safetyriskБезопасность и риск фармакотерапииSafety and Risk of Pharmacotherapy2312-78212619-1164Federal State Budgetary Institution ‘Scientific Centre for Expert Evaluation of Medicinal Products’ of the Ministry of Health of the Russian Federation (FSBI ‘SCEEMP’)10.30895/2312-7821-2021-9-1-25-33safetyrisk-206Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESИзучение влияния полиморфных маркеров гена NAT2 на риск развития нежелательных реакций у пациентов с легочными формами туберкулеза, получавших изониазид и рифампицинStudy of the Effect of Polymorphic Markers of the NAT2 Gene on the Risk of Adverse Drug Reactions in Patients with Pulmonary Tuberculosis Who Received Isoniazid and Rifampicinhttps://orcid.org/0000-0003-3194-4410КачановаА. А.KachanovaA. A.

Качанова Анастасия Алексеевна

Баррикадная ул., д. 2/1, стр. 1, Москва, 125993

Anastasia A. Kachanova

2/1/1 Barrikadnaya St., Moscow 125993

aakachanova@yandex.ruhttps://orcid.org/0000-0002-9031-2272ПименоваЮ. А.PimenovaYu. A.

Пименова Юлия Алексеевна

Баррикадная ул., д. 2/1, стр. 1, Москва, 125993

Yulia A. Pimenova

2/1/1 Barrikadnaya St., Moscow 125993

yulia.pimenova@bk.ruhttps://orcid.org/0000-0002-5031-0088ШуевГ. Н.ShuevG. N.

Шуев Григорий Николаевич

Баррикадная ул., д. 2/1, стр. 1, Москва, 125993

Gregory N. Shuev

2/1/1 Barrikadnaya St., Moscow 125993

shuevgrigorii@gmail.comhttps://orcid.org/0000-0003-3505-8520АкмаловаК. А.AkmalovaK. A.

Акмалова Кристина Анатольевна

Баррикадная ул., д. 2/1, стр. 1, Москва, 125993

Kristina A. Akmalova

2/1/1 Barrikadnaya St., Moscow 125993

kriistinkaa@mail.ruhttps://orcid.org/0000-0001-5166-7903СозаеваЖ. А.SozaevaZh. A.

Созаева Жаннет Алимовна

Баррикадная ул., д. 2/1, стр. 1, Москва, 125993

Zhannet A. Sozaeva

2/1/1 Barrikadnaya St., Moscow 125993

zhannet.sozaeva@yandex.ruhttps://orcid.org/0000-0002-4811-7801КрасноваН. М.KrasnovaN. M.

Краснова Наталия Михайловна, кандидат медицинских наук, доцент

Кулаковского ул., д. 42, Якутск, 677000

Natalia M. Krasnova, Cand. Sci. (Med.), Associate Professor

42 Kulakovskogo St., Yakutsk 677000

krasnova14@mail.ruhttps://orcid.org/0000-0002-5621-8266ГришинаЕ. А.GrishinaE. A.

Гришина Елена Анатольевна, доктор биологических наук, доцент

Баррикадная ул., д. 2/1, стр. 1, Москва, 125993

Elena A. Grishina, Dr. Sci. (Biol.), Associate Professor

2/1/1 Barrikadnaya St., Moscow 125993

gelana2010@yandex.ruhttps://orcid.org/0000-0002-4496-3680СычевД. А.SychevD. A.

Сычев Дмитрий Алексеевич , доктор медицинских наук, профессор, член-корреспондент РАН

Баррикадная ул., д. 2/1, стр. 1, Москва, 125993

Dmitry A. Sychev, Dr. Sci. (Med.), Professor, Corr. Member of RAS

2/1/1 Barrikadnaya St., Moscow 125993

dmitry.alex.sychev@gmail.comФедеральное государственное бюджетное образовательное учреждение дополнительного профессионального образования «Российская медицинская академия непрерывного профессионального образования» Министерства здравоохранения Российской ФедерацииРоссияRussian Medical Academy of Continuous Professional EducationRussian FederationМедицинский институт ФГАОУ ВО «Северо-Восточный федеральный университет имени М. К. Аммосова»РоссияM. K. Ammosov North-Eastern Federal UniversityRussian Federation202104022021912533Copyright © Качанова А.А., Пименова Ю.А., Шуев Г.Н., Акмалова К.А., Созаева Ж.А., Краснова Н.М., Гришина Е.А., Сычев Д.А., 20212021Качанова А.А., Пименова Ю.А., Шуев Г.Н., Акмалова К.А., Созаева Ж.А., Краснова Н.М., Гришина Е.А., Сычев Д.А.Kachanova A.A., Pimenova Y.A., Shuev G.N., Akmalova K.A., Sozaeva Z.A., Krasnova N.M., Grishina E.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.risksafety.ru/jour/article/view/206

Туберкулез остается одним из самых опасных и широко распространенных инфекционных заболеваний. Для лечения туберкулеза доступно более двадцати препаратов. При противотуберкулезной терапии одной из наиболее серьезных нежелательных лекарственных реакций (НР) при применении лекарственных препаратов является токсическое поражение печени.

