Thienopyridine (Ticlopidin, Clopidogrel)

A.-A. Weber; K. Schrör

doi:10.1055/s-0038-1655351

Hämostaseologie, Inhaltsverzeichnis

Hamostaseologie 1998; 18(04): 180-191
DOI: 10.1055/s-0038-1655351

Übersichtsarbeiten/Review Articles

Schattauer GmbH

Thienopyridine (Ticlopidin, Clopidogrel)

A.-A. Weber

¹Institut für Pharmakologie, Heinrich-Heine-Universität Düsseldorf

,

K. Schrör

¹Institut für Pharmakologie, Heinrich-Heine-Universität Düsseldorf

› Institutsangaben

Abstract

Zusammenfassung

Thienopyridine (Ticlopidin und Clopidogrel) hemmen spezifisch die ADP-medi- ierten Mechanismen der Thrombozytenaktivierung. Der genaue molekulare Wirkmechanismus der Thrombozytenfunktionshemmung durch Thienopyridine ist nicht bekannt. Nach bisherigen Daten beruht das wirksame Prinzip auf einer nichtkompetitiven und möglicherweise irreversiblen Reduktion der ADP-Rezep- tordichte auf Thrombozytenmembranen. Im Gegensatz zu früheren Annahmen, nach denen Thienopyridine »Prodrugs« sind und für ihre Wirksamkeit einer hepatischen Bioaktivierung bedürfen, konnte in neueren Arbeiten eine ln-vitro- Wirksamkeit dieser Substanzen nachgewiesen werden. Klinisch weisen die Thienopyridine eine gut gesicherte Wirksamkeit auf. So zeigte Clopidogrel in der kürzlich publizierten CAPRIE-Studie bei Patienten mit symptomatischer Atherosklerose eine geringe aber statistisch signifikante Überlegenheit gegenüber Acetylsalicylsäure hinsichtlich der Prävention von Schlaganfall, Myokardinfarkt und vaskulärem Tod. Neutropenien, wie sie unter Ticlopidin bei etwa einem Prozent der Patienten beobachtet werden, traten unter Clopidogrel nicht auf. Dennoch muß das Nebenwirkungsprofil dieser im Vergleich zur Acetylsalicylsäure noch jungen Substanz sorgfältig beobachtet werden.

