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Thromb Haemost 1989; 61(03): 479-484
DOI: 10.1055/s-0038-1646618
Original Article
Schattauer GmbH Stuttgart

Characterization of N,N’-bis(3-Picolyl)-4-Methoxy-Isophtalamide (Picotamide) as a Dual Thromboxane Synthase Inhibitor/Thromboxane A2 Receptor Antagonist in Human Platelets

P Gresele
1   The Centre for Thrombosis and Vascular Research, University of Leuven, Leuven, Belgium
2   The Istituto di Semeiotica Medica, University of Perugia, Perugia, Italy
,
H Deckmyn
1   The Centre for Thrombosis and Vascular Research, University of Leuven, Leuven, Belgium
,
J Arnout
1   The Centre for Thrombosis and Vascular Research, University of Leuven, Leuven, Belgium
,
G G Nenci
2   The Istituto di Semeiotica Medica, University of Perugia, Perugia, Italy
,
J Vermylen
1   The Centre for Thrombosis and Vascular Research, University of Leuven, Leuven, Belgium
› Institutsangaben
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Publikationsverlauf

Received 26. Mai 1988

Accepted after revision 02. Februar 1989

Publikationsdatum:
24. Juli 2018 (online)

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Summary

Picotamide (G137 or N,N’-bis[3-picolyl]-4-methoxy-iso- phtalamide), a drug which has shown platelet inhibitory effects in vitro and ex vivo, was investigated for its mechanism of action on human platelets in vitro. This compound suppresses the aggregation of human platelets induced by arachidonic acid (IC50: 1.8 × 1(T5 M), low-dose collagen (IC50: 3.5 × 10-4 M), U46619 (IC50: 1.4 × 10-4 M) and by authentic TxA2 (IC50: 1 × 10-4 M), without affecting the aggregation induced by A23187 or primary aggregation by ADP. Picotamide inhibits dose-dependently TxA2 synthesis by platelets (IC50: 1.5 × 10-4 M) and enhances the formation of PGE2. Picotamide-treated platelets also favour the formation of PGI2 by aspirinated endothelial cells; in addition, the drug appears to exert a direct stimulatory effect on PGI2- synthesis, at least at high concentrations. Finally, in platelet-rich plasma stimulated with arachidonic acid, picotamide increases intraplatelet cAMP while no effects on cAMP are detected in unstimulated platelets.

In conclusion, picotamide is a dual thromboxane-synthase inhibitor/thromboxane-receptor antagonist in human platelets and introduces a new class of agents potentially useful in antithrombotic therapy.

