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.
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/prostaglandin 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 (greater than or equal to 90% for 48 h), increases serum levels of immunoreactive 6-keto-PGF1 alpha, reduces platelet aggregation in P.R.P. induced by U 46619, collagen (greater than 70% for 8 h), arachidonic acid (greater than 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.
De Clerck
F
F
Department of Haematology, Janssen Research Foundation, Beerse, Belgium.
Beetens
J
J
Van de Water
A
A
Vercammen
E
E
Janssen
P A
PA
D000328:Adult; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy; D001777:Blood Coagulation / Q000187:drug effects; D003328:Coronary Thrombosis / Q000188:drug therapy; D004285:Dogs; D005342:Fibrinolysis / Q000187:drug effects; D006487:Hemostasis / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy; D010421:Pentanoic Acids / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D017482:Receptors, Thromboxane; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D014631:Valerates / Q000494:pharmacology*
D010421:Pentanoic Acids; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D014631:Valerates; D013930:Thromboxane-A Synthase; C060219:ridogrel