Schlüsselwörter

Thienopyridine - Ticlopidin - Clopidogrel - Pharmakologie

Volltext

Referenzen

LITERATUR
1 Albiero R, Hall P, Itoh A, Blengino S, Nakamura S, Martini G, Ferraro M, Colombo A. Results of a consecutive series of patients receiving only antiplatelet therapy after optimized stent implantation. Comparison of aspirin alone versus combined ticlopidine and aspirin therapy. Circulation 1997; 95: 1145-56.
2 Arcan JC, Blanchard J, Boissel JP, Destors JM, Panak E. Multicenter double-blind study of ticlopidine in the treatment of intermittent claudication and the prevention of its complications. Angiology 1988; 39: 802-11.
3 Bachmann F, Savcic M, Hauert J, Geudelin B, Kieffer G, Carou R. Rapid onset of inhibition of ADP-induced platelet aggregation by a loading dose of clopidogrel. Eur Heart J 1996; 17 (Suppl) 263.
4 Balsano F, Coccheri S, Libretti A, Nenci GG, Catalano M, Fortunato G, Grasselli S, Violi F, Hellemans H, Vanhouve P. Ticlopidine in the treatment of intermittent claudication: a 21-month double-blind trial. J Lab Clin Med 1989; 114: 84-91.
5 Balsano F, Rizzon P, Violi F, Scrutinio D, Cimminiello C, Aguglia F, Pasotti C, Rudelli G. Antiplatelet therapy with ticlopidine in unstable angina. A controlled multicenter clinical trial. The Studio della Ticlopidine neirAngina Instabile Group. Circulation 1990; 82: 296-8.
6 Bellavance A. Efficacy of ticlopidine and aspirin for prevention of reversible cerebrovascular ischemic events. The Ticlopidine Aspirin Stroke Study. Stroke 1993; 24: 1452-7.
7 Becquemin JP. Effect of ticlopidine on the long-term patency of saphenous-vein bypass grafts in the legs. Etude de la Ticlopidine après Pontage Femoro-Poplite and the Association Universitaire de Recherche en Chirurgie. N Engl J Med 1997; 337: 1726-31.
8 Berglund U, Lindahl T. Enhanced onset of platelet inhibition with a loading dose of ticlopidine in ASA-treated stable coronary patients. Int J Cardiol 1998; 64: 215-7.
9 Berglund U, Wallentin L. Influence on lipoprotein metabolism of the platelet inhibitory drug ticlopidine. Atherosclerosis 1986; 59: 241-6.
10 Bergqvist D, Almgren B, Dickinson JP. Reduction of requirement for leg vascular surgery during long-term treatment of clau- dicant patients with ticlopidine: results from the Swedish Ticlopidine Multicentre Study (STIMS). Eur J Vase Endovasc Surg 1995; 10: 69-76.
11 Bertrand ME, Allain H. Lablanche JM on behalf of the investigators of the TACT study. Results of a randomized trial of ticlopidine versus placebo for prevention of acute closure and restenosis after coronary angioplasty (PTCA). The TACT study. Circulation 1990; 82 (Suppl) 754.
12 Breddin HK. Ticlopidin und Clopidogrel bei peripherer arterieller Verschlußkrankheit. In: Schör K, Breddin HK. (Hrsg.) Ticlopidin und Clopidogrel im kardiovaskulären System. Frechen: Dr: Schör Verlag; 1998: 53-71.
13 Buur T, Larsson R, Berglund U, Donat F, Tronquet C. Pharmacokinetics and effect of ticlopidine on platelet aggregation in subjects with normal and impaired renal function. J Clin Pharmacol 1997; 37: 108-15.
14 CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: 1329-39.
15 Cattaneo M, Akkawat B, Lecchi A, Cimminiello C, Capitanio AM, Mannucio Mannucci P. Ticlopidine selectively inhibits human platelet responses to adenosine diphosphate. Thromb Haemost 1991; 66: 694-9.
16 Cazenave JP, Gachet C. Anti-platelet drugs: do they affect megakaryocytes?. Baillieres Clin Haematol 1997; 10: 163-80.
17 Ciuffetti G, Aisa G, Mercuri M, Lombardini R, Paltriccia R, Neri C, Senin U. Effects of ticlopidine on the neurologic outcome and the hemorheologic pattern in the postacute phase of ischemic stroke: a pilot study. Angiology 1990; 41: 505-11.
18 Coukell A, Markham A. Clopidogrel. Drugs 1997; 54: 745-50.
19 Daniel JL, Dangelmaier C, Jin JG, Ashby B, Smith JB, Kunapuli SP. Molecular basis for ADP-induced platelet activation I. Evidence for three distinct ADP receptors on human platelets. J Biol Chem 1998; 273: 2024-9.
20 Darius H, Rupprecht H-J, Veit K, Meyer J. Ticlopidin und Clopidogrel bei Koronarinterventionen. In: Schör K, Breddin HK. (Hrsg) Ticlopidin und Clopidogrel im kardiovaskulären System. Frechen: Dr: Schör Verlag; 1998: 72-88.