Keywords

Antithrombotics - cAMP - Platelet inhibition - Prostacyclin
 

  • 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
    CrossrefPubMedSuche in Google Scholar
  • 2 FitzGerald GA, Smith B, Pedersen AK, Brash AR. Prostacyclin biosynthesis is increased in patients with severe atherosclerosis and platelet activation. New Engl J Med 1984; 310: 1065-1068
    CrossrefPubMedSuche in Google Scholar
  • 3 Fitzgerald DJ, Roy L, Catella F, FitzGerald GA. Platelet activation in unstable coronary disease. New Engl J Med 1986; 315: 983-989
    CrossrefPubMedSuche in Google Scholar
  • 4 Vesterqvist O, Green K. Urinary excretion of 2,3-dinor-thromboxane B2in man under normal conditions, following drugs and during some pathological conditions. Prostaglandins 1984; 27: 627-635
    CrossrefPubMedSuche in Google Scholar
  • 5 Weksler BB, Tack-Goldman K, Subramanian VA, Gay WA. Cumulative inhibitory effect of low-dose aspirin on vascular prostacyclin and platelet thromboxane production in patients with atherosclerosis. Circulation 1985; 71: 332-340
    CrossrefPubMedSuche in Google Scholar
  • 6 Bertelé V, Cerletti C, Schieppati A, Di Minno G, de Gaetano G. Inhibition of thromboxane synthetase does not necessarily prevent platelet aggregation. Lancet 1981; 1: 1057-1058
    PubMedSuche in Google Scholar
  • 7 Hornby EJ, Skidmore IF. Evidence that prostaglandin endoperoxides can induce platelet aggregation in the absence of thromboxane A2production. Biochem Pharmacol 1982; 31: 1158-1160
    CrossrefPubMedSuche in Google Scholar
  • 8 Gresele P, Deckmyn H, Arnout J, Lemmens J, Janssens W, Vermylen J. BM 13.177, a selective blocker of platelet and vessel wall receptors, is active in man. Lancet 1984; 1: 991-994
    PubMedSuche in Google Scholar
  • 9 Brittain RT, Boutal L, Carter MC, Coleman RA, Collington EW, Geisow HP, Hallet P, Hornby EJ, Humphrey PP A, Jack D, Kennedy I, Lumley P, McCabe PJ, Skidmore IF, Thomas M, Wallis CJ. AH 23848: a thromboxane receptor-blocking drug that can clarify the pathophysiologic role of thromboxane A2 . Circulation 1985; 72: 1208-1218
    CrossrefPubMedSuche in Google Scholar
  • 10 Janssens WJ, Deckmyn H, Gresele P, Vermylen J. BM 13.177 selectively inhibits endoperoxide analogue induced vascular contractions. Arch Int Pharmacodyn Ther 1985; 276: 28-34
    PubMedSuche in Google Scholar
  • 11 FitzGerald GA, Brash AR, Oates JA, Pedersen AK. Endogenous prostacyclin biosynthesis and platelet function during selective inhibition of thromboxane synthase in man. J Clin Invest 1983; 71: 1336-1343
    CrossrefPubMedSuche in Google Scholar
  • 12 Gresele P, Deckmyn H, Huybrechts E, Vermylen J. Serum albumin enhances the impairment of platelet aggregation with thromboxane synthase inhibition by increasing the formation of prostaglandin D2 . Biochem Pharmacol 1984; 33: 2083-2088
    CrossrefPubMedSuche in Google Scholar
  • 13 Patrignani P, Filabozzi P, Catella F, Pugliese F, Patrono C. Differential effects of dazoxiben, a selective thromboxane synthase inhibitor, on platelet and renal prostaglandin-endoperoxide metabolism. J Pharmacol Exp Ther 1984; 228: 472-477
    PubMedSuche in Google Scholar
  • 14 Gresele P, Arnout J, Deckmyn H, Huybrechts E, Pieters G, Vermylen J. Role of pro-aggregatory and anti-aggregatory prostaglandins in hemostasis. Studies with combined thromboxane synthase inhibition and thromboxane receptor antagonism J Clin Invest 1987; 80: 1435-1445
    CrossrefPubMedSuche in Google Scholar
  • 15 Gresele P, Van Houtte E, Arnout J, Deckmyn H, Vermylen J. Thromboxane synthase inhibition combined with thromboxane receptor blockade: a step forward in antithrombotic strategy. Thromb Haemostas 1984; 52: 364
    PubMedSuche in Google Scholar
  • 16 Nicolaou KC, Magolda RL. Synthesis of stable thromboxane A2analogs: pinane thromboxane A2(PTA2) and carbocyclic thromboxane A2(CTA2). Methods Enzymol 1982; 86: 400-409
    PubMedSuche in Google Scholar
  • 17 Gorman RR, Maxey KM, Bundy GL. Inhibition of human platelet thromboxane synthetase by lla-carbathromboxane A2analogs. Biochem Biophys Res Commun 1981; 100: 184-190
    CrossrefPubMedSuche in Google Scholar
  • 18 Orzalesi G, Selleri R, Volpato I. Fibrinolysis and inhibition of platelet aggregation by N,N’-bis(3-pycolyl)-4-methoxyisophtalamide(G-137). Prog Chem Fibrinolysis Thrombolysis 1975; 1: 267-269
    PubMedSuche in Google Scholar
  • 19 Schmutzler R, Hartmann H, Casale G, Magliano A. Picotamide: effects on coagulation, fibrinolysis and platelet aggregation during prolonged administration in the aged. Age Ageing 1978; 7: 246-250
    CrossrefPubMedSuche in Google Scholar
  • 20 Berrettini M, De Cunto M, Parise P, Grasselli S, Nenci GG. Picotamide, a derivative of 4-methoxy-isophthalic acid, inhibits thromboxane synthetase and receptors in vitro and in vivo. Thromb Haemostas 1983; 50: 127 Abstr 0381
    PubMedSuche in Google Scholar
  • 21 Deckmyn H, Gresele P, Van Houtte E, Nenci GG, Vermylen J. Synergism of a thromboxane (Tx) synthase inhibitor (TSI) and a Tx receptor antagonist (TRA) in reducing platelet activation. Thromb Haemostas 1985; 54: 114 Abstr 0677
    PubMedSuche in Google Scholar
