Experience of using lumacaftor/ivacaftor in children with cystic fibrosis in the Astrakhan region

Background. Targeted therapy in patients with cystic fibrosis, which aims to restore the function of the cystic fibrosis transmembrane conductance regulator protein, is currently revolutionary in the treatment of the disease. The first drug available in Russia for the treatment of patients with this genetic disease is lumacaftor/ivacaftor (Orkambi®), which was registered on December 2, 2020.The aim. To study the efficacy of lumacaftor/ivacaftor during 12 weeks of administration in children in Astrakhan region.Materials and methods. This article presents the clinical experience of Orkambi medicine use in 3 children with F508del/F508del genotype and a severe course of cystic fibrosis for 12 weeks. According to the study design, such indices as body mass index, indexes of external respiratory function, character of respiratory tract microbiota, level of chloride in sweat fluid and pancreatic elastase in feces, dynamics of biochemical blood indexes were evaluated. The study was performed within the time periods specified in the study protocol, namely, before the start of therapy, 2, 4, and 12 weeks of treatment.Results. Two patients had a decrease in sweat test values by 11 and 19 mmol/l from the baseline, a significant increase in forced vital capacity of lungs. One patient had an adverse event in the form of hepatobiliary disorders manifested by increased liver transaminase activity, which was the reason for discontinuing the drug.Conclusions. The short-term experience of using pathogenetic therapy with lumacaftor/ ivacaftor in children in the Astrakhan region demonstrated both the expected effect on chlorine channel function and the possibility of side effects, including severe ones, that can lead to withdrawal of the drug

Current views on the role of fatty acids in the diagnosis of cardiovascular diseases (review)

An additional informative tool in the diagnosis of cardiovascular diseases in the early stages can be the analysis of changes in the fatty acid profile, which can be considered as a marker of various pathological conditions. The study of the effects of fatty acids and the mechanisms of changes in the fatty acid profile in connection with cardiovascular diseases remains relevant. We have analyzed modern data from foreign and domestic literature on issues related to the importance of fatty acids as possible markers in the diagnosis of cardiovascular diseases. Basic information about the structure of fatty acids, their functions in the human body, the relationship between the level of free fatty acids and indicators of the development of pathological processes of the cardiovascular system is presented. The factors influencing the dynamics of fatty acid concentrations both in normal conditions and during the development of pathological processes are reflected. The processes of biochemical modification of the fatty acid composition of the lipid matrix of the cell membrane are considered. The expediency of using fatty acids, together with some protein markers in the diagnosis of diseases of the cardiovascular system, has been shown. The collection and analysis of the accumulated information on the role of fatty acids helps to optimize the use of laboratory markers to determine the stages of pathogenesis of circulatory organ damage, to develop a system for evaluating the effectiveness of therapy for cardiovascular diseases, and to create a set of laboratory and instrumental tests for monitoring the condition of patients

NEUROIMMUNOENDOCRINE REGULATION OF THE SKIN FUNCTIONING

The review deals with modern ideas of neuroimmunoendocrine regulation of physiological and pathophysiological processes in skin. The present data are provided which indicate to composite mechanisms of intercellular interactions in complex regulating systems (nervous, immune, endocrine) acting at the level of skin in normal conditions, as well during the posttraumatic period. We describe different modes for participation of endocrine and nervous systems in immunologically induced skin inflammation. The data are provided confirming localization of adrenergic receptors on membranes of immunocompetent cells and leukocytes, on regulatory effects of hypothalamus upon immune functions, about multidirectional actions upon inflammation of sympathetic and parasympathetic nervous system etc.There are sufficient data on promotion of pathophysiological changes and reconstitution processes in the skin due to effects of local immune cells and bioactive substances expressed by them. The course of skin wound regeneration depend on the type of damage, degree and a phase of healing process. Posttraumatic reparative potential of skin is often limited by the infectious processes initiated by local microflora, products of cell disintegration and necrotic tissues. The cause-effect relationship is proven by arising inflammation which is implemented by inclusion of immune protection responses. The increased necrotic area and suppuration of the wound occurs die to inhibition of system of the phagocytizing macrophages. However, activation of this system brings about formation of the connective tissue capsule around the inflammation focus within early terms.We also discuss the issues of reparative skin regeneration which of great medico-social value, in connection with considerable prevalence of traumatic events and their social consequences, followed by expressed cosmetic defects. Evolving neurocognitive problems lead to decreased quality of the patient’s life, development of social disadaptation and further deprivation. The role of nervous system and psychological frustration in genesis of skin manifestations requires future development of the modern scientific direction, i.e., psychodermatology.Understanding of molecular mechanisms regulating the neuroimmunocutaneous interactions offers new prospectives in treatment of some skin diseases, as well as activation of the damaged skin recovery. According to the data presented in the review article, one may conclude on relevance of further studies on reparative potential of skin under interactions of homeostatic regulatory systems

