Effect of nafazatrom on platelet function and release: relationship to symptomatic episodes in patients with peripheral vascular disease.
We studied the effect of nafazatrom on plasma prostacyclin (PGI2) levels, platelet function, and thromboxane B2 (TxB2), and 12-hydroxy-eicosatetraenoic acid (12-HETE) production and clinical improvement in 12 patients with peripheral vascular disease (PVD) by means of a double-blind crossover trial of placebo, 800 or 1600 mg of nafazatrom four times daily for 1 week, with intervening 2-week washout periods. Plasma PGI2 levels were measured as 6-keto-PGF1 alpha by radioimmunoassay. Platelet function ex vivo was measured as collagen and adenosine diphosphate (ADP)-induced platelet aggregation, release of 12-HETE and thromboxane A2 (measured as TxB2), and was determined by high-pressure liquid chromatography (HPLC) and radioimmunoassay, respectively. The plasma 6-keto-PGF1 alpha levels were unaffected by nafazatrom treatment (p greater than 0.25). Nafazatrom treatment had no effect on TxB2 production, but significantly altered the production of the platelet 12-HETE (p less than 0.05). There was a significant association between the changes in 12-HETE production and clinical improvement. These results suggest that the mechanism of action of nafazatrom is in part related to the inhibition of platelet function via the lipoxygenase pathway, independent of PGI2 stimulation.
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000328:Adult; D000368:Aged; D001157:Arterial Occlusive Diseases / Q000097:blood*; D001792:Blood Platelets / Q000187:drug effects*; D002986:Clinical Trials as Topic; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D011464:Epoprostenol / Q000097:blood; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000097:blood; D008875:Middle Aged; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D047069:Pyrazolones; D011897:Random Allocation; D013929:Thromboxane B2 / Q000097:blood; D001620:beta-Thromboglobulin / Q000378:metabolism
D006893:Hydroxyeicosatetraenoic Acids; D011720:Pyrazoles; D047069:Pyrazolones; D001620:beta-Thromboglobulin; D013929:Thromboxane B2; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D011464:Epoprostenol; C018845:nafazatrom