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Thromb Haemost 1989; 61(01): 043-049
DOI: 10.1055/s-0038-1646524
Original Article
Schattauer GmbH Stuttgart

R 68 070: Thromboxane A2 Synthetase Inhibition and Thromboxane A2/Prostaglandin Endoperoxide Receptor Blockade Combined in One Molecule - II. Pharmacological Effects In Vivo and Ex Vivo

F De Clerck
The Department of Haematology, Janssen Research Foundation, Beerse, Belgium
,
J Beetens
The Department of Haematology, Janssen Research Foundation, Beerse, Belgium
,
A Van de Water
1   The Department of Cardiovascular Pharmacology, Janssen Research Foundation, Beerse, Belgium
,
E Vercammen
2   The Department of Clinical Research, Janssen Research Foundation, Beerse, Belgium
,
P A J Janssen
The Department of Haematology, Janssen Research Foundation, Beerse, Belgium
› Author Affiliations
Further Information

Publication History

Received 25 April 1988

Accepted after revision 05 October 1988

Publication Date:
24 July 2018 (online)

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Summary

R 68 070 or (E)-5-[[[(3-pyridinyl)[3-(trifluoromethyl)phenyl]- methylen]amino]oxy] pentanoic acid (Janssen Research Foundation, Belgium), a newly developed compound, combining specific thromboxane A2 (TXA2) synthetase inhibition with TXA2/pros- taglandin endoperoxide receptor blockade in one molecule, is active in vivo in man and in experimental animals.

In man (n = 5), a single oral 400-mg dose of R 68 070 produces deep and protracted inhibition of platelet TXA2 synthetase activity (≥90% for 48 h), increases serum levels of immuno- reactive 6-keto-PGF1α, reduces platelet aggregation in RR.R induced by U 46619, collagen (>70% for 8 h), arachidonic acid (>90% for 18 h) and prolongs template bleeding times significantly, without affecting plasma coagulation or fibrinolysis.

In rats, R 68 070 (1.25 mg/kg orally, –2 h) singly prolongs tail bleeding times as much as a combination of TXA2 synthetase inhibition (dazoxiben 10 mg/kg) and TXA2/prostaglandin endoperoxide receptor blockade (BM 13177 40 mg/kg). In dogs, the compound reduces coronary thrombosis induced by electrical damage (1.25 mg/kg i. v.) and prevents the evolution of occlusion/ reperfusion-induced arrhythmias into ventricular fibrillation (2.5 mg/kg i.v.). R 68 070 thus may be an appropriate pharmacological tool to analyze the roles and interactions of agonistic (TXA2, prostaglandin endoperoxides) and antagonistic (PGD2, PGE2, PGI2) metabolites of arachidonic acid in experimental and human pathologies.

