cardiovascularКардиоваскулярная терапия и профилактикаCardiovascular Therapy and Prevention1728-88002619-0125«SILICEA-POLIGRAF» LLCcardiovascular-1150Research ArticleИШЕМИЧЕСКАЯ БОЛЕЗНЬ СЕРДЦАCORONARY HEART DISEASEЭффективность антиагрегантной терапии клопидогрелом у пациентов, перенесших инфаркт миокарда с подъемом сегмента STClopidogrel effectiveness in patients with ST elevation myocardial infarctionСироткинаО. В.SirotkinaO. V.БогдановаЕ. В.BogdanovaE. V.БоганьковаН. А.Bogan’kovaN. A.СтоляроваА. Н.StolyarovaA. N.

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svetlanaboldueva@mail.ruСанкт-Петербургская Государственная Медицинская Академия им. И.И. Мечникова Росздрава; Петербургский институт ядерной физики им. Б.П. Константинова Российской академии наукI.I. Mechnikov St Petersburg State Medical Academy; B.P. Konstantinov St. Petersburg Institute of Nuclear Physics, Russian Academy of SciencesСанкт-Петербургская Государственная Медицинская Академия им. И.И. Мечникова РосздраваI.I. Mechnikov St Petersburg State Medical AcademyПетербургский институт ядерной физики им. Б.П. Константинова Российской академии наук.B.P. Konstantinov St. Petersburg Institute of Nuclear Physics, Russian Academy of Sciences200920022009815155Copyright © Сироткина О.В., Богданова Е.В., Боганькова Н.А., Столярова А.Н., Вавилова Т.В., Болдуева С.А., 20092009Сироткина О.В., Богданова Е.В., Боганькова Н.А., Столярова А.Н., Вавилова Т.В., Болдуева С.А.Sirotkina O.V., Bogdanova E.V., Bogan’kova N.A., Stolyarova A.N., Mvilova T.V., Boldueva S.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://cardiovascular.elpub.ru/jour/article/view/1150Цель

Цель. Анализ эффективности терапии клопидогрелом (Зилт®) у больных, перенесших инфаркт миокарда (ИМ), в зависимости от генетических вариантов цитохромов Р-450 ЗА и тромбоцитарных рецепторов для аденозиндифосфата (АДФ), фибриногена, коллагена.

Материал и методы

Материал и методы. В исследование были включены 34 пациента, перенесшие ИМ с подъемом сегмента ST (HM↑ST). в качестве контроля эффективности антиагрегантной терапии была измерена АДФ-индуцированная агрегация тромбоцитов фотометрическим методом. Детекция полиморфных вариантов A-293G CYP3A4, G6986A CYP3A5, С18Т и G36T P2Y12, Leu33Pro GPIIIa, С-154Т и Т13254С GPVI, С807Т GPIa проводилась методом полимеразной цепной реакции с последующим рестрикционным анализом с использованием соответствующих эндонуклеаз.

Результаты

Результаты. На фонетерапии средняя степень агрегации снижалась — 23,5±2,5 % 32,9±2,8 %, 40,0±3,1 % и 16,3±2,6 %, 27,0±3,0 %, 35,0±3,4 % во 1-ой и 2-ой точках измерения для 2,5, 5 и 10 мкМ АДФ, соответственно (р<0,04, р<0,1); Носители мутаций G36T P2Y12, С-154Т и Т13254С GPVI, С807Т GPIa и лица с отсутствием протективного аллеля Т18 P2Y12, изначально показывая более высокую степень агрегации, более эффективно ее снижали. Исключение составила мутация Leu33Pro GPIIIa, при которой не уменьшилась степень агрегации тромбоцитов. Была обнаружена более высокая эффективность клопидогрела у лиц с мутацией A-293G CYP3A4, для G6986A CYP3A5 статистически значимые зависимости отсутствовали.

Заключение

Заключение. Клопидогрел снижает агрегацию тромбоцитов у пациентов с HM↑ST, при этом только носительство ТеиЗЗРго GPIIIa уменьшает его эффективность.

Aim

Aim. То analyse the effectiveness of clopidogrel therapy (Zilt®) in patients with myocardial infarction (MI), according to genetic variants of Р-450 ЗА cytochromes, platelet adenosine diphosphate (ADPH) receptors, fibrinogen and collagen.