21 De Caterina R, Sicari R, Bernini W, Lazzerini G, Buti-Strata G, Giannessi D. Benefit/ risk profile of combined antiplatelet therapy with ticlopidine and aspirin. Thromb Haemost 1991; 65: 504-10.
22 Defreyn G, Gachet C, Savi P, Driot F, Cazenave JP, Maffrand JP. Ticlopidine and clopidogrel (SR 45990 C) selectively neutralize ADP inhibition of PGE_ractivated platelet adenylate cyclase in rats and rabbits. Thromb Haemost 1991; 65: 186-90.
23 De Maat MP, Arnold AE, van Buuren S, Wilson JH, Kluft C. Modulation of plasma fibrinogen levels by ticlopidine in healthy volunteers and patients with stable angina. Thromb Haemost 1996; 76: 166-70.
24 Di Minno G, Cerbone AM, Mattioll PL, Turco S, Iovine C, Mancini M. Functionally thrombasthénie state in normal subjects following the administration of ticlopidine. J Clin Invest 1985; 75: 328-38.
25 DiPerri T, Pasini FL, Frigerio C, Blardi P, Centini F, Messa GL, Ghezzi A, Volpi L. Pharmacodynamics of ticlopidine in man in relation to plasma and blood cell concentration. Eur J Clin Pharmacol 1991; 41: 429-34.
26 Donahue SR, Flockhart DA, Abernethy DR, Ko JW. Ticlopidine inhibition of phenytoin metabolism mediated by potent inhibition of CYP2C19. Clin Pharmacol Ther 1997; 62: 572-7.
27 Dubiak GR, Parker K, Humphreys BD, Kertesy SB, Dubyak GR. The P2X(1) receptor, and adenosine triphosphate-gated cation channel, is expressed in human platelets but not in human blood leukocytes. Blood 1998; 91: 3172-81.
28 Fagher B. Long-term effects of ticlopidine on lower limb blood flow, ankle/brachial index and symptoms in peripheral arteriosclerosis. A double-blind study. The STIMS Group in Lund. Swedish Ticlopidine Multicenter Study. Angiology 1994; 45: 777-88.
29 Fagura MS, Dainty IA, McKay GD, Kirk IP, Humphries RG, Robertson MJ, Dougall IG, Leff P. P2Y(1) receptors in human platelets which are pharmacologically distinct from P2Y(ADP)-receptors. Br J Pharmacol 1998; 124: 157-64.
30 Féliste R, Delebassée D, Simon MF, Chap H, Defreyn G, VallÈe E, Douste-Blazy L, Maffrand JP. Broad spectrum antiplatelet p Stivity of ticlopidine and PCR 4099 involves the suppression of the effects of released ADP. Thromb Res 1987; 48: 403-15.
31 Gachet C, Cazenave J-P, Ohlmann P, Bouloux C, Defreyn G, Driot F, Maffrand J-P. The thienopyridine ticlopidine selectively prevents the inhibitory effects of ADP but not of adrenaline on cAMP levels raised by stimulation of the adenylate cyclase of human platelets by PGE_X . Biochem Pharmacol 1990; 40: 2683-7.
32 Gachet C, Savi P, Pollmann P, Maffrand J-P, Jakobs KH, Cazenave J-P. 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.
33 Geiger J, Hönig-Liedl P, Schanzenbächer P, Walter U. Ligand specificity and ticlopidine effects distinguish three human platelet ADP receptors. Eur J Pharmacol 1998; 351: 235-46.
34 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; 01: 1215-20.
35 Goods CM, al Shaibi KF, Liu MW, Yadav JS, Mathur A, Jain SP, Dean LS, Iyer SS, Parks JM, Roubin GS. Comparison of aspirin alone versus aspirin plus ticlopidine after coronary stenting. Am J Cardiol 1996; 78: 1042-4.
36 Gregorini L, Marco J, Fajadet J, Bernies M, Cassagneau B, Brunei P, Bossi IM, Manucci PM. Ticlopidine and aspirin pretreatment reduces coagulation and platelet activation during coronary dilatation procedures. J Am Coll Cardiol 1997; 29: 13-20.
37 Gryglewski RJ, Korbut R, Swies J, Kostka-Trabka E, Bieron K, Robak J. Thrombolytic action of ticlopidine: a possible mechanism. Eur J Pharmacol 1996; 308: 61-7.
38 Hall P, Nakamura S, Maiello L, Itoh A, Blengino S, Martini G, Ferraro M, Colombo A. A randomized comparison of combined ticlopidine and aspirin therapy versus aspirin therapy alone after successfull intravascular ultrasound-guided stent implantation. Circulation 1996; 93: 215-22.
39 Harbison JW. Ticlopidine versus aspirin for the prevention of recurrent stroke. Analysis of patients with minor stroke from the Ticlopidine Aspirin Stroke Study. Stroke 1992; 23: 1723-7.
40 Hardisty RM, Powling MJ, Nokes TJC. The action of ticlopidine on human platelets: Studies on aggregation, secretion, calcium mobilization and membrane glycoproteins. Thromb Haemost 1990; 64: 150-5.