  • 22 Gresele P, Zoja C, Deckmyn H, Arnout J, Vermylen J, Verstraete M. Dipyridamole inhibits platelet aggregation in whole blood. Thromb Haemostas 1983; 50: 852-856
    PubMedSuche in Google Scholar
  • 23 Gresele P, Blockmans D, Deckmyn H, Vermylen J. Adenylate cyclase activation determines the effect of thromboxane synthase inhibitors on platelet aggregation in vitro. Comparison of platelets from responders and non-responders J Pharmacol Exp Ther 1988; 246: 301-307
    PubMedSuche in Google Scholar
  • 24 Patrono C, Ciabattoni G, Pinca E, Pugliese F, Castrucci G, De Salvo A, Satta MA, Peskar BA. Low dose aspirin and inhibition of thromboxane B2production in healthy subjects. Thromb Res 1980; 17: 317-417
    CrossrefPubMedSuche in Google Scholar
  • 25 Vermylen J, Defreyn G, Carreras LO, Van Schaeren J, Verstraete M. Thromboxane synthetase inhibition as antithrombotic strategy. Lancet 1981; 1: 1073-1075
    PubMedSuche in Google Scholar
  • 26 Li CC. Introduction to Experimental Statistics. McGraw-Hill; New York: 1964: 460 pp
    Suche in Google Scholar
  • 27 Arunlakshana O, Schild HO. Some quantitative uses of drug antagonists. Br J Pharmacol 1959; 14: 48-58
    PubMedSuche in Google Scholar
  • 28 Baezinger NL, Becherer PR, Majerus PW. Characterization of prostacyclin synthesis in cultured human arterial smooth muscle cells, venous endothelial cells and skin fibroblasts. Cell 1979; 16: 967-974
    CrossrefPubMedSuche in Google Scholar
  • 29 Orchard MA, Blair IA, Dollery CT, Lewis PJ. Blood can synthesize prostacyclin. Lancet 1983; 2: 565
    PubMedSuche in Google Scholar
  • 30 De Clerck F, Beetens J, de Chaffoy de Courcelles D, Freyne E, Janssen PA J. R68070 thromboxane A2synthetase inhibition and thromboxane A2/prostaglandin endoperoxide receptor blockade, combined in one molecule. I. Biochemical profile in vitro. Thromb Haemostas 1989; 61: 35-42
    PubMedSuche in Google Scholar
  • 31 Kenakin TP, Beek D. The effects on Schild regression of antagonist removal from the receptor compartement by a saturable process. Naunyn-Schmied/Arch Pharmacol 1987; 335: 103-108
    PubMedSuche in Google Scholar
  • 32 Feldhoff CM, Gresele P, Pieters G, Vermylen J. Acetylsalicylic acid, BM 13.177 and picotamide improve the survival of endotoxin-infused rabbits. Thromb Res 1988; 52: 487-492
    CrossrefPubMedSuche in Google Scholar
  • 33 Gresele P, Corona C, Nenci GG. Mouse antithrombotic assay: protective effects of picotamide (P). Xth International Congress on Thrombosis; Athens (Greece): 22.05.1988. Abstracts: 15 (Abstr 33)
    Suche in Google Scholar
  • 34 Avdonin PV, Svitina-Ulutina IV, Leytin VL, Thachuk VA. Interaction of stable prostaglandin endoperoxide analogs U46619 and U44069 with human platelet membranes: coupling of receptors with high-affinity GTPase and adenylate cyclase. Thromb Res 1985; 40: 101-112
    CrossrefPubMedSuche in Google Scholar
  • 35 Catella F, Nowak J, FitzGerald GA. Measurement of renal and nonrenal eicosanoid synthesis. Am J Med 1986; 81 Suppl (Suppl. 02) B 23-29
    PubMedSuche in Google Scholar
  • 36 Bertelé V, de Gaetano G. Potentiation by dazoxiben, a thromboxane synthase inhibitor, of platelet aggregation inhibitory activity of a thromboxane receptor antagonist and of prostacyclin. Eur J Pharmacol 1982; 85: 331-333
    CrossrefPubMedSuche in Google Scholar
  • 37 FitzGerald GA, Reilly IA, Pedersen AK. The biochemical pharmacology of thromboxane synthase inhibition in man. Circulation 1985; 72: 1194-1201
    CrossrefPubMedSuche in Google Scholar
  • 38 Fitzgerald DJ, Fragetta J, FitzGerald GA. Prostaglandin endoperoxides modulate the response to thromboxane synthase inhibition during coronary thrombosis. J Clin Invest 1988; 82: 1708-1713
    CrossrefPubMedSuche in Google Scholar
  • 39 Armstrong RA, Jones RL, MacDermot J, Wilson NH. Prostaglandin endoperoxide analogues which are both thromboxane receptor antagonists and prostacyclin mimetics. Br J Pharmacol 1986; 87: 543-551
    CrossrefPubMedSuche in Google Scholar
  • 40 Sills T, Heptinstall S. Effects of a thromboxane synthetase inhibitor and a cAMP phosphodiesterase inhibitor, singly and in combination, on platelet behaviour. Thromb Haemostas 1986; 55: 305-308
    PubMedSuche in Google Scholar
  • 41 Gresele P, Deckmyn H, Arnout J, Zoja C, Vermylen J. Lack of synergism between dazoxiben and dipyridamole following administration to man. Thromb Res 1985; 37: 231-236
    CrossrefPubMedSuche in Google Scholar
  • 42 Bitterman H, Phillips GR, Dragon G, Lefer AM. Potentiation of the protective effects of a converting enzyme inhibitor and a thromboxane synthetase inhibitor in hemorrhagic shock. J Pharmacol Exp Ther 1987; 242: 8-14
    PubMedSuche in Google Scholar
  • 43 Agarwal KC, Kay K, Erickson BR, Parks RE. Potentiation of forskolin on platelet aggregation by the inhibitors of cAMP phosphodiesterase and thromboxane synthase. Fed Proc 1985; 44: 1665
    PubMedSuche in Google Scholar
  • 44 Haslam RJ, Davidson MM L, Davies T, Lynham JA, McClenaghan MD. Regulation of blood platelet function by cyclic nucleotides. Adv Cyclic Nucl Res 1978; 9: 533-552
    PubMedSuche in Google Scholar