M S Zastrozhin1, A V Efimova1, VYu Skryabin1, V V Smirnov1, A E Petukhov1, E P Pankratenko1, S A Pozdniakov1, E V Kaverina1, D A Klepikov1, E A Grishina1, K A Ryzhikova1, I V Bure1, E A Bryun1, D A Sychev1. 1. Zastrozhin, M.D., PhD, Head of Laboratory of Genetics and Fundamental Studies, Associate Professor of Addiction Psychiatry Department, Bryun, M.D., PhD, Professor, President, Head of Addiction Psychiatry Department, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Moscow, Russian Federation; Moscow Research and Practical Centre on Addictions of the Moscow Department of Healthcare, Moscow, Russia. Efimova, M.D., Physician of Clinical Department, Balashikha Regional Hospital. Skryabin, M.D., Head of Clinical Department, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Moscow, Russian Federation. Smirnov, PhD, Associate Professor of Pharmaceutical Toxicology Department, Head of Laboratory of Pharmacokinetics, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation; NRC Institute of Immunology FMBA of Russia, Moscow, Russian Federation. Petukhov, M.D., PhD, Clinical Laboratory Diagnostician of the Analytical Toxicology lab of the Reference Center for Psychoactive Substances use Monitoring, Associate Professor of Pharmaceutical and Toxicological Chemistry, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Moscow, Russian Federation; I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation. Pankratenko, Paramedic-Laboratory Assistant of the Analytical Toxicology Lab of the Reference Center for Psychoactive Substances use Monitoring, Pozdniakov, Researcher of the Laboratory of Genetics and Fundamental Studies, M.D., the Researcher of the Department of Dermatovenerology and Cosmetology, M.D., PhD, Associate Professor of Addiction Psychiatry Department, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Moscow, Russian Federation. Kaverina, M.D., PhD, Associate Professor of the Department of Public Health, Healthcare and Hygiene, Peoples Friendship University of Russia, Moscow, Russian Federation, Peoples Friendship University of Russia. Klepikov, M.D., Assistant Professor of Clinical Pharmacology, Kazakh National Medical University, Almaty, Kazakhstan. Grishina, PhD, Head of Biomolecular Researchers Department of the Research Center, Ryzhikova, Research Fellow of the Biomolecular Researchers Department of the Research Center, Bure, PhD, Research Fellow of the Biomolecular Researchers Department of the Research Center, Sychev, Corresponding Member of the Academy of Sciences of Russia, M.D., PhD, Professor, Rector, Head of Clinical Pharmacology and Therapy Department, Moscow Research and Practical Centre on Addictions of the Moscow Department of Healthcare, Moscow, Russia.
Abstract
Introduction: Phenazepam is commonly administered to patients diagnosed with major depressive disorder. Some proportion of such patients do not show adequate response to treatment regimen containing phenazepam, whereas many of them experience type A adverse drug reactions. Previous studies showed that CYP2D6 IS involved in the biotransformation of phenazepam, the activity of which is highly dependent on the polymorphism of the gene encoding it. Objective. The objective of the study was to evaluate the impact of 1846G>A polymorphism of the CYP2D6 gene on the concentration/dose indicator of phenazepam, using findings on enzymatic activity of CYP2D6 (as evaluated by the 6M-THBC/pinoline ratio measurement) and on CYP2D6 expression level obtained by measuring the hsa-miR-370-3p plasma concentration levels in patients suffering from major depressive disorder. Material and methods: The study enrolled 191 patients with recurrent depressive disorder (age -40.0 ± 16.3 years). Treatment regimen included phenazepam in an average daily dose of 6.0 ± 2.3 mg per day. Treatment efficacy was assessed using the validated psychometric scales. Therapy safety was assessed using the UKU Side-Effect Rating Scale. For genotyping and estimation of the microRNA (miRNA) plasma levels we performed the real-time polymerase chain reaction (PCR Real-time). The activity of CYP2D6 was evaluated using the HPLC-MS/MS method by the content of the endogenous substrate of given isoenzyme and its metabolite in urine (6M-THBC/pinoline). Therapeutic drug monitoring has been performed using HPLC-MS/MS. Results: Our findings didn't reveal the statistically significant results in terms of the treatment efficacy evaluation (HAMA scores at the end of the treatment course): (GG) 6.0 [4.0; 8.0] and (GA) 6.0 [5.0; 7.8], p > 0.999; the statistical significance in the safety profile was not obtained (the UKU scores): (GG) 3.0 [2.0; 4.0] and (GA) 3.0 [3.0; 3.0], p > 0.999. We didn't reveal a statistical significance for concentration/dose indicator of phenazepam in patients with different genotypes: (GG) 0.812 [0.558; 1.348] and (GA) 0.931 [0.630; 1.271], p = 0.645). Analysis of the results of the pharmacotranscriptomic part of the study didn't show the statistically significant difference in the hsa-miR-370-3p plasma levels in patients with different genotypes: (GG) 22.5 [16.9; 29.8], (GA) 22.7 [15.7; 31.5], p = 0.695. At the same time, correlation analysis didn't reveal a statistically significant relationship between the phenazepam efficacy profile evaluated by changes in HAMA scale scores and the hsa-miR-370-3p plasma concentration: rs = -0.01, p = 0.866. Also, we didn't reveal the correlation between the miRNA concentration and safety profile: rs = 0.07, p = 0.348. Also we did not reveal the relationship between the CYP2D6 enzymatic activity (as evaluated by 6M-THBC/pinoline ratio measurement) and the hsa-miR-370-3p plasma concentration: rs = -0.14, p = 0.056. At the same time, correlation analysis did not reveal a statistically significant relationship between the phenazepam concentration and the hsa-miR-370-3p plasma concentration: rs = -0.05, p = 0.468. Conclusion: The effect of genetic polymorphism of the CYP2D6 gene on the efficacy and safety profiles of phenazepam was not demonstrated in a group of 191 patients with recurrent depressive disorder. At the same time, hsa-miR-370-3p does not remain a promising biomarker for assessing the level of CYP2D6 expression, because it does not correlate with encoded isoenzyme activity.
