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IMPACT OF CYP3A5, CYP2C9, CYP2C19, AND CYP2D6 POLYMORPHISMS ON PHENAZEPAM SAFETY IN PATIENTS WITH ALCOHOL WITHDRAWAL SYNDROME
- Authors: Ivashchenko D.V.1, Ryzhikova K.A.1, Sozaeva Z.A.1, Pimenova Y.A.1, Grishina E.A.1, Zastrozhin M.S.1,2, Aguzarov A.D.2, Savchenko L.M.1, Bryun E.A.1,2, Sychev D.A.1
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Affiliations:
- Russian Medical Academy of Continuous Professional Education
- Moscow Research Practical Center of Narcology
- Issue: Vol 73, No 3 (2018)
- Pages: 206-214
- Section: PSYCHOLOGY AND PSYCHIATRY: CURRENT ISSUES
- Published: 09.07.2018
- URL: https://vestnikramn.spr-journal.ru/jour/article/view/989
- DOI: https://doi.org/10.15690/vramn989
- ID: 989
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Abstract
Introduction: Phenazepam is the Russian original benzodiazepine tranquilizer. We conducted first pharmacogenetic study on Phenazepam’s safety in patients with alcohol withdrawal syndrome. Isoenzymes CYP3A4, CYP3A5, CYP2C9, and CYP2C19 are involved into benzodiazepine tranquilizers’ metabolism.
Aim: To determine predictive value of CYP3A5, CYP2C9, CYP2C19, and CYP2D6 genetic polymorphisms and their haplotypes for adverse reaction risk associated with the treatment with phenazepam.
Materials and methods: The study enrolled 102 male patients with non-comlicated alcohol withdrawal syndrome (F10.3 by ICD-10) who entered the study group in 24 hours after the admission to hospital and was administered Phenazepam for 6 days. Therapy safety was evaluated with UKU Side Effects Rating Scale on the 6th day of treatment. 5 ml of venous blood was collected from each participant for genotyping to detect CYP3A5*3, CYP2С9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3, CYP2C19*17, and CYP2D6*4 polymorphisms by real-time polymerase chain reaction. Haplotype analysis was performed by SNPStats online-tool. Statistical analysis was made in SPSS Statistics 21.0.
Results: In overall sample (n=102) CYP2C9*3 increased risk of «Increased duration of sleep» (OR 1.46; 95% CI 1.11−1.9; p=0.037) and «Constipation» (OR 13.1; 95% CI 1.44−119.2; p=0.02). The following results in subgroup «Phenazepam’s monotherapy» (n=64) were observed: CYP3A5*3 increased global severity of adverse drug reactions according to patient’s opinion (OR 2.79; 95% CI 1.26−6.22; p=0.031); CYP2C9*3 led to «Increased duration of sleep» (OR 1.57; 95% CI 1.14−2.17; p=0.034). Haplotype CYP3A5*3-CYP2C19*2-CYP2C19*17 (G-G-T) was associated with increased risk of «Concentration difficulties (OR 2.86; 95% CI 0.96−8.50; p=0.061).
Conclusion: The study findings confirmed that CYP2C9*3, CYP3A5*3, and CYP2C19*2 polymorphisms can decrease the phenazepam safety rate in patients with alcohol withdrawal syndrome. The result of haplotype analysis revealed that only CYP3A5*3-CYP2C19*2-CYP2C19*17 (G-G-T) can be used as a significant predictor of adverse reaction to phenazepam.
About the authors
D. V. Ivashchenko
Russian Medical Academy of Continuous Professional Education
Author for correspondence.
Email: dvi1991@yandex.ru
ORCID iD: 0000-0002-2295-7167
Dmitriy V. Ivashchenko – MD.
Moscow
РоссияK. A. Ryzhikova
Russian Medical Academy of Continuous Professional Education
Email: kriistinkaa@mail.ru
ORCID iD: 0000-0003-3505-8520
KristinaA. Ryzhikova.
Moscow
РоссияZh. A. Sozaeva
Russian Medical Academy of Continuous Professional Education
Email: zhannet.sozaeva@gmail.com
ORCID iD: 0000-0001-5166-7903
ZhannetA. Sozaeva.
Moscow
РоссияY. A. Pimenova
Russian Medical Academy of Continuous Professional Education
Email: yulia.pimenova@bk.ru
ORCID iD: 0000-0002-9031-2272
Yulija V. Pimenova.
Moscow
РоссияE. A. Grishina
Russian Medical Academy of Continuous Professional Education
Email: gelana2010@yandex.ru
ORCID iD: 0000-0002-5621-8266
Elena A. Grishina - PhD, Assistant professor.
Moscow
РоссияM. S. Zastrozhin
Russian Medical Academy of Continuous Professional Education; Moscow Research Practical Center of Narcology
Email: rudnmed@yandex.ru
ORCID iD: 0000-0003-0607-4812
Mikhail S. Zastrozhin - MD, PhD.
Moscow
РоссияA. D. Aguzarov
Moscow Research Practical Center of Narcology
Email: aguzarov.ad@yandex.ru
ORCID iD: 0000-0001-7664-998X
Albert D. Aguzarov – MD.
Moscow
РоссияL. M. Savchenko
Russian Medical Academy of Continuous Professional Education
Email: uch_sovet@rmanpo.ru
ORCID iD: 0000-0002-2411-3494
Lyudmila M. Savchenko - MD, PhD, Professor.
Moscow
РоссияE. A. Bryun
Russian Medical Academy of Continuous Professional Education; Moscow Research Practical Center of Narcology
Email: ea.bryun@yandex.ru
ORCID iD: 0000-0002-8366-9732
Eugeniy A. Bryun - MD, PhD, Professor.
Moscow
РоссияD. A. Sychev
Russian Medical Academy of Continuous Professional Education
Email: dmytry.alex.sychev@gmail.com
ORCID iD: 0000-0002-4496-3680
Dmitriy A. Sychev - MD, PhD, Professor.
Moscow
РоссияReferences
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