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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.

Previous pharmacogenetic studies demonstrate significant genes’ polymorphisms effect on the efficacy and safety of pharmacotherapy, including in bronchial asthma (BA). According to the literature, there are data on the effect of polymorphisms CYP3A4*22 and CYP3A5*3 on the efficacy of inhaled corticosteroids in children with BA. Further research on the effect of pharmacogenetic features on the efficacy and safety of drugs is one of the way to optimize asthma therapy in children.Purpose. Identification of possible ways to optimize asthma therapy by the analysis of CYP3A5 (A6986G) gene polymorphism effect on the asthma therapy efficacy.Materials and methods. The study was conducted on the basis of three children’s polyclinics of Moscow. 100 children aged 6–17 years with an established diagnosis of BA were included. Dynamic assessment of asthma control and the amount of therapy needed was carried out. All patients underwent genotyping for the A6986G polymorphism of CYP3A5 gene by real-time PCR. Statistical data analysis was carried out using a programming language for statistical data processing R.3.4.0.Results. It was found that 8% of children with asthma were heterozygous for the A6986G polymorphism of the CYP3A5 gene, 92% of respondents were homozygous with the GG genotype. In 6 out of 8 heterozygotes, the amount of control therapy corresponded the third and fourth therapy stages according to GINA criteria. In the group of moderate and severe BA, the number of heterozygotes for the A6986G polymorphic marker of the CYP3A5 gene was statistically higher compared to the group of children with mild BA (p = 0,048).Conclusion. Thus, we identified a statistically significant difference in the occurrence of heterozygotes for the A6986G polymorphism of the CYP3A5 gene between groups of children with mild asthma and patients with moderate and severe asthma. The AG genotype and the presence of the A allele (CYP3A5 gene (A6986G)) are associated with more severe BA and the need for more anti-inflammatory 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.

Atopic dermatitis (Ad) is a multifactorial skin disease. As shown by recent studies, a significant role in the pathogenesis of atopic dermatitis is a disturbance of the structural elements of the skin barrier, which contributes to skin xerosis, increase of its permeability to allergens and development of chronic inflammation. As a result, an allergic inflammation develops in the skin. Accordingly, in the treatment of atopic dermatitis great attention should be paid to effective external therapy. In the period of exacerbation of the skin process effective and safe external preparations are drugs of activated zinc pyrithione (APTS) - a line of Skin-Cap products. Use of APTS in atopic dermatitis in children leads to a significant reduction in the severity of inflammation, reduction of the area of skin lesions and severity of symptoms, reducing the need for additional administration of antihistamine and anti-inflammatory drugs, allowing you to reach persistent clinical remission.

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).