R 68 070: Thromboxane A2 Synthetase Inhibition and Thromboxane A2/Prostaglandin Endoperoxide Receptor Blockade Combined in One Molecule - II. Pharmacological Effects In Vivo and Ex Vivo

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Abstract
R 68 070 or (E)-5-[[[(3-pyridinyl)[3-(trifluoromethyl)phenyl]- methylen]amino]oxy] pentanoic acid (Janssen Research Foundation, Belgium), a newly developed compound, combining specific thromboxane A2 (TXA2) synthetase inhibition with TXA2/pros- taglandin endoperoxide receptor blockade in one molecule, is active in vivo in man and in experimental animals. In man (n = 5), a single oral 400-mg dose of R 68 070 produces deep and protracted inhibition of platelet TXA2 synthetase activity (≥90% for 48 h), increases serum levels of immuno- reactive 6-keto-PGF1α, reduces platelet aggregation in RR.R induced by U 46619, collagen (>70% for 8 h), arachidonic acid (>90% for 18 h) and prolongs template bleeding times significantly, without affecting plasma coagulation or fibrinolysis. In rats, R 68 070 (1.25 mg/kg orally, –2 h) singly prolongs tail bleeding times as much as a combination of TXA2 synthetase inhibition (dazoxiben 10 mg/kg) and TXA2/prostaglandin endoperoxide receptor blockade (BM 13177 40 mg/kg). In dogs, the compound reduces coronary thrombosis induced by electrical damage (1.25 mg/kg i. v.) and prevents the evolution of occlusion/ reperfusion-induced arrhythmias into ventricular fibrillation (2.5 mg/kg i.v.). R 68 070 thus may be an appropriate pharmacological tool to analyze the roles and interactions of agonistic (TXA2, prostaglandin endoperoxides) and antagonistic (PGD2, PGE2, PGI2) metabolites of arachidonic acid in experimental and human pathologies.