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Согласно национальным и международным клиническим рекомендациям, наиболее эффективными препаратами контролирующей терапии бронхиальной астмы (БА) являются ингаляционные глюкокортикостероиды (ИГКС). Однако терапия ИГКС не всегда способствует полному контролю симптомов БА. Помимо внешних факторов, включающих низкую приверженность медицинским рекомендациям, ошибки в технике ингаляции, коморбидные состояния, а иногда и неправильную диагностику заболевания, в последнее время большое внимание уделяется фармакогенетическим механизмам снижения эффективности терапии БА. В статье представлены обзорные данные по фармакогенетическим особенностям снижения эффективности ИГКС в терапии БАAccording to national and international clinical guidelines, inhaled glucocorticosteroids (IGCS) are the most effective drugs in bronchial asthma (BA) therapy. However, IGCS do not always contribute to the full asthma control. In addition to external factors, including low adherence to medical recommendations, errors in the inhalation technique, comorbid conditions, lack of control over the effectiveness of therapeutic measures, and sometimes incorrect diagnosis, recently, much attention has been paid to pharmacogenetic mechanisms in reducing the effectiveness of asthma therapy. The article presents overview data on the pharmacogenetic features of reducing the effectiveness of inhaled corticosteroids in bronchial asthma therapy.

The search for factors affecting the efficacy of bronchial asthma (BA) therapy in children is an actual problem. subject of many modern scientific studies. Authors note that adherence to therapy in patients with asthma ranges from 30 to 70%. Often this index does not exceed 50%. Analysis of adherence to medical recommendations in children with asthma and the search for compliance reduction factors is one of the ways for optimizing therapy and improving the quality of life for children with asthma.Purpose. In order to optimize bronchial asthma therapy in pediatric practice, we analysed adherence to medical recommendations and its effect on the controllability of the disease in children with asthma.Materials and methods. The study included 94 children aged 6 to 17 years with an established diagnosis of bronchial asthma. All patients had previously been recommended basic therapy in the form of inhaled glucocorticosteroids (ICS) or their fixed combinations with long-acting beta2-adrenomimetikami (LABA). An assessment of BA control symptoms was carried out, and factors affecting adherence to medical recommendations were analyzed. The effect of decreased patient compliance on the control of asthma symptoms was evaluated.Results. 61.7% of children with asthma have insufficient disease control. In 42.55% of patients, a survey revealed insufficient adherence to medical recommendations. 88.3% of children and their parents reported the presence of factors capable of influencing the decrease in compliance. The most frequently occurring factor in reducing adherence to therapy turned out to be insufficient patient awareness of the disease itself, the mechanisms of therapy action, and the prospect of treatment. Statistical data processing showed a statistically significant decrease in adherence to medical recommendations in the group of patients with insufficient asthma symptom control (p = 0.038).Conclusion. Only 38.3% of children had complete asthma symptom control. The statistically significant reduction in adherence to medical recommendations in the group of children with insufficient symptom control suggests the need for educational activities for children with BA and their parents in order to increase adherence to medical recommendations, optimize the effectiveness of therapy and improve the quality of patients’ life.

Inhaled glucocorticosteroids are the main drugs used to control bronchial asthma in children. P450-cytochrome of 3A (CYP3A) family is involved in their metabolism. CYP3A5-isoenzyme plays the leading role in the respiratory tract. We described 6986A>G polymorphism in the CYP3A5 gene encoding this isoenzyme.Aim of the study. To evaluate the association of CYP3A5 (6986A> G) gene polymorphism with the effectiveness of drugs in children with bronchial asthma.Materials and methods. We examined 108 children from 6 to 17 years with bronchial asthma. The allergist carried out the dynamic outpatient polyclinic follow-up of patients, assessed the symptoms of the disease and corrected the corresponding basic therapy. All children underwent genotyping for the 6986A> G polymorphic marker of the CYP3A5 gene.Results. Ten (9.26%) children were heterozygous for the 6986A> G polymorphic marker of the CYP3A5 gene (AG genotype). The authors obtained statistically significant differences in the frequency of the AG genotype between the patients receiving control therapy for bronchial asthma of the 1st – 2nd stage and the patients with control therapy of the 3rd and higher stages in accordance with GINA criteria (p=0.031). In the group with severe bronchial asthma, the number of heterozygotes for the 6986A> G polymorphic marker of the CYP3A5 gene was significantly higher than among children with a mild course of the disease (p=0.029).Conclusion. The AG genotype and A-allele (CYP3A5 gene, A6986A> G polymorphism) are associated with the need for greater volume of control therapy for bronchial asthma and they are risk factors of a more severe course of the disease.