SEVERE ASTHMA IN CHILDREN

The definition of severe asthma is based on the criteria for clinical control, the treatment received, as well as the response to therapy, the assessment of future risk. In severe bronchial asthma, control can be achieved only at the highest possible level of therapy, namely, in treatment corresponding to the 4th or 5th stage. The article highlights the features of the clinical phenotype of severe bronchial asthma in children. Purpose: to identify the predictors of severe phenotype in children, the analysis of clinical and anamnestic features, to study the dynamics of disease control. Materials and methods: a group of patients with different degrees of severity of bronchial asthma aged 3 to 12 years, both sexes, was studied. The clinical aspects of the disease, the dynamics of control over bronchial asthma have been studied. Functional tests were carried out: examination of the function of external respiration, pyclofometry. Data of a specific allergic diagnosis (skin tests with non-bacterial allergens, detection of specific IgE antibodies), self-monitoring tests were studied. Statistical methods used a nonparametric method, a c2 distribution, a Pearson test, using conjugacy tables. Results and discussion: the family female phenotype is a predictor of severe bronchial asthma in patients in this group. The severity of the disease on the background of therapy for five years in a group of patients was revised only in a third of children. With this phenotype, partial control over the disease was achieved. The ineffectiveness of control is associated with the presence of a comorbid background: the pathology of the nervous system, the gastrointestinal tract, endocrine disorders. The severe phenotype of bronchial asthma, independently of age debut, was significantly less frequent than in the case of moderate disease

ASSOCIATION OF CC16 POLYMORPHISM WITH RISK FACTORS OF FORMATION OF BRONCHO-OBSTRUCTIVE SYNDROME IN CHILDREN

Syndrome of bronchial obstruction is a symptomatic complex arising on the background of constriction or occlusion of bronchial tubes of different caliber due to bronchospasm, edema and inflammation of the bronchial mucosa, hypersecretion of mucus or compression by surrounding structures. Bronchoobstructive syndrome (BOS) is one of the most common pathological conditions in pediatric practice. The outcome of BOS can be different: from the complete disappearance of clinical manifestations to the process, disability or even death. Accordingly, the study of this problem and the search for methods for early diagnosis and prediction of the outcome of BOS is a very urgent problem. In order to identify risk factors for BOS and to clarify the association with polymorphism of the CC16 gene, 126 children belonging to the main group and 58 from the comparison group were examined. In the course of the study, the triggers influence on the formation of the BOS of concomitant ENT pathology, burdened personal and family allergic anamnesis, and also the recurrent nature of respiratory infections in the first year of life was proved. The association of polymorphism of AA gene of CC16 with the presence of weighed allergic anamnesis and frequent episodes of ARVI, as well as the influence of this genotype on the early debut of respiratory diseases in children, has been revealed. The relationship of the GG genotype with the concomitant ENT pathology among patients with recurrent BOS has been proved

Screening studies of antimicrobial activity of pyrimidine derivative

Aim of the study was to screen the antimicrobial activity of pyrimidine derivative 3-[2-(1-naphthyl)-2-oxoethyl]-6-bromoquinazoline-4(3H)-oh with laboratory cipher VMA–13–06 in relation to pathogenic and opportunistic flora. Material and methods. Antimicrobial activity of VMA–13–06 was established in vitro against strains of Staphylococcus aureus, Klebsiella pneumonia, Streptococcus pyogenes, Escherichia coli, Acinetobacter baumannii and Citrobacter freundii by the method of serial dilutions, by forming rows with different concentrations of the compound under study. Results. VMA–13–06 was found to exhibit high antibacterial activity against S. aureus, S. pyogenes, E. coli and K. pneumonia at concentrations of 128 and 64 μg/ml comparable to the activity of the comparison drug norfloxacin. At a concentration of 32 μg/ml, the studied derivative is highly active against S. aureus and S. pyogenes and shows average activity against E. coli and K. pneumonia. The compound VMA–13–06 in dilution from 16 to 4 μg/ml is moderately active against the above-mentioned microorganisms. At concentrations from 2 to 0.25 μg/ml, the pyrimidine derivative is inactive against S. aureus, S. pyogenes, E. coli and K. pneumonia, in all dilutions – against C. freundii and A. baumannii. Conclusions. The results of a screening study indicate a pronounced bactericidal effect of VMA–13–06 against S. aureus, S. pyogenes, E. coli и K. pneumonia comparable to the comparison drug norfloxacin

