Ticlopidine and abciximab are what type of drugs?

Abstract—The thienopyridines ticlopidine and clopidogrel are inhibitors of platelet function in vivo. Their mode of action has not been defined, but it appears that they require conversion to as yet unidentified metabolites that are noncompetitive antagonists of the platelet ADP receptor. Inhibition of platelet aggregation with these compounds is delayed until 24 to 48 hours after administration. Maximum inhibition occurs after 3 to 5 days, and recovery is slow after drug withdrawal. Ticlopidine is effective in preventing cardiovascular events in cerebrovascular, cardiovascular, and peripheral vascular disease, with an efficacy that is similar to aspirin. However, its use is associated with significant and sometimes fatal adverse reactions, specifically neutropenia and bone marrow aplasia. Gastrointestinal side effects and skin rashes are common and result in discontinuation of therapy in up to 10% of patients. Clopidogrel is at least as effective as aspirin in preventing cardiovascular events in patients with a history of vascular disease. It appears to be safer than ticlopidine, although its efficacy in acute coronary syndromes or post–coronary-stent insertion has not been reported. Important outstanding issues are whether clopidogrel adds to the benefit of aspirin and whether the combination of these agents is safe. If so, this combination may become the standard for antithrombotic therapy in cardiovascular disease.

References

  • 1 The CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events. Lancet.1996; 348:1329–1339.CrossrefMedlineGoogle Scholar
  • 2 Meyers KM, Holmsen H, Seachord CL. Comparative study of platelet dense granule constituents. Am J Physiol.1982; 243:R454–R461.MedlineGoogle Scholar
  • 3 Gardner A, Jonsen J, Laland S, Hellem A, Owren P. Adenosine diphosphate in red blood cells as a factor in the adhesiveness of human blood platelets. Nature.1961; 192:531–532.CrossrefMedlineGoogle Scholar
  • 4 Abbracchio MP, Burnstock G. Purinoceptors: are there families of P2X and P2Y purinoceptors? Pharmacol Ther.1994; 64:445–475.CrossrefMedlineGoogle Scholar
  • 5 Jin J, Daniel J, Kunapuli S. Molecular basis for ADP induced platelet aggregation: the P2Y1 receptor mediates ADP-induced intracellular calcium mobilization and shape change in platelets. J Biol Chem.1998; 273:2030–2034.CrossrefMedlineGoogle Scholar
  • 6 Sun B, Li J, Okahara K, Kambayashi J. P2X1 purinoceptor in human platelets: molecular cloning and functional characterization after heterologous expression. J Biol Chem.1998; 273:11544–11547.CrossrefMedlineGoogle Scholar
  • 7 Savi P, Bornia J, Salel V, Delfaud M, Herbert JM. Characterization of P2X1 purinoreceptors on rat platelets: effect of clopidogrel. Br J Haematol.1997; 98:880–886.CrossrefMedlineGoogle Scholar
  • 8 Hechler B, Leon C, Vial C, Vigne P, Frelin C, Cazenave JP, Gachet C. The P2Y1 receptor is necessary for adenosine 5′-diphosphate-induced platelet aggregation. Blood.1998; 92:152–159.CrossrefMedlineGoogle Scholar
  • 9 Leon C, Hechler B, Vial C, Leray C, Cazenave JP, Gachet C. The P2Y1 receptor is an ADP receptor antagonized by ATP and expressed in platelets and megakaryoblastic cells. FEBS Lett.1997; 403:26–30.CrossrefMedlineGoogle Scholar
