Azetylsalizylsäure und Thromboxaninhibitoren

Zusammenfassung

Azetylsalizylsäure (ASA) ist seit über 100 Jahren Standardtherapeutikum zur Behandlung von Schmerzen und Entzündungen und seit etwa 40 Jahren Standardsubstanz als Plättchenfunktionshemmer. Grundlage dieser vielfältigen Wirkungen von ASA ist die Hemmung der Fettsäure-Cyclooxygenase (COX). Diese beruht auf einer irreversiblen Acetylierung des Serin 530 im Cyclooxygenasemolekül und nachfolgender sterischer Hinderung des Zutritts des Substrates Arachidonsäure zum katalytischen Zentrum des Enzyms. Die Antiplättchenwirkung von ASA beinhaltet ausschließlich eine Hemmung der thrombozytären Thromboxansynthese nach Inhibition der COX-1. Andere Mechanismen der Plättchenaktivierung werden nicht beeinflußt. Nebenwirkungen von ASA, z. B. Magen-Darm-Blutungen, werden ebenfalls entscheidend durch die Hemmung der Prostaglandinsynthese bestimmt. Daher wurde versucht, eine selektive Hemmung der Thromboxansynthese, Blockade von Thromboxanrezeptoren oder beides zu erreichen. Dazoxiben, Picotamide und Terbogrel sind Referenzsubstanzen für diese Entwicklungen. Die vorliegenden klinischen Daten für Dazoxiben sind weniger überzeugend, für Picotamid wurde bei Patienten mit peripherer Verschlußkrankheit eine nur tendenzielle Senkung der Reverschlußrate gezeigt. Eine größere klinische Studie mit dem kombinierten Inhibitor Terbogrel ist derzeit in Vorbereitung. Insgesamt wird ASA seinen Stellenwert als Basistherapeutikum zur Verhinderung thromboembolischer Gefäßverschlüsse sicher behalten, wobei neuere Antiplättchensubstanzen wie Abciximab bei schweren akuten Koronarsyndromen oder eine Kombination mit Thienopyridinen bei akuten Koronarinterventionen die Wirkung verstärkt. Der therapeutische Stellenwert von selektiven Thromboxaninhibitoren in der antithrombotischen Therapie ist noch zu definieren.

Schlüsselwörter

Azetylsalizyläure - Thromboxan-Synthesehemmer - Thromboxan-Rezeptorantagonist - klinische Studien

• LITERATUR

• 1 FitzGerald DJ, Roy L, Catella F, FitzGerald GA. Platelet activation in unstable coronary disease. N Engl J Med 1986; 315: 983-9.
• 2 Foegh ML, Zhao Y, Madren L, Rolnick M, Stair TO, Huang KS, Ramwell PW. Urinary thromboxane A₂ metabolites in patients presenting in the emergency room with acute chest pain. J Intern Med 1994; 235: 153-61.
• 3 Rasmanis GO, Vesterqvist O, Green K, Henriksson P. Implications of the prognostic importance of exercise-induced thromboxane formation in survivors of an acute myocardial infarction. Prostaglandins 1995; 49: 247-53.
• 4 Fisher M, Zipser R. Increased excretion of immunoreactive thromboxane B₂ in cerebral ischemia. Stroke 1985; 16: 10-4.
• 5 Dorn GWI, Liel N, Trask JL, Mais DE, Assey ME, Halushka PV. Increased platelet thromboxane A₂/prostaglandin H₂ receptors in patients with acute myocardial infarction. Circulation 1990; 65: 538-45.
• 6 Mehta J, Mehta P, Conti CR. Platelet function studies in coronary heart disease. IX. Increased platelet prostaglandin generation and abnormal platelet sensitivity to prostacyclin and endoperoxide analog in angina pectoris. Am J Cardiol 1980; 46: 943-7.
• 7 Modesti PA, Colella A, Cecioni I, Costoli A, Biagini D, Migliorini A, Neri GGSerneri. Increased number of thromboxane A₂-prostaglandin H₂ platelet receptors in active unstable angina and causative role of enhanced thrombin formation. Am Heart J 1995; 129: 873-9.