Introduction: Phenazepam is commonly administered to patients diagnosed with major depressive disorder. Some proportion of such patients do not show adequate response to treatment regimen containing phenazepam, whereas many of them experience type A adverse drug reactions. Previous studies showed that CYP2D6 IS involved in the biotransformation of phenazepam, the activity of which is highly dependent on the polymorphism of the gene encoding it. Objective. The objective of the study was to evaluate the impact of 1846G>A polymorphism of the CYP2D6 gene on the concentration/dose indicator of phenazepam, using findings on enzymatic activity of CYP2D6 (as evaluated by the 6M-THBC/pinoline ratio measurement) and on CYP2D6 expression level obtained by measuring the hsa-miR-370-3p plasma concentration levels in patients suffering from major depressive disorder. Material and methods: The study enrolled 191 patients with recurrent depressive disorder (age -40.0 ± 16.3 years). Treatment regimen included phenazepam in an average daily dose of 6.0 ± 2.3 mg per day. Treatment efficacy was assessed using the validated psychometric scales. Therapy safety was assessed using the UKU Side-Effect Rating Scale. For genotyping and estimation of the microRNA (miRNA) plasma levels we performed the real-time polymerase chain reaction (PCR Real-time). The activity of CYP2D6 was evaluated using the HPLC-MS/MS method by the content of the endogenous substrate of given isoenzyme and its metabolite in urine (6M-THBC/pinoline). Therapeutic drug monitoring has been performed using HPLC-MS/MS. Results: Our findings didn't reveal the statistically significant results in terms of the treatment efficacy evaluation (HAMA scores at the end of the treatment course): (GG) 6.0 [4.0; 8.0] and (GA) 6.0 [5.0; 7.8], p > 0.999; the statistical significance in the safety profile was not obtained (the UKU scores): (GG) 3.0 [2.0; 4.0] and (GA) 3.0 [3.0; 3.0], p > 0.999. We didn't reveal a statistical significance for concentration/dose indicator of phenazepam in patients with different genotypes: (GG) 0.812 [0.558; 1.348] and (GA) 0.931 [0.630; 1.271], p = 0.645). Analysis of the results of the pharmacotranscriptomic part of the study didn't show the statistically significant difference in the hsa-miR-370-3p plasma levels in patients with different genotypes: (GG) 22.5 [16.9; 29.8], (GA) 22.7 [15.7; 31.5], p = 0.695. At the same time, correlation analysis didn't reveal a statistically significant relationship between the phenazepam efficacy profile evaluated by changes in HAMA scale scores and the hsa-miR-370-3p plasma concentration: rs = -0.01, p = 0.866. Also, we didn't reveal the correlation between the miRNA concentration and safety profile: rs = 0.07, p = 0.348. Also we did not reveal the relationship between the CYP2D6 enzymatic activity (as evaluated by 6M-THBC/pinoline ratio measurement) and the hsa-miR-370-3p plasma concentration: rs = -0.14, p = 0.056. At the same time, correlation analysis did not reveal a statistically significant relationship between the phenazepam concentration and the hsa-miR-370-3p plasma concentration: rs = -0.05, p = 0.468. Conclusion: The effect of genetic polymorphism of the CYP2D6 gene on the efficacy and safety profiles of phenazepam was not demonstrated in a group of 191 patients with recurrent depressive disorder. At the same time, hsa-miR-370-3p does not remain a promising biomarker for assessing the level of CYP2D6 expression, because it does not correlate with encoded isoenzyme activity.
Authors: M S Zastrozhin; V Y Skryabin; V V Smirnov; E A Grishina; K A Ryzhikova; E M Chumakov; E A Bryun; D A Sychev Journal: Can J Physiol Pharmacol Date: 2019-05-17 Impact factor: 2.273
Authors: Michael S Zastrozhin; Anastasiya P Antonenko; Elena V Nesterenko; Leyla I Seyfullaeva; Violetta R Mustafina; Antonina P Esakova; Elena A Grishina; Alexandr S Sorokin; Valentin Yu Skryabin; Ludmila M Savchenko; Evgeny A Bryun; Dmitry A Sychev Journal: Drug Metab Pers Ther Date: 2018-12-19
Authors: Carmen Gimeno; Marisa Luisa Dorado; Carlos Roncero; Nestor Szerman; Pablo Vega; Vicent Balanzá-Martínez; F Javier Alvarez Journal: Front Psychiatry Date: 2017-09-22 Impact factor: 4.157