41 Harker LA, Bruno JJ. Ticlopidine’s mechanism of action on human platelets. In: Hass WK, Easton JD. (Hrsg.) Ticlopidine, Platelets and Vascular Disease. Springer; New York: 1993: 41-69.
42 Hass WK, Easton JD, Adams Jr HP, PrysePhillips 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 1990; 322: 404-5.
43 Hechler B, Léon C, Vial C, Vigne P, Frelin C. Cazenave J-P, Gachet C. The P2Y1 receptor is necessary for adenosine 5’-diphos- phate-induced platelet aggregation. Blood 1998; 92: 152-9.
44 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: 1310-5.
45 Herbért J-M, Tissinir A, Defreyn G, Maffrand JP. Inhibitory effect of clopidogrel on platelet adhesion and intimai proliferation after arterial injury in rabbits. Arterioscler Thromb Vase Biol 1993; 13: 1171-9.
46 Herbért J-M, Bernat A, Savi P. Hypercholesterolemia does not affect the antiplatelet activity of clopidogrel. Platelets 1995; 06: 412-3.
47 Hohlfeld T, Scharnowski F, Braun M, Schrör K. Antiplatelet effects of ticlopidine are reduced in experimental hypercholesterolemia. Thromb Haemost 1994; 71: 112-8.
48 Humbert M, Nurden P, Bihour C, Pasquet J-M, Winder J, Heilmann E, Savi P, Herbért J-M, Kunicki TJ, Nurden AT. Ultrastruc- tural studies of platelet aggregates from human subjects receiving clopidogrel and from a patient with an inherited defect of an ADP-dependent pathway of platelet activation. Arterioscler Thromb Vase Biol 1996; 16: 1532-43.
49 Hutt HJ. Drexler für das CAPRIE Steering Committee. CAPRIE: Ziele und Ergebnisse. In: Schör K, Breddin HK. (Hrsg.) Ticlopidin und Clopidogrel im kardiovaskulären System. Dr. Schör; Verlag, Frechen, Germany: 1998: 35-52.
50 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: 301-8.
51 Jin JG, Kunapuli SP. Coactivation of two different G protein-coupled receptors is essential for ADP-induced platelet aggregation. Proc Natl Acad Sei USA 1998; 95: 8070-4.
52 Jin JG, Daniel JL, Kunapuli SP. Molecular basis for ADP-induced platelet aggregation II. The P2Y1 receptor mediates ADP-induced intracellular calcium mobilization and shape change in platelets. J Biol Chem 1998; 273: 2030-4.
53 Kastrati A, Schuhlen H, Hausleiter J, Walter H, Zitzmann-Roth E, Hadamitzky M, Elezi S, Ulm K, Dirschinger J, Neumann FJ, Schömig 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: 383-5.
54 Knudsen JB, Bastain W, Sefton CM, Allen JG, Dickinson JP. Pharmacokinetics of ticlopidine during chronic oral administration to healthy volunteers and its effects on anti- pyrine pharmacokinetics. Xenobiotica 1992; 22: 579-89.
55 Lablanche JM, McFadden EP, Bonnet JL, Grollier G, Danchin N, Bedossa M, Leclercq C, Vahanian A, Bauters C, Van Belle E, Bertrand ME. Combined antiplatelet therapy with ticlopidine and aspirin. A simplified approach to intracoronary stent management. Eur Heart J 1996; 17: 1373-80.
56 Léon C, Hechler B, Vial C, Leray C, Cazenave J-P, 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.
57 Lipinski B, Krolewski AS. Ticlopidine may reduce functional fibrinogen levels by inhibition of MCP incorporation into fibrin. Thromb Haemost 1997; 77: 603-4.
58 Masuhr F, Weber JR, Einhäupl KM. Ticlopidin und Clopidogrel bei der Prävention des Schlaganfalls. In: Schör K, Breddin HK. (Hrsg.) Ticlopidin und Clopidogrel im kardiovaskulären System. Dr. Schör Verlag; Frechen, Germany: 1998: 89-105.
59 Mazoyer E, Ripoll L, Boisseau MR, Drouet L. How does ticlopidine treatment lower plasma fibrinogen?. Thromb Res 1994; 75: 361-70.
60 Mills DCB, Puri R, Hu C-J, Minniti C, Grana G, Freedman MD, Colman RF, Colman RW. Clopidogrel inhibits the binding of ADP analogues to the receptor mediating inhibition of platelet adenylate cyclase. Ar- terioscl Thromb 1992; 12: 430-6.
61 Mills DCB. ADP receptors on platelets. Thromb Haemost 1996; 76: 835-56.
62 Neumann FJ, Gawaz M, Dickfeld T, Wehninger A, Walter H, Blasini R, Schömig A. Antiplatelet effects of ticlopidine after coronary stenting. J Am Coll Cardiol 1997; 29: 1515-9.
63 Palareti G, Poggi M, Torricelli P, Balestra V, Coccheri S. Long-term effects of ticlopidine on fibrinogen and haemorheology in patients with peripheral arterial disease. Thromb Res 1988; 52: 621-9.
