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DOI: 10.1055/s-0038-1651595
Effect of the Infusion of OKY-046, a Thromboxane A2 Synthase Inhibitor, on Urinary Metabolites of Prostacyclin and Thromboxane A2 in Healthy Human Subjects
Publication History
Received 07 August 1992
Accepted after revision 09 November 1992
Publication Date:
05 July 2018 (online)
Summary
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 μg 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 F1α, 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.
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References
- 1 Hamberg M, Svensson J, Samuelsson B. Thromboxanes: A new group of biologically active compounds derived from prostaglandin endoperoxides. Proc Natl Acad Sci USA 1975; 72: 2994-2998
- 2 Antiplatelet trialists’ collaboration. Secondary prevention of vascular disease by prolonged antiplatelet treatment. Br Med J 1988; 296: 320-331
- 3 Steering committee of physicians’ health study research group. Final report on the aspirin component of the ongoing physicians’ health study. N Engl J Med 1989; 321: 129-135
- 4 Verheugt FWA, Laarse AVD, Fünke-Kupper AJ, Sterkman LGW, Galema TW, Roos JP. Effects of early intervention with low-dose aspirin (100 mg) on infarct size, reinfarction and mortality in anterior wall acute myocardial infarction. Am J Cardiol 1990; 66: 267-270
- 5 Needleman P, Raz A, Ferrendelli JA, Minkes M. Application of imidazole as a selective inhibitor of thromboxane synthetase in human platelets. Proc Natl Acad Sci USA 1977; 74: 1716-1720
- 6 Moncada S, Buting S, Mullane K, Thorogood P, Vane JR, Raz A, Needleman P. Imidazole: A selective inhibitor of thromboxane synthetase. Prostaglandins 1977; 13: 611-618
- 7 Smith JB. Pharmacology of thromboxane synthetase inhibitors. Fed Proc 1987; 46: 139-143
- 8 Korbut R, Dembiñska-Kiec A, Swies J, Zmuda A, Gryglewski RJ. On the mechanism of thrombolytic action of thromboxane synthetase inhibitors. Thromb Haemostas 1987; 58: 827-830
- 9 Vermylen J, Defreyn G, Carreras LO, Machin SJ, Sehaeren JV, Verstraete M. Thromboxane synthetase inhibition as antithrombotic strategy. Lancet 1981; 1: 1073-1075
- 10 Marcus AJ, Weksler BB, Jaffe EA, Broekman JM. Synthesis of prostacyclin from platelet-derived endoperoxides by cultured human endothelial cells. J Clin Invest 1980; 66: 979-986
- 11 Schafer AI, Crawford DD, Gimbrone MAJ. Unidirectional transfer of prostaglandin endoperoxides between platelets and endothelial cells. J Clin Invest 1984; 73: 1105-1124
- 12 FitzGerald GA, Oates JA. Selective and nonselective inhibition of thromboxane formation. Clin Pharmacol Ther 1984; 35: 633-640
- 13 Reilly IAG, FitzGerald GA. Inhibition of thromboxane formation in vivo and ex vivo: Implications for therapy with platelet inhibitory drugs. Blood 1987; 69: 180-186
- 14 Fischer S, Struppler M, Bohlig B, Bernutz C, Weber W, Weber PC. The influence of selective thromboxane synthetase inhibition with a novel imidazole derivative, UK-38,485, on prostanoid formation in man. Circulation 1983; 68: 821-826
- 15 Henriksson P, Rasmanis G, Edhag O, Vesteqvist O, Gréen K. Thromboxane synthase inhibition: “endoperoxide shunt phenomenon” does not occur in healthy humans in vivo. Prostaglandins 1990; 39: 99-107
- 16 FitzGerald GA, Brash AR, Falardeau P, Oates JA. Estimated rate of prostacyclin secretion into circulation of normal man. J Clin Invest 1981; 68: 1272-1276
- 17 Rosenkranz B, Fischer C, Weimer K, Frölich J. Metabolism of prostacyclin and 6-keto-prostaglandin F1α in man. J Biol Chem 1980; 255: 10194-10198
- 18 Wennmalm A, FitzGerald GA. Excretion of prostacyclin and thromboxane A2 metabolites during leg exercise in humans. Am J Physiol 1988; 255: H15-H18
- 19 Vesterqvist O, Gréen K. Development of a GC-MS method for quantitation of 2,3-dinor-6-keto-PGF1α and determination of the urinary excretion rates in healthy humans under normal conditions and following drugs. Prostaglandins 1984; 28: 139-154
- 20 Vesterqvist O, Gréen K. Urinary excretion of 2,3-dinor-thromboxane B2 in man under normal conditions, following drugs and during some pathological conditions. Prostaglandins 1984; 27: 627-644
