pmedpharmФармация и фармакологияPharmacy & Pharmacology2307-92662413-2241Pyatigorsk Medical and Pharmaceutical Institute - branch of Volgograd State Medical Univer10.19163/2307-9266-2020-8-6-392-404pmedpharm-768Research ArticleОБЗОРЫ, ЛЕКЦИИREVIEWS, LECTURESФАРМАКОГЕНЕТИЧЕСКИЕ ОСНОВЫ ИНДИВИДУАЛЬНОЙ ЧУВСТВИТЕЛЬНОСТИ И ПЕРСОНАЛИЗИРОВАННОГО НАЗНАЧЕНИЯ АНТИАГРЕГАНТНОЙ ТЕРАПИИ В РАЗЛИЧНЫХ ЭТНИЧЕСКИХ ГРУППАХPHARMACOGENETIC BASES OF INDIVIDUAL SENSITIVITY AND PERSONALIZED ADMINISTRATION OF ANTIPLATELET THERAPY IN DIFFERENT ETHNIC GROUPShttps://orcid.org/0000-0003-3278-2556КантемироваБ. И.KantemirovaB. I.

доктор медицинских наук, доцент, профессор кафедры фармакологии ФГБОУ ВО «Астраханский государственный медицинский университет» Минздрава России

Doctor of Sciences (Medicine), Associate Professor, Professor of the Department of Pharmacology of Astrakhan State Medical University

belakantemirova@rambler.ruhttps://orcid.org/0000-0002-9126-1171ОрловаЕ. А.OrlovaE. A.

кандидат медицинских наук, доцент, заведующая кафедрой фармакологии ФГБОУ ВО «Астраханский государственный медицинский университет» Минздрава России

Candidate of Sciences (Medicine), Associate Professor, the Head of the Department of Pharmacology of Astrakhan State Medical University

eorlova56@mail.ruhttps://orcid.org/0000-0001-8299-6582ПолунинаО. С.PoluninaO. S.

доктор медицинских наук, профессор, заведующая кафедрой внутренних болезней педиатрического факультета ФГБОУ ВО «Астраханский государственный медицинский университет» Минздрава России

Doctor of Sciences (Medicine), Professor, Head of the Department of Internal Diseases of the Pediatric Faculty of Astrakhan State Medical University

admed@yandex.ruhttps://orcid.org/0000-0001-8884-1178ЧернышеваЕ. Н.ChernyshevaE. N.

доктор медицинских наук, доцент, заведующая кафедрой кардиологии факультета последипломной подготовки 

Doctor of Sciences (Medicine), Associate Professor, Head of the Department of Cardiology of the Faculty of Postgraduate Training of Astrakhan State Medical University

lena.chernysheva@inbox.ruhttps://orcid.org/0000-0001-7374-2660АбдуллаевМ. А.AbdullaevM. A.

аспирант кафедры фармакологии ФГБОУ ВО «Астраханский государственный медицинский университет» Минздрава России

postgraduate student of the Department of Pharmacology of Astrakhan State Medical University

abdullaev-musalitdin@mail.ruhttps://orcid.org/0000-0002-5195-4301СычевД. А.SychevD. A.

доктор медицинских наук, профессор, ректор ФГБОУ ВО ДПО «Российская медицинская академии непрерывного профессионального образования» Минздрава России; заведующий кафедрой клинической фармакологии и терапии; член-корреспондент РАН

Doctor of Sciences (Medicine), Professor, Rector of Russian Medical Academy of Continuing Professional Education; Head of the Department of Clinical Pharmacology and Therapy; Corresponding Member of the Russian Academy of Sciences

dimasychev@mail.ruФедеральное государственное бюджетное образовательное учреждение высшего образования «Астраханский государственный медицинский университет» Министерства здравоохранения Российской ФедерацииРоссияAstrakhan State Medical UniversityRussian FederationФедеральное государственное бюджетное образовательное учреждение дополнительного профессионального образования «Российская медицинская академия непрерывного профессионального образования» Министерства здравоохранения Российской ФедерацииРоссияRussian Medical Academy of Continuing Professional Education (RMA CPE)Russian Federation20201705202186392404Copyright © Кантемирова Б.И., Орлова Е.А., Полунина О.С., Чернышева Е.Н., Абдуллаев М.А., Сычев Д.А., 20212021Кантемирова Б.И., Орлова Е.А., Полунина О.С., Чернышева Е.Н., Абдуллаев М.А., Сычев Д.А.Kantemirova B.I., Orlova E.A., Polunina O.S., Chernysheva E.N., Abdullaev M.A., Sychev D.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.pharmpharm.ru/jour/article/view/768

Сердечно-сосудистые заболевания (ССЗ) являются ведущей причиной инвалидности и смертности населения во всем мире. Повышенное тромбообразование является пусковым моментом развития различных ССЗ и их осложнений, в связи с чем, терапия ингибиторами P2Y12-рецепторов всегда является патогенетически обоснованной и жизненно необходимой. Однако, по разным данным, у 10-25% пациентов, получающих клопидогрел, отмечается «резистентность» к антиагрегантной терапии. Причины формирования резистентности до сих пор не ясны. Общепризнанной, стандартной методики определения резистентности к антиагрегантам не существует. Кроме того, нет методологических подходов по выявлению пациентов с невосприимчивостью к антиагрегационным препаратам и стандартизированных схем коррекции низкой чувствительности к ним.