Overview of metabolomic markers used for diagnosing cardiovascular diseases

At present, metabolomics is an intensively developing approach to the specific diagnosis of cardiovascular diseases. Metabolic analysis allows the study of complete metabolomic profiles and their deviations resulting from changes, for example, gene and RNA expression, protein activity, or environmental factors. Analysis of the metabolomic blood profile helps in solving a large number of scientific and clinical problems, one of which is the search for markers of diseases, in particular, cardiovascular diseases (CVD). Aim of the study was to investigate metabolomic markers used for the diagnosis of cardiovascular diseases on the basis of literature data. Material and methods. The literature data was analyzed for key words: cardiovascular diseases, metabolomics, metabolic profile, metabolomic markers in da- tabases PubMed, Scopus, Web of Science, CyberLeninka, PatentDB, Science Direct Open Access, eLibrary. Results. Analysis of literature data and patent search confirms the high importance of metabolomic markers in the diagnosis of CVD. In the patent literature, BNP/NT-proBNP is most common used as a metabolic marker of CVD (11.27 %). The use of CRP (8.99 %) and troponin (8.49 %) is also common. PICP (0.02 %), sVCAM-1 (0.09 %), stimulating growth factor ST-2 (0.12 %) and thrombomodulin (0.12 %) as metabolic markers of CVD. Conclusions. Against the backdrop of analytical methods, metabolomics is the most important diagnostic area. At the same time, it should be noted that by combining the results of the analysis of metabolic studies with others, for example, genomic and proteomic, one can get a complete picture of the pathogenesis of diseases, assess the risk of complications, and also determine the effectiveness of the treatment

ИНФОРМАЦИОННАЯ ЗНАЧИМОСТЬ МОНИТОРИНГА ПОПУЛЯЦИЙ СD4+ Т-ЛИМФОЦИТОВ В ДИАГНОСТИКЕ И ПРОГНОЗИРОВАНИИ РЕАКЦИИ ОРГАНИЗМА НА ТРАНСПЛАНТАТ

In this review article the necessity of adaptation and introduction into clinical practice of simultaneous monitoring of immune blood cells and cytokines in patients with grafted organs for a choice of individual tactic of immuno- suppressive therapy, determination of its efficiency and forecasting is proved. It is emphasized, that with the spe- cial attention it ought to concern to characteristic of CD4 + T-lymphocytes and to definition of an interrelation of their separate populations in peripheral blood (Treg, Th17, Tact memory cells – CD4+CD25hiCD127hiCD45RO) since they are the basic participants of immune system reaction on grafts. В обзоре обосновывается необходимость внедрения в клиническую практику комплексного мониторинга иммунных клеток крови и цитокинов у больных с пересаженными органами для выбора индивидуальной тактики иммуносупрессивной терапии, оценки ее эффективности и прогнозирования результатов. Подчеркивается, что с особым вниманием следует отнестись к характеристике CD4+ T-лимфоцитов и определению соотношения их отдельных популяций в периферической крови (Treg, Th17, Tact клетки памяти CD4+CD25hiCD127hiCD45RO), так как именно они являются основными участниками ответа иммунной системы организма на трансплантат.

ДИНАМИКА АКТИВНОСТИ НЕКОТОРЫХ КОМПОНЕНТОВ КОМПЛЕМЕНТА ПРИ ЛЕЧЕНИИ АТОПИЧЕСКОГО ДЕРМАТИТА У ДЕТЕЙ

The article describes immunoassay methods of determining the functional activity of the components C3 and C9 and C1 inhibitor for diagnostic and prognostic purposes in the treatment of patients. The activity of these components, as well as the activity and the amount of C1 inhibitor in the blood serum of children aged 6 months to 18 years suffering from atopic dermatitis have been analyzed before and after treatment to determine the involvement of the complement system in the pathogenesis of this disease. The developed methods of enzyme immunoassay for determination of the functional components of the complement system have shown high sensitivity and reliability. The activity of C9 component involved in the membrane attack of the complement was significantly below normal in children with atopic dermatitis. That indicates the involvement of membrane attack complex components in the skin necrotic processes. Component C3 activity is also reduced. C3 is the key component of the activation cascade involved in the inflammatory processes. Specific activity of C1 inhibitor increased before and during the treatment, indicating an increased biosynthesis of this acute phase protein. Positive tendency towards the normalization of the status of complement after treatment has been observed. Data obtained in this study indicate the involvement of complement system in the pathological process of atopic dermatitis in children.Разработаны иммуноферментные методы определения функциональной активности компонентов С3, С9 и С1 ингибитора системы комплемента для решения диагностических и прогностических задач при лечении больных. Исследованы активности этих компонентов, а также активности и количества С1 ингибитора в сыворотках крови детей в возрасте от 6 месяцев до 18 лет, больных атопическим дерматитом, до и после лечения для выяснения участия системы комплемента в патогенезе этого заболевания. Разработанные методы иммуноферментного анализа для определения функциональной компонентов системы комплемента показали высокую чувствительность и надежность. У детей с атопическим дерматитом активность компонента С9, участвующего в мембранной атаке комплемента была существенно ниже нормы, что указывает на участие компонентов мембраноатакующего комплекса в осуществлении некротических процессов в области кожных поражений. Снижена была также активность компонента С3 ключевого компонента каскада активации, участвующего в процессах воспаления. До и в ходе лечения больных удельная активность С1 ингибитора была повышена, что свидетельствовало о повышенном биосинтезе этого белка, являющегося белком острой фазы. Прослеживаются позитивные сдвиги в сторону нормализации статуса комплемента после лечения. Полученные в работе данные указывают на участие системы комплемента в патологическом процессе при атопическом дерматите у детей.