Material and methods

Material and methods. The study included 34 patients with ST elevation MI (MI-ST). Antiaggregant therapy effectiveness was assessed based on ADPH-induced platelet aggregation (photometric method by Bom). Polymorphisms A-293G CYP3A4, G6986A CYP3A5, C18T and G36T P2Y12, Leu33Pro GPIIIa, C-154T and T13254C GPVI, C807T GPIa were detected by polymerase chain reaction method, with subsequent restriction endonuclease-based analysis.

Results

Results. Clopidogrel therapy was associated with reduced aggregation — 23,5±2,5 %., 32,9±2,8 %, 40,0±3,1% and 16,3±2,6 Щ, 27,0±3,0 %, 35,0±3,4 % at points 1 and 2 for 2,5, 5 and 10 mkM of ADPH, respectively (p<0,04, p<0,l). Individuals with polymorphisms G36T P2Y12, C-154T and T13254C GPVI, C807T GPIa, as well as people with no protective allele T18 P2Y12, demonstrated higher aggregation at baseline and more effective reduction associated with therapy. One exception, Leu33Pro GPIIIa mutation, was observed, linked to no reduction in platelet aggregation. Clopidogrel was more effective in participants with A-293G CYP3A4 mutation, while no clear associations were observed for G6986A CYP3A5.

Conclusion

Conclusion. Clopidogrel effectively reduced platelet aggregation in patients with MI-ST, with one exception — Leu33Pro GPIIIa mutation.