  • 10 Savi P, Laplace MC, Herbert JM. Evidence for the existence of two different ADP-binding sites on rat platelets. Thromb Res.1994; 76:157–169.CrossrefMedlineGoogle Scholar
  • 11 Savi P, Beauverger P, Labouret C, Delfaud M, Salel V, Kaghad M, Herbert JM. Role of P2Y1 purinoceptor in ADP-induced platelet activation. FEBS Lett.1998; 422:291–295.CrossrefMedlineGoogle Scholar
  • 12 Daniel J, Dangelmaier C, Jin J, Ashby B, Smith J, Kunapuli S. Molecular basis for ADP-induced platelet activation: evidence for three distinct ADP receptors on human platelets. J Biol Chem.1998; 273:2024–2029.CrossrefMedlineGoogle Scholar
  • 13 Jin J, Kunapuli SP. Coactivation of two different G protein-coupled receptors is essential for ADP-induced platelet aggregation. Proc Natl Acad Sci U S A.1998; 95:8070–8074.CrossrefMedlineGoogle Scholar
  • 14 Defreyn G, Gachet C, Savi P, Driot F, Cazenave JP, Maffrand JP. Ticlopidine and clopidogrel (SR 25990C) selectively neutralize ADP inhibition of PGE1-activated platelet adenylate cyclase in rats and rabbits. Thromb Haemost.1991; 65:186–190.CrossrefMedlineGoogle Scholar
  • 15 Geiger J, Brich J, Honig-Liedl P. Thienopyridine-based antiplatelet drugs inhibit ADP effects on prostaglandin-stimulated, cAMP/PKA-mediated phosphorylation of the cytoskeletal protein VASP in human platelets. Circulation. 1998;98(suppl I):I-595. Abstract.Google Scholar
  • 16 Gachet C, Savi P, Ohlmann P, Maffrand JP, Jakobs KH, Cazenave JP. ADP receptor induced activation of guanine nucleotide binding proteins in rat platelet membranes: an effect selectively blocked by the thienopyridine clopidogrel. Thromb Haemost.1992; 68:79–83.CrossrefMedlineGoogle Scholar
  • 17 Savi P, Pflieger AM, Herbert JM. cAMP is not an important messenger for ADP-induced platelet aggregation. Blood Coagul Fibrinolysis.1996; 7:249–252.CrossrefMedlineGoogle Scholar
  • 18 Savi P, Combalbert J, Gaich C, Rouchon MC, Maffrand JP, Berger Y, Herbert JM. The antiaggregating activity of clopidogrel is due to a metabolic activation by the hepatic cytochrome P450–1A. Thromb Haemost.1994; 72:313–317.CrossrefMedlineGoogle Scholar
  • 19 Di Minno G, Cerbone AM, Mattioli PL, Turco S, Lovine C, Mancini M. Functionally thrombasthenic state in normal platelets following the administration of ticlopidine. J Clin Invest.1985; 75:328–338.CrossrefMedlineGoogle Scholar
  • 20 Desager JP. Clinical pharmacokinetics of ticlopidine. Clin Pharmacokinet.1994; 26:347–355.CrossrefMedlineGoogle Scholar
  • 21 Shah J, Fratis A, Ellis D, Murakami S, Teitelbaum P. Effect of food and antacid on absorption of orally administered ticlopidine hydrochloride. J Clin Pharmacol.1990; 30:733–736.MedlineGoogle Scholar
  • 22 Heptinstall S, May JA, Glenn JR, Sanderson HM, Dickinson JP, Wilcox RG. Effects of ticlopidine administered to healthy volunteers on platelet function in whole blood. Thromb Haemost.1995; 74:1310–1315.CrossrefMedlineGoogle Scholar
  • 23 Chignard M, Lalau Keraly C, Delautier D, Sebag C, Bouloux C, Motte G, Benveniste J. Reduced sensitivity of human platelets to PAF-acether following ticlopidine intake. Haemostasis.1989; 19:213–218.MedlineGoogle Scholar
  • 24 Cattaneo M, Akkawat B, Lecchi A, Cimminiello C, Capitanio AM, Mannucci PM. Ticlopidine selectively inhibits human platelet responses to adenosine diphosphate. Thromb Haemost.1991; 66:694–699.CrossrefMedlineGoogle Scholar