Key words

R 68 070 - TXA2-synthetase - Receptor blockade - Man - Experimental models
 

  • References

  • 1 FitzGerald GA, Reilly IA G, Pedersen A K. The biochemical pharmacology of thromboxane synthetase inhibition in man. Circulation 1985; 72: 1194-1201
    CrossrefPubMedGoogle Scholar
  • 2 Clerck FDe, Xhonneux B, Van Gorp L, Beetens J, Janssen PA J. S2–serotonergic receptor inhibition (ketanserin), combined with thromboxane A2/prostaglandin endoperoxide receptor blockade (BM 13.177): enhanced anti-platelet effect. Thromb Haemostas 1986; 56: 236
    PubMedGoogle Scholar
  • 3 De Freyn G, Deckmyn H, Vermylen J. A thromboxane synthetase inhibitor reorients endoperoxide metabolism in whole blood towards prostacyclin and prostaglandin E2 . Thromb Res 1982; 26: 389-400
    CrossrefPubMedGoogle Scholar
  • 4 Aiken JW, Shebuski RJ, Miller OV, Gorman RR. Endogenous prostacyclin contributes to the efficacy of a thromboxane synthetase inhibitor for preventing coronary artery thrombosis. J Pharmacol Exp Ther 1981; 219: 299-308
    PubMedGoogle Scholar
  • 5 Hornby EJ, Skidmore IF. Evidence that prostaglandin endoperoxides can induce platelet aggregation in the absence of thromboxane A2 production. Biochem Pharmacol 1982; 31: 1153-1160
    CrossrefPubMedGoogle Scholar
  • 6 Gresele P, Van Houtte E, Arnout J, Deckmyn H, Vermylen J. Thromboxane synthetase inhibition combined with thromboxane receptor blockade: a step forward in antithrombotic strategy. Thromb Haemostas 1984; 52: 364
    PubMedGoogle Scholar
  • 7 Rybicki JP, Le Breton GC. Prostaglandin H2 directly lowers human platelet cAMP levels. Thromb Res 1983; 30: 407-417
    CrossrefPubMedGoogle Scholar
  • 8 Gresele P, Arnout J, Deckmyn H, Vermylen J. Endogenous antiaggregatory prostaglandins can contribute to inhibition of hemostasis: a pharmacological study in vivo in humans. Adv Prostaglandin Thromboxane Leukotriene Res 1987; 17: 248-253
    PubMedGoogle Scholar
  • 9 FitzGerald DJ, Fragetta J, Fenelon LC, FitzGerald GA. Thromboxane synthetase inhibition and thromboxane/endoperoxide receptor antagonism in a chronic canine model of coronary thrombosis. Adv Prostaglandin Thromboxane Leukotriene Res 1987; 17: 496-500
    PubMedGoogle Scholar
  • 10 De Clerck F, Somers Y, Van Gorp L. Platelet-vessel wall interactions in hemostasis: implication of 5-hydroxytryptamine. Agents Actions. 1984; 15: 627-635
    PubMedGoogle Scholar
  • 11 Ivy AC, Nelson P, Butcher G. The standardization of certain factors in the cutaneous venostasis bleeding time technique. J Lab Clin Med 1941; 26: 1812-1822
    PubMedGoogle Scholar
  • 12 Babson SR, Babson AC. Development and evaluation of a disposable device for performing simultaneous duplicate bleeding time determinations. Am J Clin Pathol 1978; 70: 406-408
    CrossrefPubMedGoogle Scholar
  • 13 Romson JL, Haack DW, Lucchesi BR. Electrical induction of coronary artery thrombosis in the ambulatory canine: a model for in vivo evaluation of anti-thrombotic agents. Thromb Res 1980; 17: 841-853
    CrossrefPubMedGoogle Scholar
  • 14 Romson JL, Haack DW, Abrams GD, Lucchesi BR. Prevention of occlusive coronary artery thrombosis by prostacyclin infusion in the dog. Circulation 1981; 64: 906-914
    CrossrefPubMedGoogle Scholar
  • 15 Coker SJ, Parratt JR. Effects of dazoxiben on arrhythmias and ventricular fibrillation induced by coronary artery occlusion and reperfusion in anaesthetized greyhounds. Br J Clin Pharmacol 1983; 15: 87S-95S
    CrossrefPubMedGoogle Scholar
  • 16 Wainwright CL, Parratt JR. Antiarrhythmic effects of the thromboxane antagonist BM 13.177. Eur J Pharmacol 1987; 133: 257-264
    CrossrefPubMedGoogle Scholar
  • 17 Patrono C. et al Low dose aspirin and inhibition of thromboxane B2 production in healthy subjects. Thromb Res 1980; 17: 317-327