клопидогрелагрегация тромбоцитовгенетические полиморфизмытромбоцитарные рецепторыцитохром Р-450 ЗА4цитохром Р-450 ЗА5clopidogrelplatelet aggregationgenetic polymorphismsplatelet receptorscytochrome P-450 3A4cytochrome P-450 3A5РФФИ № 08-04—00377-а; Программа РАН “Фундаментальные науки — медицине ”ReferencesA randomized, blinded, trail of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 1996; 348: 1329—39.A randomized, blinded, trail of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 1996; 348: 1329—39.The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators (CURE). Effect of clopidogrel in addition to: aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345: 494-502.The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators (CURE). Effect of clopidogrel in addition to: aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345: 494-502.Steinhubl S, Berger P, Maim J, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention. A,randomized controlled trial. JAMA 2002; 288: 2411-20.Steinhubl S, Berger P, Maim J, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention. A,randomized controlled trial. JAMA 2002; 288: 2411-20.Angiolillo D, Femandez-Ortiz A, Bernardo H, et al. High clopidogrel loading dose during coronary stenting: effects of drag response and interindividual variability. Eur Heart J 2004; 25: 1903-10.Angiolillo D, Femandez-Ortiz A, Bernardo H, et al. High clopidogrel loading dose during coronary stenting: effects of drag response and interindividual variability. Eur Heart J 2004; 25: 1903-10.Gurbel P, Bliden K, Hayes K, et al. The relation of dosing to clopidogrel responsiveness and the incidence of high post-treatment platelet aggregation in patients undergoing coronary stenting. JACC 2005; 45: 1392-6.Gurbel P, Bliden K, Hayes K, et al. The relation of dosing to clopidogrel responsiveness and the incidence of high post-treatment platelet aggregation in patients undergoing coronary stenting. JACC 2005; 45: 1392-6.Rocca B, Patrono C, Determination of the interindividual variability in response to antiplatelet drags. JThromb Haemost 2005; 3: 1597-602.Rocca B, Patrono C, Determination of the interindividual variability in response to antiplatelet drags. JThromb Haemost 2005; 3: 1597-602.Jaremo P, Lindahl T, Fransson S, Richter A. Individual variations of platelet inhibition after loading doses of clopidogrel. J Intern Med 2002; 252: 233-8.Jaremo P, Lindahl T, Fransson S, Richter A. Individual variations of platelet inhibition after loading doses of clopidogrel. J Intern Med 2002; 252: 233-8.Gurbel P, Bliden K, Hiatt B, O’Connor C. Clopidogrel for coronary stenting: response variability, drag resistance, and the effect of pretreatment platelet reactivity. Circulation 2003; 107: 2908-13.Gurbel P, Bliden K, Hiatt B, O’Connor C. Clopidogrel for coronary stenting: response variability, drag resistance, and the effect of pretreatment platelet reactivity. Circulation 2003; 107: 2908-13.Savi P, Heilmaim Ё, Nurden P, et al. Clopidogrel: an antitrom-botic drug acting on the ADP-dependent activation pathway of human platelets. Clin Appl Thromb Haemost 1996; 2: 35—42.Savi P, Heilmaim Ё, Nurden P, et al. Clopidogrel: an antitrom-botic drug acting on the ADP-dependent activation pathway of human platelets. Clin Appl Thromb Haemost 1996; 2: 35—42.Schafer A. Genetic and Acquired Determinants of individual variability of response to antiplatelet drugs. Circulation 2003; 108: 910-1.Schafer A. Genetic and Acquired Determinants of individual variability of response to antiplatelet drugs. Circulation 2003; 108: 910-1.Michelson A. Platelet function testing in cardiovascular diseases. Circulation 2004; 110: e489-93.Michelson A. Platelet function testing in cardiovascular diseases. Circulation 2004; 110: e489-93.Fontana P, Reny J. Pharmacogenetics and antiplatelet drugs. Rev Med Interne 2005; 26: 725-32.Fontana P, Reny J. Pharmacogenetics and antiplatelet drugs. Rev Med Interne 2005; 26: 725-32.van Schaik R, de Wildt S, Brosens R, et al. The CYP3A4*3 allele: Is it really rare? Clinical Chemistry 2001; 47: 1104-6.van Schaik R, de Wildt S, Brosens R, et al. The CYP3A4*3 allele: Is it really rare? Clinical Chemistry 2001; 47: 1104-6.Smith S, Heather M, Peters G, et al. Common sequence variations in the P2Y12 and CYP3A5 genes do not explain the variability in the inhibitory effects of clopidogrel therapy. Platelets 2006; 17: 250-8.Smith S, Heather M, Peters G, et al. Common sequence variations in the P2Y12 and CYP3A5 genes do not explain the variability in the inhibitory effects of clopidogrel therapy. Platelets 2006; 17: 250-8.Sirotkina O, Novikova A, Vavilova T. The new single nucleotide polymorphisms of ADP receptor P2Y12 gene affected platelet aggregation and myocardial infarction development were found in Russia. J Thromb Haemost 2005; 3(Suppl 1): P0980.Sirotkina O, Novikova A, Vavilova T. The new single nucleotide polymorphisms of ADP receptor P2Y12 gene affected platelet aggregation and myocardial infarction development were found in Russia. J Thromb Haemost 2005; 3(Suppl 1): P0980.Newman PJ, Derbes RS, Aster RH. The human platelet alloan-tigens, P1A1 and P1A2, are associated with a leucine33/pro-line33 amino acid polymorphism in membrane glycoprotein 111% and are distinguishable by DNA typing. J Clin Invest 1989; 83: 1778-81.Newman PJ, Derbes RS, Aster RH. The human platelet alloan-tigens, P1A1 and P1A2, are associated with a leucine33/pro-line33 amino acid polymorphism in membrane glycoprotein 111% and are distinguishable by