64 Privitera M, Welty TE. Acute phenytoin toxicity followed by seizure breakthrough from a ticlopidine-phenytoin interaction. Arch Neurol 1996; 53: 1191-2.
65 Qian S, Iwai T. Effect of ticlopidine on the cutaneous circulation in peripheral vascular disease. Angiology 1993; 44: 627-31.
66 Reimann S, Weber A-A, Schrör K. Specific inhibition of ADP-induced platelet aggregation by clopidogrel in vitro without hepatic biotransformation. Platelets. 1998 in press, Abstract)
67 Saito S, Hosokawa FG, Kim K, Tanaka S, Miyake S. Primary stent implantation without coumadin in acute myocardial infarction. J Am Coll Cardiol 1996; 28: 74-81.
68 Savi P, Herbért JM, Pflieger AM, Dol F, Delebassee D, Mobalbert J, Defreyn G, Maffrand JP. Importance of hepatic metabolism in the antiaggregating activity of the thienopyridine clopidogrel. Biochem Pharmacol 1992; 44: 527-32.
69 Savi P, Combalbert J, Gaich C, Rouchon MC, Maffrand JP, Berger Y, Herbért JM. The antiaggregating activity of clopidogrel is due to a metabolic activation by the hepatic cytochrome P450-1A. Thromb Haemost 1994; 72: 313-7.
70 Savi P, Laplace MC, Maffrand J, Herbért J-M. Binding of [3H]-2-methylthio ADP to rat platelets - effect of clopidogrel and ticlopidine. J Pharmacol Exp Ther 1994; 269: 772-7.
71 Savi P, Pflieger AM, Herbért J-M. cAMP is not an important messenger for ADP- induced platelet aggregation. Blood Coagul Fibrinolysis 1996; 07: 249-52.
72 Savi P, Artcanuthurry V, Bornia J, Grelac F, Maclouf J, Vevy Toledano S, Herbért J-M. Effect of clopidogrel treatment on ADP- induced phosphorylation in rat platelets. Br J Haematol 1997; 97: 185-91.
73 Savi P, Beauverger P, Labouret C, Delfaud M, Salel V, Kaghad M, Herbért J-M. Role of P2Y1 purinoceptor in ADP-induced platelet activation. FEBS Lett 1998; 422: 291-5.
74 Schömig A, Neumann JF, Kastrati A, Schuhlen H, Blasini R, Hadamitzky M, Walater 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: 1084-9.
75 Schrör K. Clinical pharmacology of the adenosine diphosphate (ADP) receptor antagonist, clopidogrel. Vase Med. 1998 (in press)
76 Schuhlen H, Hadamitzky M, Walter H, Ulm K, Schömig A. Major benefit from antiplatelet therapy for patients at high rist for adverse cardiac events after coronary Palmaz-Schatz stent placemen: analysis of a prospective risk stratification protocol in the Intracoronary Stenting and Antithrombotic Regimen (ISAR) trial. Circulation 1997; 95: 2015-21.
77 Shah J, Teitelbaum P, Molony B, Gabuzda T, Massey I. Single and multiple dose pharmacokinetics of ticlopidine in young and elderly subjects. Br J Clin Pharmacol 1991; 32: 761-4.
78 Splawinska B, Kuznier J, Malinga K, Mazurek AP, Splawinski J. The efficacy and potency of antiplatelet activity of ticlopidine is increased by aspirin. Int J Clin Pharmacol Ther 1996; 34: 352-6.
79 Sun B, Li J, Okahara K, Kambayashi J. P2X(1) purinoceptor in human platelets - molecular cloning and functional characterization after heterologous expression. J Biol Chem 1998; 273: 11544-7.
80 Tanahashi N, Fukuuchi Y, Tomita M, Matsuoka S, Takeda H. Ticlopidine improves the enhanced erythrocyte aggregability in patients wit cerebral infarction. Stroke 1993; 24: 1083-6.
81 Teitelbaum P. Pharmacodynamics and pharmacokinetics of ticlopidine. In: Hass WK, Easton JD. (Hrsg.) Ticlopidine, Platelets and Vascular Disease. New York: Springer; 1993: 27-40.
82 Thebault JJ, Blatrix CE, Blanchard JF, Panak EA. The interactions of ticlopidine and aspirin in normal subjects. J Int Med Res 1997; 05: 405-11.
83 Toghi H, Takahashi H, Kashiwaya M, Watanaby K. Effect of plasma fibrinogen concentration on the inhibition of platelet aggregation after ticlopidine compared with aspirin. Stroke 1994; 25: 2017-21.
84 Uchiyama S, Sone R, Nagayama T, Shibagaki Y, Kobayashi I, Maruyama S, Kusakabe K. Combination therapy with low-dose aspirin and ticlopidine in cerebral ischemia. Stroke 1989; 20: 1643-7.
85 Van Belle E, McFadden EP, Lablanche JM, Bauters C, Hamon M, Bertrand ME. Two- prolonged antiplatelet therapy with aspirin and ticlopidine without systemic anticoagulation: an alternative therapeutic strategy after bailout stent implantation. Coron Artery Dis 1995; 06: 341-5.
86 Yang LH, Fareed J. Vasomodulatory action of clopidogrel and ticlopidine. Thromb Res 1997; 86: 479-91.