• 8 Fletcher BS, Lim RW, Varnum BC, Kujubu DA, Koski RA, Herschman HR. Structure and expression of TIS21, a primary response gene induced by growth factors and tumor promoters. J Biol Chem 1991; 266: 14511-8.
• 9 Hla T, Neilson K. Human cyclooxygenase-2 cDNA. Proc Natl Acad Sei USA 1992; 89: 7384-8.
• 10 Creminon C, Habib A, Maclouf J, Pradelles P, Grassi J, Frobert Y. Differential measurement of constitutive (COX-1) and inducible (COX-2) cyclooxygenase expression in human umbilical vein endothelial cells using specific immunometric enzyme immunoassays. Biochim Biophys Acta 1995; 1254: 341-8.
• 11 Mitchell JA, Akarasereenont P, Thiemermann C, Flower RJ, Vane JR. Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc Natl Acad Sei 1994; 90: 11693-7.
• 12 Marcus AJ, Safier LB, Ullman HL, Islam N, Broekman MJ, Falck JR, Fischer S, von Schacky C. Cell-cell interactions in the eicosanoid pathway. Ann NY Acad Sei 1987; 516: 407-11.
• 13 Nowak J, FitzGerald GA. Redirection of prostaglandin endoperoxide metabolism at the platelet-vascular interface in man. J Clin Invest 1989; 83: 380-5.
• 14 FitzGerald GA, Reilly IA, Pedersen AK. The biochemical pharmacology of thromboxane synthase inhibition in man. Circulation 1985; 72: 1194-201.
• 15 Bertele V, De Gaetano G. Potentiation by dazoxiben, a thromboxane synthetase inhibitor, of platelet aggregation inhibitory activity of a thromboxane receptor antagonist and of prostacyclin. Eur J Pharmacol 1982; 85: 331-3.
• 16 Narumiya S, Ushikubi F, Nakajima M, Hirata M, Okuma M. Purification and characterization of the human platelet TXA2/ PGH2 receptor. Adv Prostagl Thromb Leukot Res 1991; 21A: 339-46.
• 17 Morinelli TA, Niewiarowski S, Daniel JL, Smith JB. Receptor-mediated effects of a PGH₂ analogue (U 46619) on human platelets. Am J Physiol 1987; 253: H1035-43.
• 18 Arita H, Nakano T, Hanasaki K. Thromboxane A₂: its generation and role in platelet activation. Prog Lipid Res 1989; 28: 273-301.
• 19 Halushka PV, Pawate S, Martin ML. Thromboxane A₂ and other eicosanoids. In: Platelets and their factors. von Bruchhausen F, Walter U. (Eds). Berlin: Springer; 1997: 459-82.
• 20 Smith 3d EF. Thromboxane A₂ in cardiovascular and renal disorders: is there a defined role for thromboxane receptor antagonists or thromboxane synthase inhibitors?. Eicosanoids 1989; 02: 199-212.
• 21 Vermylen J, Deckmyn H. Thromboxane synthase inhibitors and receptor antagonists. Cardiovasc Drugs Ther 1992; 06: 29-33.
• 22 Gresele P, Arnout J, Deckmyn H, Huybrechts E, Pieters G, Vermylen J. Role of proaggregatory and antiaggregatory prostaglandins in hemostasis. Studies with combined thromboxane synthase inhibition and thromboxane receptor antagonism. J Clin Invest 1987; 80: 1435-45.
• 23 De Clerck F, Beetens J, de Chaffoy de Courcelles D, Vercammen E, Freyne E, Janssen PA. R 68 070: thromboxane A2 synthetase inhibition and thromboxane A2/prostaglandin endoperoxide receptor blockade, combined in one molecule. Prog Clin Biol Res 1989; 301: 567-72.
• 24 Gresele P, Deckmyn H, Arnout J, Nenci GG, Vermylen J. Characterization of N,N’∼ bis(3-picolyl)-4-methoxy-isophtalamide (picotamide) as a dual thromboxane synthase inhibitor/thromboxane A2 receptor antagonist in human platelets. Thromb Haemost 1989; 61: 479-84.
• 25 Muck S, Weber A-A, Schrör K. Effects of terbogrel on platelet function and prostaglandin endoperoxide transfer. Eur J Pharmacol 1998; 344: 45-8.