Цель работы

Цель работы: изучить влияние полиморфных маркеров гена NAT2 на риск развития НР у пациентов с легочными формами туберкулеза, получавших изониазид и рифампицин.

Материалы и методы

Материалы и методы: в исследование были включены 67 пациентов c различными формами туберкулеза легких, получающих комбинированную терапию изониазидом и рифампицином. Определение однонуклеотидных полиморфизмов гена NAT2 осуществлялось методом полимеразной цепной реакции в режиме реального времени. Статистическую обработку проводили с использованием программы SPSS Statistics 20.0.

Результаты

Результаты: было выявлено 6 однонуклеотидных полиморфизмов в гене NAT2, на основе которых определены фенотипы по скорости ацетилирования NAT2: 6 человек отнесены к фенотипу «быстрые» ацетиляторы, 24 – к фенотипу «промежуточные» ацетиляторы и 37 – «медленные» ацетиляторы. Проведена оценка связи между фенотипом ацетилятора и развитием НР при приеме изониазида и рифампицина. «Медленные» ацетиляторы характеризовались значимо большим увеличением уровня общего билирубина (р=0,011) по сравнению с «промежуточными» ацетиляторами. Снижение аппетита чаще регистрировалось у «быстрых» ацетиляторов в сравнении с «промежуточными» (р=0,021).

Выводы

Выводы: полученные нами данные свидетельствуют об ассоциации «медленного» типа ацетилирования NAT2 с риском НР при химиотерапии туберкулеза легких с использованием изониазида и рифампицина. Среди зарегистрированных НР у «быстрых» ацетиляторов чаще отмечалось снижение аппетита, однако результаты данного наблюдения требуют расширения выборки и дополнительного изучения. Изучаемые полиморфизмы оказывают влияние на развитие НР при химиотерапии туберкулеза легких изониазидом и рифампицином и, в перспективе, могут быть использованы для прогнозирования профиля безопасности фармакотерапии у данной категории пациентов.

Tuberculosis remains one of the most dangerous and widespread infectious diseases. More than 20 medicinal products are currently available for the treatment of tuberculosis. One of the most serious adverse drug reactions (ADRs) associated with anti-tuberculosis medicines is hepatotoxicity.

The aim of the study was to assess the effect of polymorphic markers of the NAT2 gene on the ADR risk in patients with pulmonary tuberculosis who received isoniazid and rifampicin.

Materials and methods

Materials and methods. The study included 67 patients with different forms of pulmonary tuberculosis who received combination therapy with isoniazid and rifampicin. Single nucleotide polymorphisms (SNPs) of the NAT2 gene were determined by real-time PCR. Statistical processing was performed using SPSS Statistics 20.0.

Results

Results: Six SNPs were identified in the NAT2 gene. Based on these SNPs the following phenotypes were determined by the rate of NAT2 acetylation: fast acetylators—6 subjects, intermediate acetylators—24 subjects, and slow acetylators—37 subjects. The study assessed the relationship between the acetylator phenotype and the development of ADRs during combination therapy with isoniazid and rifampicin. Slow acetylators had a significantly greater increase in total bilirubin level (p=0.011) compared to intermediate acetylators. Loss of appetite was more often observed in fast acetylators than in intermediate acetylators (p=0.021).

Conclusions

Conclusions. The obtained data suggest interrelation between the slow type of NAT2 acetylation and the risk of ADRs in patients undergoing pulmonary tuberculosis chemotherapy with isoniazid and rifampicin. Out of all the ADRs registered in the study, the fast acetylators were more likely to have loss of appetite, however, the expansion of the study population is needed to verify this observation. The studied polymorphisms have an impact on the development of ADRs in patients undergoing pulmonary tuberculosis chemotherapy with isoniazid and rifampicin and may be used to predict the safety profile of pharmacotherapy in this group of patients.

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