DNA typing. J Clin Invest 1989; 83: 1778-81.Best D, Senis Y, Jarvis G, et al. GPVI levels in platelets: relationship to platelet function at high shear. Blood 2003; 102: 2811—8.Best D, Senis Y, Jarvis G, et al. GPVI levels in platelets: relationship to platelet function at high shear. Blood 2003; 102: 2811—8.Croft S, Samani N, Teare M, et al. Novel platelet membrane glycoprotein VI dimorphism is a risk factor for myocardial infarction. Circulation 2001; 104: 1459—63.Croft S, Samani N, Teare M, et al. Novel platelet membrane glycoprotein VI dimorphism is a risk factor for myocardial infarction. Circulation 2001; 104: 1459—63.Di Paola J, Federici A, Mannucci P, et al. Low platelet a2abl levels in type 1 von Willebrand disease correlate with impaired platelet function in a high shear stress system. Blood 1999; 93: 3578-82.Di Paola J, Federici A, Mannucci P, et al. Low platelet a2abl levels in type 1 von Willebrand disease correlate with impaired platelet function in a high shear stress system. Blood 1999; 93: 3578-82.Берковский А.Л., Васильев C.A. 2007. Пособие по изучению адгезивно-агрегационной функции тромбоцитов. Москва, НПО “РЕНАМ”.Берковский А.Л., Васильев C.A. 2007. Пособие по изучению адгезивно-агрегационной функции тромбоцитов. Москва, НПО “РЕНАМ”.Committee for proprietary medicinal products. Note for guidance on investigation of bioavailability and bioequivalence. EMEA 2001.Committee for proprietary medicinal products. Note for guidance on investigation of bioavailability and bioequivalence. EMEA 2001.Jarvis B, Simpson K. Clopidogrel. A review of its use in the prevention of atherothrombosis. Drugs 2000; 60: 347—77.Jarvis B, Simpson K. Clopidogrel. A review of its use in the prevention of atherothrombosis. Drugs 2000; 60: 347—77.Savi P, Herbert J. Clopidogrel and ticlopidine: P2Y12 adenosine diphosphate-receptor antagonists for the prevention of atherothrombosis. Semin Thromb Hemost 2005; 31: 174—83.Savi P, Herbert J. Clopidogrel and ticlopidine: P2Y12 adenosine diphosphate-receptor antagonists for the prevention of atherothrombosis. Semin Thromb Hemost 2005; 31: 174—83.Ivandic B, Schlick P, Staritz P, et al. Determination of clopidogrel resistance by whole blood platelet aggregometry and inhibitors of the P2Y12 receptors. Clinical Chemistry 2006; 52: 383-8.Ivandic B, Schlick P, Staritz P, et al. Determination of clopidogrel resistance by whole blood platelet aggregometry and inhibitors of the P2Y12 receptors. Clinical Chemistry 2006; 52: 383-8.Angiolillo D, Fernandez-Ortiz A, Bernardo Ё, et al. Contribution of gene sequence variations of the hepatic cytochrome P450 3A4 enzyme to variability in individual responsiveness to clopidogrel. Arterioscler thromb Vase Biol 2006; 26: 1895-900.Angiolillo D, Fernandez-Ortiz A, Bernardo Ё, et al. Contribution of gene sequence variations of the hepatic cytochrome P450 3A4 enzyme to variability in individual responsiveness to clopidogrel. Arterioscler thromb Vase Biol 2006; 26: 1895-900.Fontana P, Hulot J, De Moerloose P, Gaussem P. Influence of CYP2C19 and CYP3A4 gene polymorphisms on clopidogrel responsiveness in healthy subjects, J Thromb Haemost 2007; 5: 2153—5.Fontana P, Hulot J, De Moerloose P, Gaussem P. Influence of CYP2C19 and CYP3A4 gene polymorphisms on clopidogrel responsiveness in healthy subjects, J Thromb Haemost 2007; 5: 2153—5.Joutsi-Korhonen L, Smethurst P, Rankin A, et al. The low-frequency allele of the platelet collagen signaling receptor glycoprotein VI is associated with reduced functional responses and expression. Blood 2003; 101: 4372-9.Joutsi-Korhonen L, Smethurst P, Rankin A, et al. The low-frequency allele of the platelet collagen signaling receptor glycoprotein VI is associated with reduced functional responses and expression. Blood 2003; 101: 4372-9.Szczeklik A, Musial J, Undas A, Sanak M. Aspirin resistence. J Thromb Haemost 2005; 3: 1655—62.Szczeklik A, Musial J, Undas A, Sanak M. Aspirin resistence. J Thromb Haemost 2005; 3: 1655—62.Пчелина C.H., Сироткина O.B., Шейдина A.M. и др. Генетические факторы риска развйтнят-шфаркта миокарда у мужчин молодого возраста, проживающих в северо-западном регионе России. Кардиология 2007; 7: 29—34.Пчелина C.H., Сироткина O.B., Шейдина A.M. и др. Генетические факторы риска развйтнят-шфаркта миокарда у мужчин молодого возраста, проживающих в северо-западном регионе России. Кардиология 2007; 7: 29—34.Undas A, Sanak М, Musial J, Szczeklik A. Platalet glicoprotein Ша polymorphism, aspirin and thrombin generation. Lancet 1999;353:982-3.Undas A, Sanak М, Musial J, Szczeklik A. Platalet glicoprotein Ша polymorphism, aspirin and thrombin generation. Lancet 1999;353:982-3.Dropinski J, Musial J, Jakiela B, et al. Anti-thrombotic action Of clopidogrel and РЦА1/А2) polymorphism of beta3 integrin in patients with coronary artery disease not being treated with aspirin. Thromb Haemost 2005; 94: 1300—5.Dropinski J, Musial J, Jakiela B, et al. Anti-thrombotic action Of clopidogrel and РЦА1/А2) polymorphism of beta3 integrin in patients with coronary artery disease not being treated with aspirin. Thromb Haemost 2005; 94: 1300—5.Cooke G, Liu-Stratton Y, Ferketich A, et al. Effect of platelet antigen polymorphism on platelet inhibition by aspirin, clopidogrel, or their combination. JACC 2006; 47: 541-6.Cooke G, Liu-Stratton Y, Ferketich A, et al. Effect of platelet antigen polymorphism on platelet inhibition by aspirin, clopidogrel, or their combination. JACC 2006; 47: 541-6.

The authors declare that there are no conflicts of interest present.