Vol 73, No 3 (2018)

MOLECULAR MEDICINE AND GENETICS: CURRENT ISSUES
THE PERSONALIZED APPROACH TO ANTIHYPERTENSIVE THERAPY DURING PREGNANCY IN TERMS OF CLINICAL PHARMACOGENETICS
Ignatko I.V., Strizhakov L.A., Florova V.S., Martirosova A.L.

Abstract

The right drug at the right dose administered to a patient in time is the goal which all medical specialists aim at when prescribing medicines to patients. Pregnancy is a condition when the principle of personalized pharmacotherapy is especially relevant. Due to the developing fetus and the occurring changes in the maternal organism, the selection of drug therapy during pregnancy is especially difficult for a clinician. This issue is tightly intertwined with clinical pharmacogenetics since the genetic code of a woman that determines the activity of the liver cytochrome, the fetus-placental barrier, and renal clearance contributes to the peculiarities of the drug metabolism during pregnancy. Additional data provides the opportunities to form therapeutic models and to determine the ways of personifying pharmacotherapy in pregnancy. The purpose of this review is to summarize the available data on the pharmacogenetics of antihypertensive drugs used during pregnancy.

Annals of the Russian academy of medical sciences. 2018;73(3):149-156
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NEUROLOGY AND NEUROSURGERY: CURRENT ISSUES
MEDICAL AND SOCIAL CHARACTERISTICS OF POST-STROKE PATIENTS UNDERGOING MEDICAL REHABILITATION IN OUTPATIENT SETTINGS
Badrutdinova L.R., Manerova O.A., Kostenko E.V.

Abstract

Background: According to the statistics of death rates in the Russian Federation in recent years, diseases of the circulatory system are regarded as the leading cause of mortality (50.07%, or 653.9 per 100 thousand in 2015). Identification of the main trends specific to the dynamics of the health state of post-stroke patient provides an opportunity to conduct substantiated medical and rehabilitation measures focused on the improvement of health status and life quality of this category of people with the greatest economic efficiency which is essential and relevant under the conditions of permanent financial limitation in medical and social care.

Aims: To assess the medical and social characteristics of patients who had acute cerebrovascular accidents and underwent medical rehabilitation in outpatient settings.

Materials and methods: A retrospective research was performed; the subject of the study is post-stroke patients who received medical rehabilitation in outpatient settings in the period 2011−2015. The data was obtained by collecting information from the outpatient’s medical documents and processed by statistical and analytical methods of investigation.

Results: The study analyzed 400 records of post-stroke patients who underwent medical rehabilitation in outpatient settings. The investigated data revealed some medical and social characteristics of the “typical” patient undergoing medical rehabilitation: working-age patient with first stroke who had no defined disability category but had comorbid pathology in past medical history and high-stress intellectual profession.

Conclusions: The analysis allows selecting the priority areas of medical and preventive work aimed at improving the quality of life and health of the population. Specification of the patient’s medical and social characteristics is the key element in the formation of targeted programs of preventive and rehabilitation measures.

Annals of the Russian academy of medical sciences. 2018;73(3):157-163
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TRAUMATOLOGY: CURRENT ISSUES
SURGICAL TREATMENT OF ISOLATED ASEPTIC ACETABULAR LOOSENING IN PATIENTS WITH STABLE FEMORAL COMPONENT
Markov D.A., Zvereva K.P., Sertakova A.V., Belonogov V.N., Troshkin A.Y.

Abstract

Background: Aseptic acetabular loosening currently occupies the 1st place in the structure of delayed complications after total hip arthroplasty. The basis of treatment is the replacement of a loosening cup and a pair of friction. The tactics of surgical treatment of the stable correctly oriented femoral component have not been determined, thoroughly which confirms the relevance of the study.

Aims: Compare the effectiveness of total hip revision and isolated acetabular revision in patients with aseptic acetabular loosening and stable correctly oriented femoral component.

Materials and methods: The study presented the results of surgical treatment performed in 44 patients (45 revisions) with isolated aseptic acetabular loosening and stable correctly oriented femoral component were presented, Patients were divided into two groups depending on the severity of surgery. The first group included 16 patients with a total revision due to irregular cone of the stem. The second group included 28 patients (29 revisions) with an isolated replacement of the unstable cup and a pair of friction.

