Thromboxane synthetase inhibition as antithrombotic strategy.
The imidazole derivative UK-37 248, a thromboxane synthetase inhibitor, reduces the in-vitro formation of thromboxane B2 and hydroxyheptadecatrienoic acid by washed platelets, and this is compensated for by an increased production of prostaglandins E2 and F2 alpha; arachidonic acid challenged platelets pretreated with UK-37 248 also stimulate the production of prostacyclin by aspirin pretreated cultured endothelial cells. In a double-blind placebo controlled study to examine the in vivo properties of UK-37 248, human volunteers ingested 200 mg of the compound. Their serum thromboxane B2 levels dropped and their plasma 6-keto-prostaglandin F1 alpha values rose. Arachidonic acid induced platelet aggregation was completely inhibited whereas that elicited by adenosine-5'-diphosphate was unaffected. By reducing formation of pro-aggregatory tromboxane A2 and increasing production of anti-aggregatory prostacyclin, thromboxane synthetase inhibitors may be better than aspirin as antithrombotic agents.
D015121:6-Ketoprostaglandin F1 alpha; D000328:Adult; D001792:Blood Platelets / Q000378:metabolism; D002986:Clinical Trials as Topic; D004311:Double-Blind Method; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D010974:Platelet Aggregation / Q000187:drug effects; D011458:Prostaglandins E / Q000097:blood; D011460:Prostaglandins F / Q000097:blood / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000097:blood; D013929:Thromboxane B2 / Q000096:biosynthesis; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D005343:Fibrinolytic Agents; D007093:Imidazoles; D011458:Prostaglandins E; D011460:Prostaglandins F; C029166:dazoxiben; D013929:Thromboxane B2; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha; D010088:Oxidoreductases; D013930:Thromboxane-A Synthase