According to national and international clinical guidelines, inhaled glucocorticosteroids (IGCS) are the most effective drugs in bronchial asthma (BA) therapy. However, IGCS do not always contribute to the full asthma control. In addition to external factors, including low adherence to medical recommendations, errors in the inhalation technique, comorbid conditions, lack of control over the effectiveness of therapeutic measures, and sometimes incorrect diagnosis, recently, much attention has been paid to pharmacogenetic mechanisms in reducing the effectiveness of asthma therapy. The article presents overview data on the pharmacogenetic features of reducing the effectiveness of inhaled corticosteroids in bronchial asthma therapy.

INTRODUCTION: Mirtazapine is commonly administered to patients with recurrent depressive disorder. Some of these patients do not show adequate response to the therapy with mirtazapine, whereas many of them experience dose-dependent adverse drug reactions. Previous research revealed that CYP2D6 is involved in the metabolism of mirtazapine, the activity of which is highly dependent on the polymorphism of the gene encoding it. OBJECTIVE: The objective of this study was to investigate the effect of polymorphisms of the CYP3A4, CYP2C9, CYP3A5, ABCB1, CYP2C19, SCL6A4, and 5-HTR2A genes on the concentration/dose indicator of mirtazapine and on the CYP3A expression level obtained by measuring the miR-27b plasma concentration levels in patients suffering from a recurrent depressive disorder. MATERIAL AND METHODS: Our study included 108 patients with recurrent depressive disorder (average age – 35.2 ± 15.1 years). The treatment regimen included mirtazapine in an average daily dose of 45.0 [30.0; 60.0] mg per week. Therapy efficacy was assessed using the international 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. The activity of CYP3A was evaluated using the HPLC-MS/MS method by the content of the endogenous substrate of the given isoenzyme and its metabolite in urine (6b-HC/cortisol). Therapeutic drug monitoring has been performed using HPLC-MS/MS. RESULTS: Our study didn’t reveal any statistically significant results in terms of the treatment efficacy and safety of the therapy. We also didn’t reveal a statistical significance for the concentration/dose indicator of mirtazapine in patients with different genotypes. Analysis of the results of the pharmacotranscriptomic part of the study didn’t demonstrate the statistically significant difference in the miR-27b plasma levels in patients with different genotypes. At the same time, correlation analysis didn’t reveal a statistically significant relationship between the mirtazapine efficacy profile evaluated by changes in HAMD scale scores and the miR-27b plasma concentration: rs = −0.2, p = 0.46. Also, we didn’t reveal the correlation between the miRNA concentration and safety profile: rs = 0.029, p = 0.93. In addition, we didn’t reveal the relationship between the CYP3A enzymatic activity and the miR-27b plasma concentration: rs = −0,188, p = 0.85. However, the difference in the CYP3A enzymatic activity in carriers of AG and GG genotypes of the 6986A > G polymorphism of CYP3A5 gene has been revealed: (AG) 4.75 [1.28; 7.34] vs (GG) 8.83 [4.73; 13.62], p-value = 0.023. CONCLUSION: Thus, the effect of genetic polymorphism of the CYP3A4, CYP2C9, CYP2C9, CYP3A5, ABCB1, CYP2C19, CYP2C19, CYP2C19, SCL6A4, 5-HTR2A gene on the efficacy and safety profiles of mirtazapine was not demonstrated in a group of 108 patients with depressive disorder and alcohol use disorder.

