Benzoxepins; Collagen; Disease Models, Animal; Femoral Artery; Guinea Pigs; Male; Phenylacetates; Platelet Aggregation; Sulfonamides; Thrombosis; Thromboxane A2