• 26 Vezza R, Spina D, Tallarida RJ, Nathan M, Page CP, Gresele P. Antivasoconstrictor and antiaggregatory activities of picotamide unrelated to thromboxane A2 antagonism. Thromb Haemost 1997; 78: 1385-91.
• 27 Funk CD, Funk LB, Kennedy ME, Pong AS, FitzGerald GA. Human platelet/erythroleukemia cell prostaglandin G/H synthase: cDNA cloning, expression, and gene chromosomal assignment. FASEB J 1991; 05: 2304-12.
• 28 Smith WL, Meade EA, de Wit DL. Pharmacology of prostaglandin endoperoxidase synthase isoenzymes-1 and -2. Ann NY Acad Sei 1994; 714: 136-42.
• 29 Griswold DE, Adams JL. Constitutive cyclooxygenase (COX-1) and inducible cyclooxygenase (COX-2): rationale for selective inhibition and progress to date. Med Res Rev 1998; 16: 181-206.
• 30 FitzGerald GA, Oates JA, Hawiger J, Maas RL, Roberts 2d LJ, Lawson JA, Brash AR. Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man. J Clin Invest 1983; 71: 676-88.
• 31 Zaragoza R, Le Breton GC. Effect of single-dose aspirin on TXA2 and PGI2 cyclooxygenases in vivo. Haemostasis 1987; 17: 40-8.
• 32 Vanags D, Rodgers SE, Lloyd JV, Bochner F. The antiplatelet effect of daily low dose enteric-coated aspirin in man: a time course of onset and recovery. Thromb Res 1990; 59: 995-1005.
• 33 Chiabrando C, Rivoltella L, Martelli L, Valzacchi S, Fanelli R. Urinary excretion of thromboxane and prostacyclin metabolites during chronic low-dose aspirin: evidence for an extrarenal origin of urinary thromboxane B2 and 6-keto-prostaglandin FI alpha in healthy subjects. Biochim Biophys Acta 1992; 1133: 247-54.
• 34 Patrono C. Aspirin and human platelets: from clinical trials to acétylation of cyclooxygenase and back. Trends Pharmacol Sei 1989; 10: 453-8.
• 35 Gautier P, Bertrand JP, Guiraudou P. Effects of SR 44866, a potassium channel opener, on action potentials of rabbit, guinea pig, and human heart fibers. J Cardiovasc Pharmacol 1991; 17: 692-700.
• 36 Tohgi H, Konno S, Tamura K, Kimura B, Kawano K. Effects of low-to-high doses of aspirin on platelet aggregability and metabolites of thromboxane A2 and prostacyclin [see comments]. Stroke 1992; 23: 1400-3.
• 37 Kallmann R, Nieuwenhuis HK, de Groot PG, van Gijn J, Sixma JJ. Effects of low doses of aspirin, 10 mg and 30 mg daily, on bleeding time, thromboxane production and 6-keto-PGFl alpha excretion in healthy subjects. Thromb Res 1987; 45: 355-61.
• 38 Preston FE, Greaves M, Jackson CA, Stoddard CJ. Low-dose aspirin inhibits platelet and venous cyclo-oxygenase in man. Thromb Res 1982; 27: 477-84.
• 39 Kyrie PA, Eichler HG, Jager U, Lechner K. Inhibition of prostacyclin and thromboxane A2 generation by low-dose aspirin at the site of plug formation in man in vivo. Circulation 1987; 75: 1025-9.
• 40 Cerletti C, Marchi S, Lauri D, Domanin M, Lorenzi G, Urso R, Dejana E, Latini R, De Gaetano G. Pharmacokinetics of entericcoated aspirin and inhibition of platelet thromboxane A2 and vascular prostacyclin generation in humans. Clin Pharmacol Ther 1987; 42: 175-80.
• 41 Clarke RJ, Mayo G, Price P, FitzGerald GA. Suppression of thromboxane A₂ but not of systemic prostacyclin by controlled- release aspirin. N Engl J Med 1991; 325: 1137-41.
• 42 Lee M, Cryer B, Feldman M. Dose effects of aspirin on gastric prostaglandins and stomach mucosal injury. Ann Intern Med 1994; 120: 184-9.