  • 25 Boneu B, Destelle G. Platelet anti-aggregating activity and tolerance of clopidogrel in atherosclerotic patients. Thromb Haemost.1996; 76:939–943.CrossrefMedlineGoogle Scholar
  • 26 Panak E, Blanchard J, Roe RL. Evaluation of the antithrombotic efficacy of ticlopidine in man. Agents Actions Suppl.1984; 15:148–166.MedlineGoogle Scholar
  • 27 Coukell AJ, Markham A. Clopidogrel. Drugs.1997; 54:745–750.CrossrefMedlineGoogle Scholar
  • 28 McTavish D, Faulds D, Goa KL. Ticlopidine: an updated review of its pharmacology and therapeutic use in platelet-dependent disorders. Drugs.1990; 40:238–259.CrossrefMedlineGoogle Scholar
  • 29 Gent M, Blakely JA, Easton JD, Ellis DJ, Hachinski VC, Harbison JW, Panak E, Roberts RS, Sicurella J, Turpie AG. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet.1989; 1:1215–1220.CrossrefMedlineGoogle Scholar
  • 30 Gill S, Majumdar S, Brown NE, Armstrong PW. Ticlopidine-associated pancytopenia: implications of an acetylsalicylic acid alternative. Can J Cardiol.1997; 13:909–913.MedlineGoogle Scholar
  • 31 Love B, Biller J, Gent M. Adverse haematological effects of ticlopidine: prevention, recognition and management. Drug Safety.1998; 19:89–98.CrossrefMedlineGoogle Scholar
  • 32 Bennett C, Weinberg P, Rozenberg-Ben-Dror K, Yarnold P, Kwaan H, Green D. Thrombotic thrombocytopenic purpura associated with ticlopidine: a review of 60 cases. Ann Intern Med.1998; 128:541–544.CrossrefMedlineGoogle Scholar
  • 33 Kupfer Y, Tessler S. Ticlopidine and thrombotic thrombocytopenic purpura. N Engl J Med.1997; 337:1245. Letter.Google Scholar
  • 34 Page Y, Tardy B, Zeni F, Comtet C, Terrana R, Bertrand JC. Thrombotic thrombocytopenic purpura related to ticlopidine. Lancet.1991; 337:774–776.CrossrefMedlineGoogle Scholar
  • 35 Yim HB, Lieu PK, Choo PW. Ticlopidine induced cholestatic jaundice. Singapore Med J.1997; 38:132–133.MedlineGoogle Scholar
  • 36 Hass WK, Easton JD, Adams HP, Pryse-Phillips W, Molony BA, Anderson S, Kamm B. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients: Ticlopidine Aspirin Stroke Study Group. N Engl J Med.1989; 321:501–507.CrossrefMedlineGoogle Scholar
  • 37 Rupprecht HJ, Darius H, Borkowski U, Voigtlander T, Nowak B, Genth S, Meyer J. Comparison of antiplatelet effects of aspirin, ticlopidine, or their combination after stent implantation. Circulation.1998; 97:1046–1052.CrossrefMedlineGoogle Scholar
  • 38 Herbert J, Dol F, Bernat A, Falotico R, Lale A, Savi P. The antiaggregating and antithrombotic activity of clopidogrel is potentiated by aspirin in several experimental models in the rabbit. Thromb Haemost.1998; 80:512–518.CrossrefMedlineGoogle Scholar
  • 39 Umemura K, Kondo K, Ikeda Y, Nakashima M. Enhancement by ticlopidine of the inhibitory effect on in vitro platelet aggregation of the glycoprotein IIb/IIIa inhibitor tirofiban. Thromb Haemost.1997; 78:1381–1384.CrossrefMedlineGoogle Scholar
  • 40 Rindone JP, Bryan GN. Phenytoin toxicity associated with ticlopidine administration. Arch Intern Med.1996; 156:1113. Letter.CrossrefGoogle Scholar
  • 41 Donahue SR, Flockhart DA, Abernethy DR, Ko JW. Ticlopidine inhibition of phenytoin metabolism mediated by potent inhibition of CYP2C19. Clin Pharmacol Ther.1997; 62:572–577.CrossrefMedlineGoogle Scholar
  • 42 Brown RI, Cooper TG. Ticlopidine-carbamazepine interaction in a coronary stent patient. Can J Cardiol.1997; 13:853–854.MedlineGoogle Scholar
