Intravenous infusion of a selective inhibitor of thromboxane A2 synthetase in man: influence on thromboxane B2 and 6-keto-prostaglandin F1 alpha levels and platelet aggregation.
The effect of the selective thromboxane A2 synthetase inhibitor OKY-1581, a pyridine derivative [sodium (E)-3-(4-(3-pyridylmethyl)phenyl)-2-methyl-2-propenoate], on thromboxane B2 and 6-keto-prostaglandin F1 alpha levels and platelet aggregation was studied in human volunteers. To clarify its effectiveness as an enzyme inhibitor, OKY-1581, at doses of 17, 83, 167, 417, 833, and 1667 micrograms/kg (n = 5 for each group), was injected intravenously, or was infused (10 micrograms/kg/min; n = 5) over 3 hr on 3 successive days. OKY-1580 (OKY-1581 free acid) was rapidly converted to its main beta-oxidized product, OKY-1565, and its reduced form, OKY-1558. During the study, plasma thromboxane B2 levels, inhibition of thromboxane B2 production in serum, and inhibition of rabbit platelet thromboxane A2 synthetase were monitored continuously. Twenty-five minutes after the injection of the above doses, plasma thromboxane B2 levels decreased by 4 +/- 7%, 40 +/- 14%, 57 +/- 7%, 68 +/- 6%, 93 +/- 5%, and 96 +/- 5% (mean +/- SD), respectively. Thromboxane B2 production in serum was decreased by 2 +/- 8%, 70 +/- 10%, 75 +/- 8%, 81 +/- 10%, and 96 +/- 8%, respectively, and rabbit platelet thromboxane A2 synthetase by 2 +/- 7%, 52 +/- 8%, 79 +/- 10%, 80 +/- 9%, 96 +/- 8%, and 95 +/- 7%. These parameters returned to the control levels 24 hr after the injection.(ABSTRACT TRUNCATED AT 250 WORDS)
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood*; D000179:Acrylates / Q000494:pharmacology*; D000328:Adult; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D001711:Biotransformation; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D008689:Methacrylates / Q000097:blood / Q000494:pharmacology*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D010974:Platelet Aggregation / Q000187:drug effects*; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*; D013929:Thromboxane B2 / Q000037:antagonists & inhibitors / Q000097:blood*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D013931:Thromboxanes / Q000037:antagonists & inhibitors* / Q000097:blood*
D000179:Acrylates; D001095:Arachidonic Acids; D008689:Methacrylates; D013931:Thromboxanes; D016718:Arachidonic Acid; D013929:Thromboxane B2; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha; C031517:2-methyl-3-(4-(3-pyridinylmethyl)phenyl)-2-propenoic acid; D010088:Oxidoreductases; D013930:Thromboxane-A Synthase