- 21 Garcia-Szabo R, Kern DF, Malik AB. Pulmonary vascular response to thrombin: Effects of thromboxane synthetase inhibition with OKY-046 and OKY-1581. Prostaglandins 1984; 28: 851-866
- 22 Hirafuji M, Ogura Y. Endogenous biosynthesis of prostaglandin I2 and thromboxane A2 by isolated rat dental pulp. Biochem Pharmacol 1983; 32: 2983-2985
- 23 Kubo K, Kobayashi T, Handa K, Kusama S, Sakai A, Ueda G. Effects of OKY-046 on endotoxin-induced lung injury in conscious sheep. Am Rev Resp Dis 1983; 127: 303
- 24 Westlund P, Kumlin M, Nordenström A, Granström E. Circulating and urinary thromboxane B2 metabolites in the rabbit: 11-dehydrothromboxane B2 as parameter of thromboxane production. Prostaglandins 1986; 31: 413-443
- 25 Westlund P, Granström E, Kumlin M, Nordenström A. Identification of 11-dehydro-TXB2 as a suitable parameter for monitoring thromboxane production in the human. Prostaglandins 1986; 31: 929-960
- 26 Balazy M, Brass EP, Gerber JG, Nies AS. Facile method for preparation of 2,3-dinor-6-keto-PGF1α. The major urinary metabolite of prostacyclin. Prostaglandins 1988; 36: 421-430
- 27 Lawson JA, Patrono C, Ciabattoni G, FitzGerald GA. Long-lived enzymatic metabolites of thromboxane B2 in human circulation. Anal Biochem 1986; 155: 198-205
- 28 Fukushima M, Kubo K, Yoshimura K, Shibamoto T, Fujimoto K, Hirai K, Kobayashi T, Kusama S, Komatsu H, Hamano S, Ujiie A, Shimizu M, Miyagi M, Morita K, Mikoshiba I, Hiraku S, Ohki S. Phase I study of OKY-046, a selective thromboxane inhibitor; Study on one-shot and continuous intravenous administration. Yakuri-to-Chiryo 1986; 14: 277-307
- 29 Otomo E, Ktsuzawa T, Kogure K, Hirai S, Goto F, Terashi A, Tazaki Y, Araki G, Ito E, Fujishima M, Nakashima M. Clinical usefulness of OKY-046 on the acute stage of cerebral thrombosis. Double blind trial in comparison with placebo. Rinsho-Iyaku 1991; 7: 353-388
- 30 Takenaga M, Kitagawa H, Hirai A, Tamura Y, Yoshida S. Mechanism of anti-platelet aggregating action of dilazep. J Pharmacobio-Dyn 1985; 8: 77-83
- 31 Lands WEM, Culp BR, Hirai A, Gorman R. Relationship of thromboxane generation to the aggregation of platelet from humans: Effects of eicosapentaenoic acid. Prostaglandins 1985; 30: 819-825
- 32 Powell WS. Rapid extraction of oxygenated metabolites of arachidonic acid from biological samples using octadecylsilylsilica. Prostaglandins 1980; 20: 947-957
- 33 Kumlin M, Granström E. Radioimmunoassay for 11-dehydro-TXB2: A method for monitoring thromboxane production in vivo. Prostaglandins 1986; 32: 741-767
- 34 Chiabrando C, Pinciroli V, Campoleoni A. Quantitative profiling of 6-ketoprostaglandin F1α, 2,3-dinor-6-ketoprostaglandin F1α, thromboxane B2 and 2,3-dinor-thromboxane B2 in human and rat urine by immunoaffinity extraction with gas chromatography-mass spectrometry. J Chromatogr 1989; 495: 1-11
- 35 Nakagawa A, Kobayashi N, Haruyama H, Takayama T, Muramatsu S, Nakamura K. Studies on the determination of 2,3-dinor-6-keto-PGF1α by GC-MS. Proc Jpn Soc Biomed Mass Spectrum 1990; 15: 123-128
- 36 Tallarida RJ, Murray RB. Manual of Pharmacologic Calculation with Computer Programs. 2.. New York: Springer; 1986
- 37 Casas J, Rosello J, Gelpi E. Determination of 2,3-dinor-6-ketopros-taglandin F1α in urine samples by liquid chromatography and radioimmunoassay. J Chromatogr 1986; 383: 317-324
- 38 Ciabattoni G, Boss AH, Daffonchio L, Daugherty J, FitzGerald GA, Catella F, Dray F, Patrono C. Radioimmunoassay measurement of 2.3-dinor metabolites of prostacyclin and thromboxane in human urine. Adv Prostaglandin Thromboxane Leukotriene Res 1987; 17: 598-602
- 39 Lellouche F, Fradin A, FitzGerald G, Maclouf J. Enzyme immunoassay measurement of the urinary metabolites of thromboxane A2 and prostacyclin. Prostaglandins 1990; 40: 297-310
- 40 Hoet B, Arnout J, Geet CV, Deckmyn H, Verhaeghe R, Vermylen J. Ridogrel, a combined thromboxane synthase inhibitor and receptor blocker, decreases elevated plasma β-thromboglobulin levels in patients with documented peripheral arterial disease. Thromb Haemostas 1990; 64: 87-90