Results: In the 1st group, revision surgery was performed to replace both cup with the friction pair and stable correctly oriented stem which finally results in lower postoperative red blood counts (erythrocytes, hemoglobin, hematocrit), as well as higher intraoperative blood loss volume and longer duration of surgical intervention if compare to the 2nd group where the stable correctly oriented femoral component was not changed. Postoperative results assessed using Harris scales and Oxford Hip Score in the comparison group were at a higher level during the whole period of follow-up. A moderate coorelation between the severity of the revision intervention and its results was detected.

Conclusions: Preservation of a stable correctly oriented stem allows to reduce the severity of the revision intervention which improves the results and shortens the period of patient rehabilitation.

Annals of the Russian academy of medical sciences. 2018;73(3):164-171
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ENDOCRINOLOGY: CURRENT ISSUES
TRANSCRIPTOMICS RESEARCH IN THE CLINICAL AND EXPERIMENTAL INVESTIGATION OF PATHOGENETIC MECHANISMS OF ALIMENTARY OBESITY
Gmoshinski I.V., Apryatin S.A., Sharafetdinov K.K., Nikitjuk D.B., Tutelyan V.A.

Abstract

The review considers the significant role of changes in the transcriptome of organs and tissues for studying the molecular mechanisms of obesity development. Modern methods of transcriptomics including technologies for quantitative RT-PCR and DNA microarrays provided a new approach to the search for sensitive molecular markers as obesity predictors Differential gene expression profiles are mostly organo- and tissue-specific for adipose tissue, liver, brain, and other organs and tissues; can significantly differ in animal in vivo models with genetically determined and dietary induced obesity. At the same time, coordinated regulation is registered in the organs and tissues of expression of extensive groups of genes associated with lipid, cholesterol, and carbohydrate metabolism, the synthesis and circulation of neurotransmitters of dopamine and serotonin, peptide hormones, cytokines which induce systemic inflammation. For systemic regulation mechanisms causing a concerted change in the transcription of tens and hundreds of genes in obesity, the adipokines effects should be pointed out, primarily leptin, as well as pro-inflammatory cytokines, the micro-RNA (miRs) system and central effects developing at NPY/AgRP+ and POMC/CART+ neurons of the arcuate nucleus of the hypothalamus. Results of transcriptomic studies can be used in preclinical trials of new drugs and methods of dietary correction of obesity in animal’s in vivo models, as well as in the search for clinical predictors and markers of metabolic abnormalities in patients with obesity receiving personalized therapy. The main problem of transcriptomic studies in in vivo models is incomplete consistency between the data obtained with full-transcriptional profiling and the results of quantitative RT-PCR expression of individual candidate genes, as well as metabolic and proteomic studies. The identification and elimination of the causes of such discrepancies can be one of the promising areas for improving transcriptomical research.

Annals of the Russian academy of medical sciences. 2018;73(3):172-180
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HEALTH CARE MANAGEMENT: CURRENT ISSUES
CHANGE MANAGEMENT OF DRUG PRODUCTS REGISTRATION CONDITIONS: NEW ICH Q12 GUIDELINE
Meshkovskii A.P., Pyatigorskaya N.V., Beregovykh V.V., Aladysheva Z.I., Belyaev V.V., Pyatigorsky A.M., Ivashechkova N.S.

Abstract

Introduction of amendments to the registration dossier is the responsibility of the marketing application holder (MAH). Increased knowledge on pharmaceuticals, its manufacturing and control processes can reduce the number of documents submitted to the regulatory authorities. The existing requirements establishing the procedure for the introduction of amendments differ in terms of change classification, period of notification of regulatory authorities, ways of conformity validation of pharmaceutical properties, etc. ICH proposed draft guideline Q12 «Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management» which covers the problem of harmonization of regulatory approaches to the changes provided in the «Quality» section of CTD during the commercial phase of drug life cycle. The new guideline can be considered as the continuation and elaboration of previous ICH documents. The article provides explanations on the main provisions and regulatory mechanisms introduced by the draft guideline ICH Q12: categorization of post-approval changes, established conditions, post-approval change management protocol, and drug product lifecycle management.

