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Thromb Haemost 1996; 76(01): 094-098
DOI: 10.1055/s-0038-1650529
Original Article
Schattauer GmbH Stuttgart

The Antiaggregating and Antithrombotic Activity of Ticlopidine Is Potentiated by Aspirin in the Rat

J M Herbert
The Sanofi Recherche, Haemobiology Research Department, Toulouse, France
,
A Bernat
The Sanofi Recherche, Haemobiology Research Department, Toulouse, France
,
M Samama
1   Laboratoire Central d’hématologie, Hôtel-Dieu, Paris, France
,
J P Maffrand
The Sanofi Recherche, Haemobiology Research Department, Toulouse, France
› Author Affiliations
Further Information

Publication History

Received 23 October 1995

Accepted after resubmission 27 March 1996

Publication Date:
10 July 2018 (online)

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Summary

Since ticlopidine specifically inhibits ADP-induced platelet aggregation without affecting prostaglandin metabolism, it seemed interesting to evaluate the effect of aspirin with regard to the antithrombotic efficacy of ticlopidine. Ticlopidine was administered orally to rats alone or in combination with aspirin and the efficacy of the association was determined in several experimental models. A synergistic effect of the ticlopidine/aspirin association was demonstrated with regard to ADP- and collagen-induced platelet aggregation measured ex vivo but also in several experimental thrombosis models including silk thread-induced thrombosis in an arteriovenous shunt, wire coil-induced thrombosis and 111In-labelled platelet deposition on the subendothelium following air drying injury of the rat carotid artery. Similar results were obtained with regard to myointimal proliferation following air-induced injury of the rat carotid artery which occurred as a consequence of vascular injury. The ticlopidine/aspirin combination showed only additive-type effects on bleeding time prolongation induced by tail transection in the rat.

 

