Enhancement of tissue-type plasminogen activator-induced thrombolysis and prevention of reocclusion by sodium (E)-11-[2-(5,6-dimethyl-1-benzimidazolyl)- ethylidene]-6,11-dihydrodibenz[b,e]oxepine-2-carboxylate monohydrate in a canine model of femoral thrombosis.
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)
Higo
K
K
Department of Pharmacology, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
Karasawa
A
A
Kubo
K
K
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000473:pathology / Q000517:prevention & control; D001562:Benzimidazoles / Q000627:therapeutic use*; D001584:Benzoxepins / Q000627:therapeutic use*; D004285:Dogs; D005260:Female; D005263:Femoral Artery / Q000473:pathology; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D012008:Recurrence; D013927:Thrombosis / Q000188:drug therapy* / Q000473:pathology; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*
D001562:Benzimidazoles; D001584:Benzoxepins; D005343:Fibrinolytic Agents; D011450:Prostaglandin Endoperoxides, Synthetic; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D010959:Tissue Plasminogen Activator; C065729:KW 3635