• 43 Hecker M, Haurand M, Ullrich V, Terao S. Spectral studies on structure-activity relationships of thromboxane synthase inhibitors. Eur J Biochem 1986; 157: 217-23.
• 44 Lorenz RL, Fischer S, Wober W, Wagner HA, Weber PC. Effects on prostanoid formation and pharmacokinetics of dazmegrel (UK-38,485), a novel thromboxane synthase inhibitor, in man. Biochem Pharmacol 1986; 35: 761-6.
• 45 Tyler HM, Saxton CA, Parry MJ. Administration to man of UK-37,248-01, a selective inhibitor of thromboxane synthetase. Lancet 1981; 01: 629-32.
• 46 Gatti G, Bartoli A, Bertin Strolin MBenedetti, Perucca E. Pharmacokinetic and pharmacodynamic studies following single and multiple doses of rolafagrel, a novel inhibitor of thromboxane synthase, in normal volunteers. Eur J Clin Pharmacol 1994; 47: 275-80.
• 47 Halushka PV. Pharmacology of thromboxane A₂ receptor antagonists. Z Kardiol 1989; 78: 42-7.
• 48 Halushka PV, Allan CJ, Davis KLBruno. Thromboxane A2 receptors. J Lipid Médiat Cell Signal 1995; 12: 361-78.
• 49 Kotze HF, Lamprecht S, Badenhorst PN, van Wyk V, Roodt JP, Alexander K. In vi inhibition of acute platelet-dependent thrombosis in a baboon model by Bay U3405, a thromboxane A2-receptor antagonist. Thromb Haemost 1993; 70: 672-5.
• 50 Rote WE, Mu DX, Lucchesi BR. Thromboxane antagonism in experimental canine carotid artery thrombosis. Stroke 1993; 24: 820-7.
• 51 Fujita T, Hasan S, Storer BL, Shebuski RJ. Effect of selective endoperoxide/thromboxane A2 receptor antagonism with sulotroban on tPA-induced thrombolysis in a rabbit model of femoral arterial thrombosis. Fundam Clin Pharmacol 1989; 03: 643-53.
• 52 Shebuski RJ, Smith Jr JM, Storer BL, Granett JR, Bugelski PJ. Influence of selective endoperoxide/thromboxane A2 receptor antagonism with sulotroban on lysis time and reocclusion rate after tissue plasminogen activator-induced coronary thrombolysis in the dog. J Pharmacol Exp Ther 1988; 246: 790-6.
• 53 Golino P, Ashton JH, Glas PGreenwalt, McNatt J, Buja LM, Willerson JT. Mediation of reocclusion by thromboxane A2 and serotonin after thrombolysis with tissuetype plasminogen activator in a canine preparation of coronary thrombosis. Circulation 1988; 77: 678-84.
• 54 Patscheke H. Thromboxane A₂/prostaglandin H₂ receptor antagonists - A new therapeutic principle. Stroke. 1990 21. IV-139-IV-42.
• 55 De Clerck F, Beetens J, Van de Water A, Vercammen E, Janssen PA. R 68 070: thromboxane A2 synthetase inhibition and thromboxane A2/prostaglandin endoperoxide receptor blockade combined in one molecule-II. Pharmacological effects in vivo and ex vivo. Thromb Haemost 1989; 61: 43-9.
• 56 Gresele P, Deckmyn H, Nenci GG, Vermylen J. Thromboxane synthase inhibitors, thromboxane receptor antagonists and dual blockers in thrombotic disorders. Trends Pharmacol Sei 1991; 12: 158-63.
• 57 Hoet B, Arnout J, Deckmyn H, Vermylen J. Synergistic antiplatelet effect of ridogrel, a combined thromboxane receptor antagonist and thromboxane synthase inhibitor, and UDCG-212, a cAMP-phosphodiesterase inhibitor. Thromb Haemost 1993; 70: 822-5.
• 58 Willerson JT, Golino P, McNatt J, Eidt J, Yao SK, Buja LM. Role of new antiplatelet agents as adjunctive therapies in thrombolysis. Am J Cardiol 1991; 67: 12A-8A.
• 59 Bhagwat SS. Novel antithrombotic agents with combined thromboxane receptor antagonist (TxRA)/thromboxane synthase inhibitor (TxSI) activities. Drugs Future 1994; 19: 765-77.
