Inhibition of Platelet Aggregation by a New Agent, Ticlopidine

Summary

Effect of Ticlopidine, 5-(2-chlorobenzyl)-4, 5, 6, 7-tetrahydro[3,2-C]pyridine hydrochloride, on platelet aggregation was studied in the rat. Ticlopidine was found to be a potent, long-lasting inhibitor of platelet aggregation. It inhibited the aggregation induced by any of ADP, collagen, thrombin, arachidonic acid and prostaglandin endoperoxides and/or thromboxane A₂-like substance. Ticlopidine was effective at doses as low as 30 mg/kg when orally given to rats, and the effect lasted as long as the life span of the circulating platelets (half time: about 48 hours).

Ticlopidine inhibited also nucleotide release from and prostaglandin synthesis in the platelets, but did not significantly affect platelet adhesiveness to glass, platelet factor 3 availability and clot retraction.

• References

• 1 Ashida S, Abiko Y. 1975; Protective effect of pantethine on experimental thrombocytopenia in the rat. Thrombosis et Diathesis Haemorrhagica 33: 528
• 2 Ashida S, Abiko Y. (in press) Mode of action of Ticlopidine in inhibition of platelet aggregation in the rat. Thrombosis and Haemostasis.
• 3 Aster RH. 1967; Studies of the mechanism of hypersplenic thrombocytopenia in rat. Journal of Laboratory and Clinical Medicine 70: 836
• 4 Flower RJ, Cheung HS, Cushman DW. 1973; Quantitative determination of prostaglandins and malondialdehyde formed by the arachidonate oxygenase(prostaglandin synthetase) system of bovine seminal vesicle. Prostaglandins 4: 325
• 5 Godard P, Zini R, Hoareau A, Tillement JP. (submitted) The fate of ticolpidine in the organism. I. Distribution and elimination of¹⁴C-Ticlopidine after a single I. V. injection in the rat.
• 6 Hamberg M, Svensson J, Samuelsson B. 1975; Thromboxanes: a new group of biologically active compounds derived from prostaglandin endoperoxides. Proceedings of the National Academy of Science, U.S.A 72: 2994
• 7 Malmsten C, Granstrôm E, Samuelsson B. 1976; Cyclic AMP inhibits synthesis of prostaglandin endoperoxide(PGG₂) in human platelets. Biochemical and Biophysical Research Communications 68: 569
• 8 Needleman P, Moncada S, Bunting S, Vane JR, Hamberg M, Samuelsson B. 1976; Identification of an enzyme in platelet microsomes which generates thromboxane A₂ from prostaglandin endoperoxides. Nature 261: 558
• 9 Podesta M, Aubert D, Ferrand JC. 1974; Contribution à l’étude pharmacologique de thienopyridines et d’analogues furanniques. European Journal of Medicinal Chemistry 9: 487
• 10 Sinakos Z, Caen JP. 1967; Platelet aggregation in mammalians(human, rat, rabbit, guinea-pig, horse, dog). A comparative study Thrombosis et Diathesis Haemorrhagica 17: 99
• 11 Smith JB, Ingerman C, Silver MJ. 1976; Persistence of thromboxane A₂-like material and platelet release-inducing activity in plasma. Journal of Clinical Investigation 58: 1119
• 12 Spaet TH, Cinton J. 1965; Studies on platelet factor-3 availability. British Journal of Haematology 11: 269
• 13 Thebault JJ, Blatrix CE, Blanchard JF, Panak EA. 1975; Effect of ticlopidine, a new platelet aggregation inhibitor in man. Clinical Pharmacology and Therapeutics 18: 485
• 14 Tomikawa M, Ogawa H, Abiko Y. 1974; Experimental model of pulmonary thrombosis in rat. Thrombosis et Diathesis Haemorrhagica 31: 86
• 15 Tomikawa M, Ashida S, Kakihata K, Abiko Y. 1978; Anti-thrombotic action of Ticlopidine, a new platelet aggregation inhibitor. Thrombosis Research 12: 1157
• 16 Wolfe SM, Shulman NR. 1970; Inhibition of platelet energy production and release reaction by PGE₁theophylline and cAMP. Biochemical and Biophysical Research Communications 41: 128