  • 43 Colli A, Buccino G, Cocciolo M, Parravicini R, Elli GM, Scaltrini G. Ticlopidine-theophylline interaction. Clin Pharmacol Ther.1987; 41:358–362.CrossrefMedlineGoogle Scholar
  • 44 Yao SK, Ober JC, Ferguson JJ, Maffrand JP, Anderson HV, Buja LM, Willerson JT. Clopidogrel is more effective than aspirin as adjuvant treatment to prevent reocclusion after thrombolysis. Am J Physiol.1994; 267:H488–H493.MedlineGoogle Scholar
  • 45 Herbert JM, Bernat A, Sainte-Marie M, Dol F, Rinaldi M. Potentiating effect of clopidogrel and SR 46349, a novel 5-HT2 antagonist, on streptokinase-induced thrombolysis in the rabbit. Thromb Haemost.1993; 69:268–271.CrossrefMedlineGoogle Scholar
  • 46 Balsano F, Rizzon P, Violi F, Scrutinio D, Cimminiello C, Aguglia F, Pasotti C, Rudelli G. Antiplatelet treatment with ticlopidine in unstable angina: a controlled multicenter clinical trial: the Studio della Ticlopidina nell’Angina Instabile Group. Circulation.1990; 82:17–26.CrossrefMedlineGoogle Scholar
  • 47 Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy, I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ.1994; 308:81–106.CrossrefMedlineGoogle Scholar
  • 48 Leon M, Baim D, Popma J, Gordon P, Cutlip D, Ho K, Giambartolomei A, Diver D, Lasorda D, Williams D, Pocock S, Kuntz R. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. N Engl J Med.1998; 339:1665–1671.CrossrefMedlineGoogle Scholar
  • 49 Bertrand M, Legrand V, Boland J, Fleck E, Bonnier J, Emmanuelson H, Vrolix M, Missault L, Chierchia S, Casaccia M, Niccoli L, Oto A, White C, Webb-Peploe M, Van Belle E, McFadden E. Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting: the Full Anticoagulation Versus Aspirin and Ticlopidine (FANTASTIC) study. Circulation.1998; 98:1597–1603.CrossrefMedlineGoogle Scholar
  • 50 Urban P, Macaya C, Rupprecht H, Kiemeneij F, Emanuelsson H, Fontanelli A, Pieper M, Wesseling T, Sagnard L. Randomized evaluation of anticoagulation versus antiplatelet therapy after coronary stent implantation in high-risk patients: the Multicenter Aspirin and Ticlopidine Trial after Intracoronary Stenting (MATTIS). Circulation.1998; 98:2126–2132.CrossrefMedlineGoogle Scholar
  • 51 Schomig A, Neumann FJ, Kastrati A, Schuhlen H, Blasini R, Hadamitzky M, Walter H, Zitzmann-Roth EM, Richardt G, Alt E, Schmitt C, Ulm K. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med.1996; 334:1084–1089.CrossrefMedlineGoogle Scholar
  • 52 Berger PB, Bell MR, Grill DE, Melby S, Holmes DR Jr. Frequency of adverse clinical events in the 12 months following successful intracoronary stent placement in patients treated with aspirin and ticlopidine (without warfarin). Am J Cardiol.1998; 81:713–718.CrossrefMedlineGoogle Scholar
  • 53 Kastrati A, Schuhlen H, Hausleiter J, Walter H, Zitzmann-Roth E, Hadamitzky M, Elezi S, Ulm K, Dirschinger J, Neumann FJ, Schomig A. Restenosis after coronary stent placement and randomization to a 4-week combined antiplatelet or anticoagulant therapy: six-month angiographic follow-up of the Intracoronary Stenting and Antithrombotic Regimen (ISAR) trial. Circulation.1997; 96:462–467.MedlineGoogle Scholar
