11-dehydro-thromboxane-b2 and ozagrel

Leukotriene (LT) and thromboxane A2 (TXA2) receptor antagonists have been used in the treatment of asthma.. We examined the effects of an LT receptor antagonist, TXA2 receptor antagonist, and TXA2 synthetase inhibitor on bronchoprovocation test (BPT) in patients with mild-to-moderate atopic asthma.. BPT was performed four times in each of six asthmatics. Development of the immediate asthmatic reaction (IAR) and late asthmatic reaction (LAR) was confirmed on the first BPT (BPT1). After a 7-day washout period, an LT receptor antagonist (pranlukast, 450 mg/d), TXA2 receptor antagonist (seratrodast, 80 mg/d), or TXA2 synthetase inhibitor (ozagrel, 800 mg/d) was administered orally over 7 days at random using a cross-over method (BPT2-4). Blood levels of LTB4, LTC4, LTD4, 11-dehydrothromboxane B2, eosinophil cationic protein, and histamine were measured at reaction phases of pre-BPT, IAR, and LAR.. Administration of pranlukast suppressed IAR by 80.5% (p < 0.0001) and LAR by 54.6% (p = 0.0391). Ozagrel significantly suppressed IAR by 39.5% (p = 0.0413), but the fall in FEV1 was >20% (21.56+/-4.173%). Seratrodast did not suppress IAR or LAR. Blood levels of chemical mediators did not correlate with the suppressive effects of the tested drugs.. The LT receptor antagonist was considered to be the most effective. LT might play a more important role in the pathogenesis of asthma than TXA2. Our data showed that measurement of blood levels of chemical mediators is not useful in identifying the pathogenic mechanisms of asthma.

Topics: Administration, Oral; Adult; Anti-Asthmatic Agents; Antigens; Asthma; Benzoquinones; Blood Proteins; Bronchial Provocation Tests; Bronchoconstriction; Chromones; Cross-Over Studies; Eosinophil Granule Proteins; Female; Follow-Up Studies; Heptanoic Acids; Histamine; Humans; Leukotriene Antagonists; Male; Membrane Proteins; Methacrylates; Receptors, Leukotriene; Receptors, Thromboxane; Ribonucleases; Thromboxane B2; Thromboxane-A Synthase; Treatment Outcome

The influence of OKY-046, a selective thromboxane synthase inhibitor, on prostanoid formation in healthy human subjects was studied. Vehicle (5% glucose solution) or OKY-046 in 5% glucose solution at 15 micrograms kg-1 min-1 was intravenously administered to five male healthy volunteers for 6 h. Platelet aggregation and thromboxane B2 (TXB2) formation induced by collagen and arachidonic acid were suppressed by the infusion of OKY-046, while both were not affected by the infusion of vehicle. Urinary excretion of 11-dehydro-thromboxane B2, one of major urinary metabolites of thromboxane A2 (TXA2) was decreased by the infusion of OKY-046, while that of 2,3-dinor-6-keto-prostaglandin F1 alpha, one of major urinary metabolites of prostacyclin (PGI2) was increased. The present study demonstrated that the infusion of OKY-046 improved the balance of TXA2/PGI2 into antithrombotic state in healthy subjects. It was also suggested that endogenously produced (probably platelet-derived) endoperoxides could be redirected into prostacyclin in vivo.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Epoprostenol; Humans; Male; Methacrylates; Platelet Aggregation; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase