Summary
Fenflumizole (2-(2,4-difluorophenyl)-4,5-bis(4-methoxyphenyl)imidazole), a new non-steroidal anti-inflammatory drug, was given to healthy subjects in single oral doses of 0.1, 1 and 2 mg/kg. The effect of the drug was followed for up to 8 h by repeated tests of arachidonic acid-induced platelet aggregation and was related to its concomitant plasma concentration. Fenflumizole reversibly inhibited platelet aggregation and the degree of inhibition was found to be linearly correlated with the log plasma concentration. There was depression of the formation of thromboxane B2 and 6-keto-prostaglandin F1α (the stable metabolites of thromboxane A2 and prostacyclin) in clotted whole blood measured by radioimmunoassay after fenflumizole 1 mg/kg. This effect was directly related to the concentration of the drug in plasma, the maximum effect being reached at fenflumizole concentrations >200 ng/ml. EC50-values for inhibition of the formation of thromboxane B2 and 6-keto-prostaglandin \(F_{1\alpha } \) were approximately 20 and 40 ng/ml, respectively. The results suggest that orally administered fenflumizole is a potent inhibitor of platelet aggregation and prostanoid formation.
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References
Corell T, Hasselmann G (1983) Pharmacodynamics and toxicology of fenflumizole, a new non-steroidal anti-inflammatory imidazole derivative. Acta Pharmacol Toxicol 53: 288–296
Corell T, Hasselmann G, Splawinski J, Wojtaszek B (1983) Fenflumizole: interactions with the arachidonic acid cascade. Acta Pharmacol Toxicol 53: 297–303
Born GVR (1962) Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature 194: 297–299
Vargaftig BB, Zirinis P (1973) Platelet aggregation induced by arachidonic acid is accompanied by release of potential inflammatory mediators distinct from PGE2 and PGF2. Nature New Biol 244: 114–116
Kinlough-Rathbone RL, Reimers HJ, Mustard JF (1976) Sodium arachidonate can induce platelet shape change and aggregation which are independent of the release reaction. Science 192: 1011–1012
Midskov C (1983) Reversed-phase chromatography of fenflumizole, a new potential anti-inflammatory agent and its application in pharmacokinetic studies in rat, dog and man. J Chromatogr 278: 109–115
Patrono C, Ciabattoni G, Pinca E, Pugliese F, Castrucci G, De Salvo A, Satta MA, Peskar BA (1980) Low dose aspirin and inhibition of thromboxane B2 production in healthy volunteers. Thromb Res 17: 317–327
Midskov C, Vinge E, Andersson K-E (1984) On the pharmacokinetics of fenflumizole, a novel anti-inflammatory agent, after single oral administration to healthy subjects. Acta Pharmacol Toxicol 54: 408–413
Fratantoni JC, Poindexter BJ (1981) Characterization of the platelet response to exogenous arachidonic acid. Thromb Res 22: 157–166
Robak J, Dembinska-Kiec A, Gryglewski R (1975) The influence of saturated fatty acids on prostaglandin synthetase activity. Biochem Pharmacol 24: 2057–2060
Dutilh CE, Haddeman E, Don JA, ten Hoor F (1981) The role of arachidonate lipoxygenase and fatty acids during irreversible blood platelet aggregation in vitro. Prostaglandins Medicine 6: 111–126
Aharony D, Smith JB, Silver MJ (1982) Regulation of arachidonate-induced platelet aggregation by the lipoxygenase product, 12-hydroperoxyeicosatetraenoic acid. Biochim Biophys Acta 718: 193–200
Gimeno MF, Shattner MA, Borda E, Gimeno AL, Lazzari MA (1983) Lipoxygenase inhibitors alter aggregation and adhesiveness of human blood platelets from aspirin-treated patients. Prostaglandins Leukotrienes Medicine 11: 109–119
Viinikka, Toivanen, Ylikorkala O (1982) The effect of prolonged treatment with sulphinpyrazone on thromboxane A2 and prostacyclin in man. Br J Clin Pharmacol 14: 456–458
Weksler BB, Pett SB, Alonso D, Richter RC, Stelzer P, Subramanian V, Tack-Goldman K, Gay Jr WA (1983) Differential inhibition by aspirin of vascular and platelet prostaglandin synthesis in atherosclerotic patients. N Engl J Med 308: 800–805
Thorngren M, Shafi S, Born GVR (1983) Thromboxane A2 in skin-bleeding-time blood and in clotted venous blood before and after administration of acetylsalicylic acid. Lancet i 1075–1078
Greaves M, Preston FE (1982) Plasma 6-keto-prostaglandin F1α: fact or fiction. Thromb Res 26: 145–157
FitzGerald GA, Pedersen AK, Patrono C (1983) Analysis of prostacyclin and thromboxane biosynthesis in cardiovascular disease. Circulation 67: 1174–1177
Parry MJ, Randall MJ, Tyler HM, Myhre E, Dale J, Thaulow E (1982) Selective inhibition of thromboxane synthetase by dazoxiben increases prostacyclin production by leukocytes in angina patients and healthy volunteers. Lancet ii 164
Pitzke B, Rucker W, Schrör K (1983) Formation of PGI2, PGE2 and TXB2 in whole blood in vitro and its pharmacological modification. Abstract presented at the British Pharmacological Society Meeting 1983, Galway, Ireland Br J Pharmacol 80: 700 P
Grimm LJ, Knapp DR, Senator D, Halushka PV (1981) Inhibition of platelet thromboxane syntesis by 7-(l-imidazolylyl)heptanoic acid: Dissociation from inhibition of aggregation. Thrombosis Res 24: 307–317
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Vinge, E., Corell, T. & Andersson, K.E. Effects of fenflumizole on aggregation ex vivo of human platelets and formation of thromboxane B2 and 6-keto-prostaglandin-\(F_{1\alpha } \) . Eur J Clin Pharmacol 26, 711–717 (1984). https://doi.org/10.1007/BF00541930
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DOI: https://doi.org/10.1007/BF00541930