Citalopram is commonly prescribed to patients suffering from major depressive disorder. Some of them do not respond adequately to therapy with citalopram, while many of them experience type A adverse drug reactions. Current research revealed that CYP2C19 isoenzyme is involved in the biotransformation of citalopram. The objective of our study was to investigate the impact of 681GA polymorphism of the CYP2C19 gene on the efficacy, safety and the concentration/dose indicator of citalopram. Our study enrolled 130 patients with major depressive disorder and comorbid alcohol use disorder (average age-38.7 ± 14.1 years). Therapy regimen included citalopram in an average daily dose of 31.1 ± 14.4 mg per week. Therapy efficacy and safety were evaluated using the international psychometric scales. For genotyping, we performed the real-time polymerase chain reaction. Our findings revealed the statistically significant results in terms of the treatment efficacy evaluation (HAMD scores at the end of the treatment course): (GG) 8.0 [8.0; 9.0] and (GA) 10.0 [9.0; 11.0], p 0.001. In the safety profile (the UKU scores), the statistical significance was also obtained: (GG) 3.0 [3.0; 4.0] and (GA) 5.0 [4.0; 5.0], p 0.001. We revealed a statistical significance for concentration/dose indicator of citalopram in patients with different genotypes: (GG) 2.543 [1.659; 4.239] and (GA) 4.196 [2.643; 5.753], p 0.001). The effect of CYP2C19 genetic polymorphism on the efficacy and safety profiles of citalopram was demonstrated in a group of 130 patients with major depressive disorder.

Alprazolam is used in the treatment of patients with anxiety disorders comorbid with alcohol use disorder. Some proportion of these patients does not respond adequately to treatment with alprazolam, while many of them experience dose-dependent adverse drug reactions. Results of the previous studies have shown that CYP3A is involved in the biotransformation of alprazolam, the activity of which is dependent, inter alia, on the polymorphism of the encoding gene. Objective The objective of our study was to investigate the effect of 99366316G>A polymorphism of the CYP3A4 gene on the concentration/dose indicator of alprazolam in patients with anxiety disorders comorbid with alcohol use disorder, using findings on enzymatic activity of CYP3A (as evaluated by the 6-beta-hydroxy-cortisol/cortisol ratio measurement) and on CYP3A4 expression level obtained by measuring the miR-27b plasma concentration levels in patients with anxiety disorders comorbid with alcoholism. Material and methods Our study enrolled 105 patients with anxiety disorders comorbid with alcohol use disorder (age - 37.8±14.6 years). Therapy included alprazolam in an average daily dose of 5.6±2.4 mg per day. Treatment efficacy was evaluated using the 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. The activity of CYP3A was evaluated using the HPLC-MS/MS method by the content of the endogenous substrate of the given isoenzyme and its metabolite in urine (6- beta-hydroxy-cortisol/cortisol). Therapeutic drug monitoring (TDM) has been performed using HPLC-MS/MS. Results Our study revealed the statistically significant results in terms of the treatment efficacy evaluation (HAMA scores at the end of the treatment course): (GG) 3.0 [2.0; 5.0] and (GA) 4.0 [4.0; 5.0], p = 0.007; at the same time, the statistical significance in the safety profile was not obtained (the UKU scores): (GG) 3.0 [2.0; 3.8] and (GA) 3.0 [1.5; 4.0], p = 0.650. We revealed a statistical significance for concentration/dose indicator of alprazolam in patients with different genotypes: (GG) 1.583 [0.941; 2.301] and (GA) 2.888 [2.305; 4.394], p = 0.001). Analysis of the results of the pharmacotranscriptomic part of the study didn't show the statistically significant difference in the miR-27b plasma levels in patients with different genotypes: (GG) 25.6 [20.4; 28.8], (GA) 25.7 [19.7; 33.1], p = 0.423. At the same time, correlation analysis revealed a statistically significant relationship between the alprazolam efficacy profile evaluated by changes in HAMA scale scores and the miR-27b plasma concentration: rs = 0.20, p = 0.042. Also, we didn’t reveal the correlation between the miRNA concentration and safety profile: rs = 0.15, p = 0.127. In addition, we revealed the relationship between the CYP3A enzymatic activity (as evaluated by 6-beta-hydroxycortisol/ cortisol ratio measurement) and the miR-27b plasma concentration: rs = −0.27, p = 0.006. At the same time, correlation analysis revealed a statistically significant relationship between the alprazolam concentration and the miR-27b plasma concentration: rs = 0.28, p = 0.003. Conclusion The effect of genetic polymorphism of the CYP3A4 gene on the efficacy and safety profiles of alprazolam was demonstrated in a group of 105 patients with anxiety disorders comorbid with alcohol use disorder. At the same time, miR-27b remains a promising biomarker for assessing the level of CYP3A4 expression, because it correlates with the encoded isoenzyme's activity.

