Pharmacogenetic evaluation of adverse events’ risk in patients with alcohol withdrawal syndrome taking bromdihydrochlorphenylbenzodiazepine: The role of CYP2C19 gene polymorphisms

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Abstract


Introduction. Bromdihydrochlorphenylbenzodiazepine is the Russian original tranquilizer which widely using in psychiatry, narcology, neurology and general medicine. Particularly, that drug prescribing for patients with alcohol withdrawal syndrome (AWS). Isoenzyme CYP2C19 takes part in metabolism of the most of benzodiazepines, so the gene CYP2C19 might be included into pharmacogenetics study of bromdihydrochlorphenylbenzodiazepine. There was no study of CYP2C19 polymorphisms as biomarkers of bromdihydrochlorphenylbenzodiazepine’s safety.

Methods. 102 male patients with non-comlicated AWS (F 10.3 by ICD-10) were involved into the study. During 6 days of dynamic observation each participant was prescribed bromdihydrochlorphenylbenzodiazepine (Phenazepam). 5 ml of venous blood was collected from each participant for genotyping. 38 participants were added Pagluferal (contains phenobarbitalum, natrium coffeine-benzoate, bromisoval, papaverine) and/or Carbamazepine. Blood samples were analyzed to detect the CYP2C19*2 (rs4244285), *3 (rs4986893) и *17 (rs12248560) polymorphisms. Safety of therapy was evaluated with UKU Side Effects Rating Scale. Data analysis was performed with SPSS Statistics 21.0.

Results. Carriers of CYP2C19*2 GA+AA genotypes compared to GG homozygous significantly more often had such adverse effects as «Polyuria/polydipsia» in mean grade of penetration (33,3% vs 9%, p=0,016) and “Palpitations/Tachycardia” (16,7% vs 3,8%, p=0,018). Observed relationship between «Polyuria/polydipsia» and CYP2C19*2 GA+AA genotypes was confirmed in the subgroup “Combined pharmacotherapy” (37,5% vs 0%, p=0,006). CYP2C19*17 polymorphism in tendency to significance was associated with less frequent AE «Polyuria/polydipsia» among patients taking bromdihydrochlorphenylbenzodiazepine as monotherapy carriers of allele T had that AE in 16,9%, and CC homozygous in 24,2% (p=0,067).

Conclusion. Significant associations between CYP2C19*2 polymorphism and several AE in patients with alcohol withdrawal syndrome taking bromdihydrochlorphenylbenzodiazepine. Substantial role of CYP2C19*17 as predictor of AE associated with bromdihydrochlorphenylbenzodiazepine was not confirmed. Gene CYP2C19 is the sufficient biomarker of bromdihydrochlorphenylbenzodiazepine’s safety profile and needs further research.


Dmitriy V. Ivashchenko

Russian Medical Academy of Continuous Professional Education

Author for correspondence.
Email: dvi1991@yandex.ru
ORCID iD: 0000-0002-2295-7167
SPIN-code: 9435-7794

Russian Federation, 2/1, Barrikadnaya st., Moscow, 125993, Russia

MD

Kristina A. Ryzhykova

Russian Medical Academy of Continuous Professional Education

Email: kriistinkaa@mail.ru
ORCID iD: 0000-0003-3505-8520
SPIN-code: 2604-1922

Russian Federation, 2/1, Barrikadnaya st., Moscow, 125993, Russia

Zhannet A. Sozaeva

Russian Medical Academy of Continuous Professional Education

Email: zhannet.sozaeva@gmail.com
ORCID iD: 0000-0001-5166-7903
SPIN-code: 4138-4466

Russian Federation, 2/1, Barrikadnaya st., Moscow, 125993, Russia

Mikhail 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
SPIN-code: 5681-4767

Russian Federation, 2/1, Barrikadnaya st., Moscow, 125993, Russia; 37/1, Ljublinskaya street, Moscow, 109390

MD, PhD

Elena A. Grishina

Russian Medical Academy of Continuous Professional Education

Email: gelana@mail.ru
ORCID iD: 0000-0002-5621-8266
SPIN-code: 3357-3591

Russian Federation, 2/1, Barrikadnaya st., Moscow, 125993, Russia

Lyudmila M. Savchenko

Russian Medical Academy of Continuous Professional Education

Email: uchsovet@mail.ru
SPIN-code: 6638-6651

Russian Federation, 2/1, Barrikadnaya st., Moscow, 125993, Russia

MD, PhD

Eugeniy A. Bryun

Russian Medical Academy of Continuous Professional Education; Moscow Research Practical Center of Narcology

Email: eugeniy.bryun@yandex.ru

Russian Federation, 2/1, Barrikadnaya st., Moscow, 125993, Russia; 37/1, Ljublinskaya street, Moscow, 109390

MD, PhD, Professor

Dmitriy A. Sychev

Russian Medical Academy of Continuous Professional Education

Email: dimasychev@mail.ru
ORCID iD: 0000-0002-4496-3680
SPIN-code: 4525-7556

Russian Federation, 2/1, Barrikadnaya st., Moscow, 125993, Russia

MD, PhD, Professor

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Copyright (c) 2017 Ivashchenko D.V., Ryzhykova K.A., Sozaeva Z.A., Zastrozhin M.S., Grishina E.A., Savchenko L.M., Bryun E.A., Sychev D.A.

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