  • 54 Schomig A, Neumann FJ, Walter H, Schuhlen H, Hadamitzky M, Zitzmann-Roth EM, Dirschinger J, Hausleiter J, Blasini R, Schmitt C, Alt E, Kastrati A. Coronary stent placement in patients with acute myocardial infarction: comparison of clinical and angiographic outcome after randomization to antiplatelet or anticoagulant therapy. J Am Coll Cardiol.1997; 29:28–34.CrossrefMedlineGoogle Scholar
  • 55 Madan M, Marquis J, May M, Laramee L, Leddy D, O’Brien E, Williams W, Higginson L, Jelley J, Reid F, Johansen H, Labinaz M. Coronary stenting in unstable angina: early and late clinical outcomes. Can J Cardiol.1998; 14:1109–1114.MedlineGoogle Scholar
  • 56 Gawaz M, Neumann FJ, Ott I, May A, Rudiger S, Schomig A. Changes in membrane glycoproteins of circulating platelets after coronary stent implantation. Heart.1996; 76:166–172.CrossrefMedlineGoogle Scholar
  • 57 van de Loo A, Nauck M, Noory E, Just H, Wollschlager H. Enhancement of platelet inhibition of ticlopidine plus aspirin vs aspirin alone given prior to elective PTCA. Eur Heart J.1998; 19:96–102.CrossrefMedlineGoogle Scholar
  • 58 Steinhubl S, Lauer M, Mukherjee D, Moliterno D, Lincoff A, Ellis S, Topol E. The duration of pretreatment with ticlopidine prior to stenting is associated with the risk of procedure-related non-Q-wave myocardial infarctions. J Am Coll Cardiol.1998; 32:1366–1370.CrossrefMedlineGoogle Scholar
  • 59 Makkar R, Eigler N, Kaul S, Frimerman A, Nakamura M, Shah P, Forrester J, Herbert J, Litvack F. Effects of clopidogrel, aspirin and combined therapy in a porcine ex vivo model of high-shear induced stent thrombosis. Eur Heart J.1998; 19:1538–1546.CrossrefMedlineGoogle Scholar
  • 60 Balsano F, Coccheri S, Libretti A, Nenci GG, Catalano M, Fortunato G, Grasselli S, Violi F, Hellemans H, Vanhove P. Ticlopidine in the treatment of intermittent claudication: a 21-month double-blind trial. J Lab Clin Med.1989; 114:84–91.MedlineGoogle Scholar
  • 61 Bergqvist D, Almgren B, Dickinson JP. Reduction of requirement for leg vascular surgery during long-term treatment of claudicant patients with ticlopidine: results from the Swedish Ticlopidine Multicentre Study (STIMS). Eur J Vasc Endovasc Surg.1995; 10:69–76.CrossrefMedlineGoogle Scholar
  • 62 Becquemin JP. Effect of ticlopidine on the long-term patency of saphenous-vein bypass grafts in the legs: Etude de la Ticlopidine apres Pontage Femoro-Poplite and the Association Universitaire de Recherche en Chirurgie. N Engl J Med.1997; 337:1726–1731.CrossrefMedlineGoogle Scholar
  • 63 Castelli P, Basellini A, Agus GB, Ippolito E, Pogliani EM, Colombi M, Gianese F, Scatigna M. Thrombosis prevention with ticlopidine after femoropopliteal thromboendarterectomy. Int Surg.1986; 71:252–255.MedlineGoogle Scholar
  • 64 Hiatt WR. Current and future drug therapies for claudication. Vasc Med.1997; 2:257–262.CrossrefMedlineGoogle Scholar
  • 65 Boissel JP, Peyrieux JC, Destors JM. Is it possible to reduce the risk of cardiovascular events in subjects suffering from intermittent claudication of the lower limbs? Thromb Haemost.1989; 62:681–685.CrossrefMedlineGoogle Scholar
  • 66 Janzon L, Bergqvist D, Boberg J, Boberg M, Eriksson I, Lindgarde F, Persson G, Almgren B, Fagher B, Kjellstrom T. Prevention of myocardial infarction and stroke in patients with intermittent claudication: effects of ticlopidine: results from STIMS, the Swedish Ticlopidine Multicentre Study. J Intern Med.1990; 227:301–308.CrossrefMedlineGoogle Scholar

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