Introduction: Sertralineis commonly administered topatients with depressive disorders comorbid with alcohol use disroder. Some part of such patients do not respond adequately to treatment regimen containing sertraline, whereas many of them experience type A adverse drug reactions (type A ADRs). Previous studies have shown that CYP2D6 is involved in the metabolism of sertraline, the activity of which is considerablydependent on the polymorphism of the gene encoding it. Objective: The objective of the study was to investigate the impact of 1846G>A polymorphism of the CYP2D6 gene on the concentration/dose indicator of sertralinepatients diagnosed with depressive disorders comorbid with alcoholism, using findings on 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 patients suffering from depressive disorders comorbid with alcoholism. Material and Methods: The study included 120 patients with depressive disorders comorbid with alcoholism (age - 40.5±14.7 years). Therapy included sertraline in an average daily dose of 88.8±35.6 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 assessed with HPLC-MS/MS method by the content of the endogenous substrate of given isoenzyme and its metabolite in urine (6M-THBC/pinoline). Theraputic drug monitoring (TDM) has been performed using HPLC-MS/MS. Results: Our study revealed the statistically significant results in terms of the treatment efficacy evaluation (HAMD scores at the end of the treatment course): (GG) 1.0 [1.0; 2.0] and (GA) 4.0 [3.0; 5.0], p < 0.001; at the same time, the statistical significance in the safety profile was obtained (the UKU scores): (GG) 3.0 [2.0; 3.0] and (GA) 3.0 [3.0; 3.0], p = 0.018. We didn't reveal a statistical significance for concentration/dose indicator of sertraline in patients with different genotypes: (GG) 0.749 [0.593; 1.277] and (GA) 1.030 [0.829; 1.257], p = 0.052). 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) 23.4 [16.3; 29.3], (GA) 26.1 [16.5; 28.9], p = 0.945. At the same time, correlation analysis didn't reveal a statistically significant relationship between the sertraline efficacy profile evaluated by changes in HAMD scale scores and the hsa-miR-370-3p plasma concentration: rs = -0.05, p = 0.592. Also, we didn't reveal the correlation between the miRNA concentration and safety profile: rs = 0.07, p = 0.421. Also we revealed the relationship between the CYP2D6 enzymatic activity (as evaluated by 6M-THBC/pinoline ratio measurement) and the hsa-miR-370-3p plasma concentration: rs = -0.25, p = 0.005. At the same time, correlation analysis revealed a statistically significant relationship between the sertraline concentration and the hsa-miR-370-3p plasma concentration: rs = 0.30, p < 0.001. Conclusion: Thus, the effect of genetic polymorphism of the CYP2D6 gene on the efficacy and safety profiles of sertraline was demonstrated in a group of 120 patients with depressive disorders comorbid with alcoholism. At the same time, hsa-miR-370-3p remains a promising biomarker for assessing the level of CYP2D6 expression, because it correlates with encoded isoenzyme activity. Funding Statement: This work was supported by the grant of the Russian Science Foundation (project No. 18- 75-10073). This work was financially supported by the project 16-15-00227 entitled “Fundamental research and exploratory research in priority areas of research” of the Russian Science Foundation. Declaration of Interests: The authors declare that there is no conflict of interest regarding the publication of this article. Ethics Approval Statement: The local ethical committee of the Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation approved the research (The protocol No. 6 from 5/16/2017).