• 60 Kauffman G. Aspirin-induced gastric mucosal injury: lessons learned from animal models. Gastroenterology 1989; 96: 606-14.
• 61 The Aspirin Myocardial Infarction Study Research Group. The aspirin myocardial infarction study: final results. Circulation 1980; 62: V79-84.
• 62 The SALT Collaborative Group. Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events. Lancet 1991; 338: 1345-9.
• 63 Prichard PJ, Kitchingman GK, Walt RP, Daneshmend TK, Hawkey CJ. Human gastric mucosal bleeding induced by low dose aspirin, but not warfarin. BMJ 1989; 298: 493-6.
• 64 The Dutch TIA Trial Study Group. A comparison of two doses of aspirin (30 mg vs. 283 mg a day) in patients after a transient ischemic attack or minor ischemic stroke. N Engl J Med 1991; 325: 1261-6.
• 65 Olivero JJ, Graham DY. Gastric adaptation to nonsteroidal anti-inflammatory drugs in man. Scand J Gastroenterol 1992; 193 (Suppl): 53-8.
• 66 Konturek JW, Dembinski A, Konturek SJ, Stachura J, Domschke W. Infection of Helicobacter pylori in gastric adaptation to continued administration of aspirin in humans. Gastroenterology 1998; 114: 245-55.
• 67 Ogletree ML, O’Keefe EH, Durham SK, Rubin B, Aberg G. Gastroprotective effects of thromboxane receptor antagonists. J Pharmacol Exp Ther 1992; 263: 374-80.
• 68 Walt RP, Kemp RT, Filipowicz B, Davies JG, Bhaskar NK, Hawkey CJ. Gastric mucosal protection with selective inhibition of thromboxane synthesis. Gut 1987; 28: 541-4.
• 69 Slattery J, Warlow CP, Shorrock CJ, Langman MJ. Risks of gastrointestinal bleeding during secondary prevention of vascular events with aspirin-analysis of gastrointestinal bleeding during the UK-TIA trial. Gut 1995; 37: 509-11.
• 70 Schrör K. (Hrsg). Acetylsalizylsäure. Stuttgart: Thieme; 1998
• 71 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.
• 72 Ridker PM, Manson JE, Gaziano JM, Buring JE, Hennekens CH. Low-dose aspirin therapy for chronic stable angina. A randomized, placebo-controlled clinical trial. Ann Intern Med 1991; 114: 835-9.
• 73 Juul SMöller, Edvardsson N, Jahnmatz B, Rosen A, Sorensen S, Omblus R. Doubleblind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris. The Swedish Angina Pectoris Aspirin Trial (SAPAT) Group. Lancet 1992; 340: 1421-5.
• 74 Lewis Jr HD, Davis JW, Archibald DG, Steinke WE, Smitherman TC, Doherty 3d JE, Schnaper HW, LeWinter MM, Linares E, Pouget JM, Sabharwal SC, Chesler E, DeMots H. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study. N Engl J Med 1983; 309: 396-403.
• 75 Cairns JA, Gent M, Singer J, Finnie KJ, Froggatt GM, Holder DA, Jablonsky G, Kostuk WJ, Melendez LJ, Myers MG. et al. Aspirin, sulfinpyrazone, or both in unstable angina. Results of a Canadian multicenter trial. N Engl J Med 1985; 313: 1369-75.
• 76 Wallentin LC. Aspirin (75 mg/day) after an episode of unstable coronary artery disease: long-term effects on the risk for myocardial infarction, occurrence of severe angina and the need for revascularization. Research Group on Instability in Coronary Artery Disease in Southeast Sweden [comment]. J Am Coll Cardiol 1991; 18: 1587-93.
• 77 Theroux P, Ouimet H, McCans J, Latour JG, Joly P, Levy G, Pelletier E, Juneau M, Stasiak J, deGuise P. et al. Aspirin, heparin, or both to treat acute unstable angina [see comments]. N Engl J Med 1988; 319: 1105-11.
• 78 Peto R, Gray R, Collins R, Wheatley K, Hennekens C, Jamrozik K, Warlow C, Hafner B, Thompson E, Norton S. et al. Randomised trial of prophylactic daily aspirin in British male doctors. Br Med J Clin Res Ed 1988; 296: 313-6.
