Antithrombotic effects of KW-3635, a thromboxane A2-receptor antagonist, in guinea pigs.
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.
Department of Pharmacology, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
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S
Shirakura
K
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Higo
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M
Takeda
A
A
Karasawa
D000818:Animals; D001157:Arterial Occlusive Diseases / Q000188:drug therapy; D001241:Aspirin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001584:Benzoxepins / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001777:Blood Coagulation / Q000187:drug effects*; D001792:Blood Platelets / Q000187:drug effects; D004195:Disease Models, Animal; D004906:Erythrocyte Count / Q000187:drug effects; D005263:Femoral Artery / Q000187:drug effects; D006168:Guinea Pigs; D007850:Lauric Acids / Q000008:administration & dosage / Q000633:toxicity; D008297:Male; D010648:Phenylacetates / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D010976:Platelet Count / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013927:Thrombosis / Q000188:drug therapy*; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*; D013931:Thromboxanes / Q000037:antagonists & inhibitors; D013988:Ticlopidine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use
D001562:Benzimidazoles; D001584:Benzoxepins; D007850:Lauric Acids; D010648:Phenylacetates; D013449:Sulfonamides; D013931:Thromboxanes; C030358:lauric acid; D013928:Thromboxane A2; D013988:Ticlopidine; D001241:Aspirin; C051762:daltroban; C065729:KW 3635