Цель

Цель. Целью написания данного обзора было резюмировать имеющиеся результаты зарубежных и отечественных исследований, посвященных изучению вопросов эффективности и безопасности назначения антитромбоцитарных препаратов с позиции генетической предрасположенности к изменению их метаболизма.

Материалы и методы

Материалы и методы. Для обзора использовали сведения научной литературы из открытых и доступных источников за период 1996–2020 гг., размещенных в электронных базах данных: pharmgkb.org; PubMed; Scopus; Web of Science Core Collection; Elibrary. Поисковые запросы – «генетические особенности+антиагрегационная терапия+этнические группы», «CYP2C19+клопидогрел+эффективность антитромбоцитарной терапии»; «ретромбоз стента+полиморфизм CYP2C19+ остаточная реактивность тромбоцитов» и «полиморфизм CYP2C19+этнические группы+резистентность к клопидогрелу» как в русском, так и английском эквиваленте.

Результаты

Результаты. Проблема формирования резистентности к антиагрегационным препаратам в настоящее время изучена недостаточно. Наиболее проработанным вопросом является изучение влияния носительства полиморфных аллелей гена CYP2C19 на остаточную реактивность тромбоцитов, у пациентов получающих двойную антиагрегационную терапию, включающую клопидогрел. Анализ открытых литературных источников, в целом, свидетельствует о наличии статистически значимой ассоциативной связи между носительством медленных аллелей гена CYP2C19 и остаточной реактивностью тромбоцитов, клинически проявляющуюся тромбозом и неблагоприятными сердечно-сосудистыми событиями. Частота встречаемости полиморфного носительства гена CYP2C19 варьирует в разных этнических группах, поэтому не может быть экстраполирована на отдельные субъекты, отличающиеся этническим разнообразием.

Заключение

Заключение. Для разработки превентивных и предиктивных мер по преодолению резистентности к антиагрегантам, а также методологических подходов к персонализированному назначению препаратов этой группы, требуются дальнейшие исследования, с расширением поиска причин и изучением участия других генов системы цитохрома Р450.

Cardiovascular diseases (CVDs) are the leading cause of disability and mortality worldwide. Increased thrombosis is the trigger point for the development of various CVDs and their complications, and therefore, therapy with P2Y12-receptor inhibitors is always pathogenetically justified and vital. However, according to the various data, 10-25% of patients treated with clopidogrel have “resistance” to antiplatelet therapy. The causes for the formation of resistance are still not clear. There is no generally accepted, standard methodology for determining resistance to antiplatelet agents. In addition, there are no methodological approaches to identify the patients with resistance to antiplatelet drugs, and standardized schemes for correcting a low sensitivity to these drugs.

The aim of this review was to summarize the available results of foreign and domestic studies devoted to the investigation of the effectiveness and safety problems of antiplatelet drugs administration from the point of view of the genetic predisposition to changes in their metabolism.

Materials and methods

Materials and methods. For the review, the following information from scientific literature represented in open and accessible sources for the period of 1996-2020, was used: pharmgkb.org, PubMed, Scopus, Web of Science Core Collection, Elibrary. Search queries – “Genetic features+antiplatelet therapy+ethnic groups”, “CYP2C19+clopidogrel+antiplatelet therapy effectiveness”; “Stent retrombosis+CYP2C19 polymorphism+ residual platelet reactivity” and “CYP2C19 polymorphism+ethnic groups+clopidogrel resistance” in both Russian and English equivalents. All these data are placed in electronic databases.

Results

Results. Currently, the problem of the resistance formation to antiplatelet drugs is studied insufficiently. The best thought-out issue is the research of the effect of the polymorphic alleles carriage of the CYP2C19 gene on the residual platelet reactivity in the patients administrated with dual antiplatelet treatment, including clopidogrel. In general, the analysis of open literature sources indicates the presence of a statistically significant association between the carrier of slow alleles of the CYP2C19 gene and the residual platelet reactivity, clinically manifested by thrombosis and adverse cardiovascular events. The occurrence frequency of polymorphic carriage of the CYP2C19 gene varies in different ethnic groups, so it cannot be extrapolated to individual subjects, peculiar in the ethnic diversity.

Conclusion

Conclusion. To develop preventive and predictive measures aimed at overcoming resistance to antiplatelet agents, as well as working out methodological approaches to personalized prescribtion of this group drugs, a further investigation with the expansion of the search for causes and the study of the other genes participation of the cytochrome P450 system, is required.

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