  • References

  • 1 McTavish D, Faulds D, Goa KL. Ticlopidine: an updated review of its pharmacology and therapeutic use in platelet-dependent disorders. Drugs 1990; 40 (02) 238-259
    CrossrefPubMedSearch in Google Scholar
  • 2 Féliste R, Delebassée D, Simon MF, Chap H, Defreyn G, Vallée E, Douste-Blazy L, Maffrand JP. Broad spectrum antiplatelet activity of ticlopidine and PCR 4099 involves the suppression of the effects of released ADP. Thromb Res 1987; 48: 403-415
    CrossrefPubMedSearch in Google Scholar
  • 3 Gent M, Easton JD, Hachinski VC, Panak E, Sicurella J, Blakely JA, Ellis DJ, Harbinson JW, Roberts RS, Turpie AGG. The CATS Group The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1989; 1: 1215-1220
    PubMedSearch in Google Scholar
  • 4 Hass WK, Easton JD, Harold P, Adams Jr, Pryse-Phillips W, Molonu BA, Anderson S, Kamm B. for the Ticlopidine Aspirin Stroke Study. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. N Engl J Med 1989; 321: 501-507
    CrossrefPubMedSearch in Google Scholar
  • 5 Janzon L, Bergqvist D, Boberg J, Boberg M, Eriksson I, Lindgarde F, Persson G. Prevention of myocardial infarction and stroke in patients with intermittent claudication; effects of ticlopidine. Results from STIMS, the Swedish Ticlopidine Multicentre Study. Scand J Int Med 1990; 227: 301-308
    PubMedSearch in Google Scholar
  • 6 Van Belle E, McFadden EP, Lablanche JM, Bauters C, Hamon M, Bertrand ME. Two-pronged antiplatelet therapy with aspirin and ticlopidine without systemic anticoagulation: an alternative therapeutic strategy after bailout stent implantation. Coronary Artery Disease 1995; 6: 341-345
    CrossrefPubMedSearch in Google Scholar
  • 7 Jordan C, Carvalho H, Fajadet J, Cassagneau B, Robert G, Marco J. Reduction of subacute thrombosis rate after coronary stenting using a new anticoagulant protocol. Circulation 1994; 90 (04) I125 (Abst 668).
    PubMedSearch in Google Scholar
  • 8 Morice MC, Zemour G, Benveniste E, Biron Y, Bourdonnec C, Faivre R, Fajadet J, Gaspard P, Glatt B, Joly P, Labrunie P, Lienhart Y, Marco J, Petiteau PY, Royer T, Valeix B. Intracoronary stenting without coumadin: one month results of a French multicenter study. Catheterization & Cardio-vasc Diagn 1995; 35: 1-7
    PubMedSearch in Google Scholar
  • 9 Bom GVR, Cross MJ. The aggregation of blood platelets. J Physiol 1963; 168: 178-195
    CrossrefPubMedSearch in Google Scholar
  • 10 Umetzu T, Sanai K. Effect of l-Methyl-2Mercapto-5-(3-Pyridyl)-Imida-zole (KC-6141), an anti-aggregating compound, on experimental thrombosis in rats. Thromb Haemost 1978; 39: 74-83
    Thieme ConnectPubMedSearch in Google Scholar
  • 11 Kumada T, Ishihara M, Ogawa H, Abiko Y. Experimental model of venous thrombosis in rats and effects of some agents. Thromb Res 1980; 18: 189-203
    CrossrefPubMedSearch in Google Scholar
  • 12 Fishman JA, Ryan GB, Kamovsky MJ. Endothelial regeneration in the rat carotid artery and the significance of endothelial denudation in the pathogenesis of myointimal thickening. Lab Invest 1975; 32: 339
    PubMedSearch in Google Scholar
  • 13 Dejana E, Villa S, de Gaetano G. Bleeding time in rats: a comparison of different experimental conditions. Thromb Haemost 1982; 48: 108-111
    Thieme ConnectPubMedSearch in Google Scholar
  • 14 Maffrand JP, Bemat A, Delebassee D, Defreyn G, Cazenave JP, Gordon JL. ADP plays a key role in thrombogenesis in rats. Thromb Haemost 1988; 59 (02) 225-230
    Thieme ConnectPubMedSearch in Google Scholar
  • 15 Cattaneo. Antiplatelet Trialists’ Collaboration. Secondary prevention of vascular events by prolonged antiplatelet therapy. British Med J 1988; 296: 320-331
    CrossrefPubMedSearch in Google Scholar
  • 16 Savi P, Laplace MCI, Maffrand JP, Herbert JM. Binding of [3H]-2-Methyl-thio ADP to rat platelets - Effect of clopidogrel and ticlopidine. J Pharmacol Exp Ther 1994; 269 (02) 772-777
    PubMedSearch in Google Scholar
  • 17 Cerletti C, Gambino MC, Garattini S, de Gaetano G. Biochemical selectivity of oral versus intravenous aspirin in rats. J Clin Invest 1986; 78: 323-326
    CrossrefPubMedSearch in Google Scholar
  • 18 Shand RA, Smith JR, Wallis RB. Expression of the platelet procoagulant activity in vivo in thrombus formation in an extracorporeal shunt in the rat. Thromb Res 1984; 36: 223-232
    CrossrefPubMedSearch in Google Scholar
  • 19 Herbert JM, Tissinier A, Defreyn G, Maffrand JP. Inhibitory effect of clopidogrel on platelet adhesion and intimal proliferation after arterial injury in rabbits. Atheriosclerosis and Thrombosis 1993; 13: 1171-1179
    PubMedSearch in Google Scholar
  • 20 Tallarida RJ. Statistical analysis of drug combinations for synergism. Pain 1992; 49: 93-97
    CrossrefPubMedSearch in Google Scholar
  • 21 Conard J, Lecrubier C, Scarabin PY, Horellou MH, Samama M, Bousser MG. Effects of long term administration of ticlopidine on platelet function and hemostatic variables. Thromb Res 1980; 20: 134
    PubMedSearch in Google Scholar
  • 22 Pumphrey CW, Fuster V, Dewanjee MK, Murphy KP, Vliestra RE, Kaye MP. A new in vivo model of arterial thrombosis: the effect of administration of ticlopidine and verapamil in dogs. Thromb Res 1982; 28: 663
    CrossrefPubMedSearch in Google Scholar
  • 23 Geroulanos S, Walter P, Cogan C, Binkert M, Turina M, Senning A. Platelet inhibitors. Haemostasis 1982; 12: 155
    PubMedSearch in Google Scholar
  • 24 Clowes AW, Kamovsky MJ. Failure of certain antiplatelet drugs to affect myointimal thickening following arterial endohtelial injury in the rat. Lab Invest 1977; 36: 452
    PubMedSearch in Google Scholar
  • 25 Dejana R, Cazenave JP, Groves HM, Kinlough-Rathbone RL, Richardson M, Packham MA, Mustard JF. The effect of aspirin inhibition of PGI2 production on platelet adherence to normal and damaged rabbit aortae. Thromb Res 1980; 17: 453-458
    CrossrefPubMedSearch in Google Scholar
  • 26 Reece AH, Walton PL. Inhibition of intimal proliferation of rabbit aorta by ticlopidine. Thromb Haemost 1979; 42: 367
    PubMedSearch in Google Scholar
  • 27 Bom GVR. Adenosine diphosphate as a mediator of platelet aggregation in vivo: an editorial view. Circulation 1985; 72: 741-746
    CrossrefPubMedSearch in Google Scholar
  • 28 Zawilska KM, Bom GVR, Beent NA. Effect of ADP-utilizing enzymes on the arterial bleeding time in rats and rabbits. Br J Haematol 1982; 50: 317-325
    CrossrefPubMedSearch in Google Scholar