    CrossrefPubMedGoogle Scholar
  • 18 De Clerck F, Van Nueten JM. Platelet-mediated vascular contractions. Inhibition of flunarizine, a calcium-entry blocker Biochem Pharmacol 1983; 32: 765-771
    CrossrefPubMedGoogle Scholar
  • 19 Beetens JR, Loots W, Somers Y, Coene MC, De Clerck F. Ketoconazole inhibits the biosynthesis of leukotrienes in vitro and in vivo. Biochem Pharmacol 1986; 35: 883-891
    CrossrefPubMedGoogle Scholar
  • 20 McMillan RM, MacIntyre DE, Gordon JC. Simple sensitive fluorimetric assay for malondialdehyde production by blood platelets. Thromb Res 1977; 11: 425-428
    CrossrefPubMedGoogle Scholar
  • 21 De Clerck F, Xhonneux B, Tollenaere JP, Janssen PA J. Dependence of the antagonism at human platelet 5-HT2 receptors by ketanserin on the reaction pH. Thromb Res 1985; 40: 581-96
    CrossrefPubMedGoogle Scholar
  • 22 De Clerck F, Van Gorp L, Beetens J, Reneman RS. Platelet- mediated vascular permeability in the rat: a predominant role for 5-hydroxytryptamine. Thromb Res 1985; 38: 321-339
    CrossrefPubMedGoogle Scholar
  • 23 Dacie JV, Lewis SM. Practical Haematology. J & P Churchill Ltd.; London; 1968
    Google Scholar
  • 24 Caen J, Larrieu MJ, Samama M. L’Héxmostase. Méthodes d’Explora-tion et Diagnostique Pratique. L‘ Expansion Scientifique; Paris: 1968
    Google Scholar
  • 25 Fearnly GR. Measurement of spontaneous fibrinolytic activity. J Clin Pathol 1964; 17: 307-309
    CrossrefPubMedGoogle Scholar
  • 26 Nanninga LB, Guest MM. Fibrinolytic activation of plasma by means of urokinase in vitro and in vivo. Thromb Diathes Haemorrh 1970; 24: 33-42
    PubMedGoogle Scholar
  • 27 Coleman RA, Humphrey PP A, Kennedy I, Levy GP, Lumley P. U 46619, a selective thromboxane A2-like agonist. Br J Pharmacol 1980; 68: 1278
    PubMedGoogle Scholar
  • 28 Draper NR, Smith M. Applied Regression Analysis. Wiley & Sons; New York: 1981
    Google Scholar
  • 29 Fischer S, Struppler M, Bohlig B, Bernutz C, Wober W, Weber P. The influence of selective thromboxane synthetase inhibition with a novel imidazole derivative, UK-38,485, on prostanoid formation in man. Circulation 1983; 88: 821-826
    PubMedGoogle Scholar
  • 30 MacNaß M, Foltz EL, Graves BS, Rinehart RK, Tripp SL, Feliciano WR, Sen S. The effects of a new thromboxane synthetase inhibitor, CGS-13080, in man. J Clin Pharmacol 1984; 24: 76-83
    CrossrefPubMedGoogle Scholar
  • 31 Yui Y, Hattori R, Takatsu Y, Nakajima H, Wakabayashi A, Kawai C, Kayama N, Inagawa T, Tsubojima M, Naito J. Intravenous infusion of a selective inhibitor of thromboxane A2 synthetase in man: influence on thromboxane B2 and 6-keto-prostaglandin F1α levels and platelet aggregation. Circulation 1984; 70: 599-605
    CrossrefPubMedGoogle Scholar
  • 32 Gresele P, Amout J, Janssens W, Deckmyn H, Lemmens J, Vermylen J. BM 13177, a selective blocker of platelet and vessel wall thromboxane receptors, is active in man. Lancet 1984; 1: 991-994
    PubMedGoogle Scholar
  • 33 Shea MJ, Driscoll EM, Romson JL, Pitt B, Lucchesi BR. Effect of OKY-1581, a thromboxane synthetase inhibitor, on coronary thrombosis in the conscious dog. Eur J Pharmacol 1984; 105: 285-291
    CrossrefPubMedGoogle Scholar
  • 34 Ashton DH, Schmitz JM, Campbell WB, Ogletree ML, Raheja S, Taylor AL, FitzGerald C, Buja LM, Willerson JT. Inhibition of cyclic flow variations in stenosed canine coronary arteries by thromboxane A2/prostaglandin H2 receptor antagonists. Circ Res 1986; 59: 568-578
    CrossrefPubMedGoogle Scholar
  • 35 Hammon JW, Oates JA. Interaction of platelets with the vessel wall in the pathophysiology of sudden cardiac death. Circulation 1986; 73: 224-226
    CrossrefPubMedGoogle Scholar