• 79 Steering Committee of the Physicians’ Health Study Research Group. Final report on the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med 1089; 321: 129-35.
• 80 Hennekens CH, Buring JE, Sandercock P, Collins R, Peto R. Aspirin and other antiplatelet agents in the secondary and primary prevention of cardiovascular disease. Circulation 1989; 80: 749-56.
• 81 The Medical Research Council’s General Practice Research Framework. Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. Lancet 1998; 351: 233-41.
• 82 Chesebro JH, Fuster V, Elveback LR, Clements IP, Smith HC, Holmes Jr DR, Bardsley WT, Pluth JR, Wallace RB, Puga FJ. et al. Effect of dipyridamole and aspirin on late vein-graft patency after coronary bypass operations. N Engl J Med 1984; 310: 209-14.
• 83 Brown BG, Cukingnan RA, DeRouen T, Goede LV, Wong M, Fee HJ, Roth JA, Carey JS. Improved graft patency in patients treated with platelet-inhibiting therapy after coronary bypass surgery. Circulation 1985; 72: 138-46.
• 84 Goldman S, Copeland J, Moritz T, Henderson W, Zadina K, Ovitt T, Doherty Read R, Chesler E, Sako Y. et al. Improvement in early saphenous vein graft patency after coronary artery bypass surgery with antiplatelet therapy: results of a Veterans Administration Cooperative Study. Circulation 1988; 77: 1324-32.
• 85 Rajah SM, Nair U, Rees M, Saunders N, Walker D, Williams G, Critchley A, Beton D, Campbell C, Lawson RA. et al. Effects of antiplatelet therapy with indobufen or aspirin-dipyridamole on graft patency one year after coronary artery bypass grafting. J Thorac Cardiovasc Surg 1994; 107: 1146-53.
• 86 Schwartz L, Bourassa MG, Lesperance J, Aldridge HE, Kazim F, Salvatori VA, Henderson M, Bonan R, David PR. Aspirin and dipyridamole in the prevention of restenosis after percutaneous transluminal coronary angioplasty. N Engl J Med 1988; 318: 1714-9.
• 87 Savage MP, Goldberg S, Bove AA, Deutsch E, Vetrovec G, Macdonald RG, Bass T, Margolis JR, Whitworth HB, Taussig A. Effect of thromboxane A2 blockade on clinical outcome and restenosis after successful coronary angioplasty. MultiHospital Eastern Atlantic Restenosis Trial (M-HEART II) [see comments]. Circulation 1995; 92: 3194-200.
• 88 Serruys PW, Rutsch W, Heyndrickx GR, Danchin N, Mast EG, Wijns W, Rensing BJ, Vos J, Stibbe J. Prevention of restenosis after percutaneous transluminal coronary angioplasty with thromboxane A2-receptor blockade. A randomized, double-blind, placebo-controlled trial. Coronary Artery Restenosis Prevention on Repeated Thromboxane-Antagonism Study (CARPORT). Circulation 1991; 84: 1568-80.
• 89 Fiddler GI, Lumley P. Preliminary clinical studies with thromboxane synthase inhibitors and thromboxane receptor blockers. Circulation 1998; 81 (Suppl I): I-69-I-78.
• 90 The Ridogrel Versus Aspirin Patency Trial (RAPT). Randomized trial of ridogrel, a combined thromboxane A₂ synthase inhibitor and thromboxane A₂/prostaglandin endoperoxide receptor antagonist, versus aspirin as adjunct to thrombolysis in patients with acute myocardial infarction. Circulation 1994; 89: 588-95.
• 91 Schafer AI. Effects of nonsteroidal antiinflammatory drugs on platelet function and systemic hemostasis. J Clin Pharmacol 1995; 35: 209-19.
• 92 Viigimaa M, Joudu T, Hendrikson E, Shandrik Y, Teesalu R. Antiaggregative therapy with acetylsalicylic acid and diclofenac in patients with acute myocardial infarction. Ups J Med Sei 1994; 99: 131-8.
• 93 Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy-II: Maintenance of vas-cular graft or arterial patency by antiplatelet therapy. BMJ 1994; 308: 159-68.
• 94 Barnett HJ, Kaste M, Meldrum H, Eliasziw M. Aspirin dose in stroke prevention: beautiful hypotheses slain by ugly facts [editorial; comment]. Stroke 1996; 27: 588-92.
• 95 Fields WS, Lemak NA, Frankowski RF, Hardy RJ. Controlled trial of aspirin in cerebral ischemia. Stroke 1977; 08: 301-14.
• 96 The Canadian Cooperative Study Group. A randomized trial of aspirin and sulfinpyrazone in threatened stroke. The Canadian Cooperative Study Group. N Engl J Med 1978; 299: 53-9.
• 97 The ESPS Group. The European Stroke Prevention Study (ESPS). Principal endpoints. The ESPS Group. Lancet 1987; 02: 1351-4.
• 98 Farrell B, Godwin J, Richards S, Warlow C. The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results. J Neurol Neurosurg Psychiatry 1991; 54: 1044-54.
• 99 Boysen G, Sorensen PS, Juhler M, Andersen AR, Boas J, Olsen JS, Joensen P. Danish very-low-dose aspirin after carotid endarterectomy trial. Stroke 1988; 19: 1211-5.
• 100 Harker LA, Bernstein EF, Dilley RB, Scala TE, Sise MJ, Hye RJ, Otis MJ, Roberts RS, Gent M. Failure of aspirin plus dipyridamole to prevent restenosis after carotid endarterectomy. Ann Intern Med 1992; 116: 731-6.
• 101 Swedish Cooperative Study. High-dose acetylsalicylic acid after cerebral infarction. Stroke 1987; 18: 325-34.
• 102 Sivenius J, Riekkinen PJ, Kilpelainen H, Laakso M, Penttila I. Antiplatelet therapy is effective in the prevention of stroke or death in women: subgroup analysis of the European Stroke Prevention Study (ESPS). Acta Neurol Scand 1991; 84: 286-90.
• 103 Cocozza M, Picano T, Oliviero U, Russo N, Coto V, Milani M. Effects of picotamide, an antithromboxane agent, on carotid atherosclerotic evolution. A two-year, doubleblind, placebo-controlled study in diabetic patients. Stroke 1995; 26: 597-601.
• 104 Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy-III: Reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients. BMJ 1994; 308: 235-46.
• 105 Marcus AJ. Aspirin as an antithrombotic medication. N Engl J Med 1983; 309: 1515-7.
• 106 Powers PJ, Gent M, Jay RM, Julian DH, Turpie AG, Levine M, Hirsh J. A randomized trial of less intense postoperative warfarin or aspirin therapy in the prevention of venous thromboembolism after surgery for fractured hip. Arch Intern Med 1989; 149: 771-4.
• 107 Ettinger WH, Wise RA, Schaffhauser D, Wigley FM. Controlled double-blind trial of dazoxiben and nifedipine in the treatment of Raynaud’s phenomenon. Am J Med 1984; 77: 451-6.
• 108 Balsano F, Violi F. Effect of picotamide on the clinical progression of peripheral vascular disease. A double-blind placebo-controlled study. The ADEP Group. Circulation 1993; 87: 1563-9.
• 109 Milani M, Longoni A, Maderna M. Effects of picotamide, an antiplatelet agent, on cardiovascular, events in 438 claudicant patients with diabetes: a retrospective analysis of the ADEP study. Br J Clin Pharmacol 1996; 42: 782-5.
• 110 Coto V, Cocozza M, Oliviero U, Lucariello A, Picano T, Coto F, Cacciatore L. Clinical efficacy of picotamide in long-term treatment of intermittent claudication. Angiology 1989; 40: 880-5.
• 111 Hass WK, Easton JD, Adams Jr HP, Pryse WPhillips, 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 [see comments]. N Engl J Med 1989; 321: 501-7.
• 112 The EPIC Investigation. Use of a monoclonal antibody directed against the platelet glycoprotein Ilb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 1994; 330: 956-61.
• 113 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: 543-51.
• 114 Helgason CM, Bolin KM, Hoff JA, Winkler SR, Mangat A, Tortorice KL, Brace LD. Development of aspirin resistance in persons with previous ischemic stroke. Stroke 1994; 25: 2331-6.