Annals of the Russian academy of medical sciences. 2018;73(3):181-189
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PEDIATRICS: CURRENT ISSUES
MATERNAL NUTRITION AND THE PROBLEM OF INTRAUTERINE DISEASE PROGRAMMING IN CHILDREN
Kovtun O.P., Tsyvian P.B.

Abstract

Environmental conditions during perinatal development such as maternal undernutrition or overnutrition can program changes in the integration among physiological systems leading to cardio-metabolic diseases. This phenomenon can be understood in the context of the phenotypic plasticity and refers to the adjustment of a phenotype in response to environmental input without genetic change. Experimental studies indicate that fetal exposure to an adverse maternal environment may alter the morphology and physiology that contribute to the development of cardio-metabolic diseases. The significance and role of genetic polymorphism, markers of chronic inflammation, oxidative stress, endothelial dysfunction, leptin synthesis disruption, rennin-angiotensin system in intrauterine cardio-metabolic disease programming are discussed. The study demonstrated that both maternal protein restriction and overnutrition alter the central and peripheral control of arterial pressure and metabolism. Breastfeeding may have beneficial effect on obesity risk later in life in genetically predisposed groups. Understanding the mechanisms which affect health outcomes in the offspring influenced by the macronutrient composition of the maternal diet during pregnancy or lactation may lead to new maternal nutrition recommendations, disease prevention strategies, and therapies that reduce the increasing incidence of cardio-metabolic diseases in children and adults.

Annals of the Russian academy of medical sciences. 2018;73(3):190-194
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INFECTIOUS DISEASES: CURRENT ISSUES
POSSIBLE MECHANISMS OF SELF-REGULATION OF PARASITIC SYSTEMS IN THE BIOGEOCENOSIS
Yakovlev A.A., Pozdeeva E.S.

Abstract

The current epidemiological literature mainly presents the mechanisms of self-regulation of a single parasitic system influenced by natural and social factors. At the same time, epidemiology traditionally considers particularly the epidemic process of individual infections. In the human population however, many pathogenic microorganisms circulate and cause diseases in humans simultaneously; nevertheless the possibility of interactions between the various parasitic systems included in biogeocenosis and the influence of the considered interrelation on the development of the epidemic process and its manifestations is not taken into account generally. The presented study basing on the analysis of literary publications discusses possible mechanisms causing processes of self-regulation of parasitic systems in the conditions of biogeocenosis and, primarily, the integrative-competitive relations that develop between them as the leading regulating force. Therefore the following position is justified: regulatory processes in one parasitic system occur when influenced by self-regulation processes in biogeocenosis as a whole in response to the influence of both external and internal factors. Ultimately, the authors associate tendencies in the incidence of individual nosological forms, transformation of the structure of infectious pathology in different time periods, and some other manifestations of the epidemic process with the self-adaptation of ecosystems.
Annals of the Russian academy of medical sciences. 2018;73(3):195-205
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PSYCHOLOGY AND PSYCHIATRY: CURRENT ISSUES
IMPACT OF CYP3A5, CYP2C9, CYP2C19, AND CYP2D6 POLYMORPHISMS ON PHENAZEPAM SAFETY IN PATIENTS WITH ALCOHOL WITHDRAWAL SYNDROME
Ivashchenko D.V., Ryzhikova K.A., Sozaeva Z.A., Pimenova Y.A., Grishina E.A., Zastrozhin M.S., Aguzarov A.D., Savchenko L.M., Bryun E.A., Sychev D.A.

Abstract

Introduction: Phenazepam is the Russian original benzodiazepine tranquilizer. We conducted first pharmacogenetic study on Phenazepam’s safety in patients with alcohol withdrawal syndrome. Isoenzymes CYP3A4, CYP3A5, CYP2C9, and CYP2C19 are involved into benzodiazepine tranquilizers’ metabolism.

Aim: To determine predictive value of CYP3A5, CYP2C9, CYP2C19, and CYP2D6 genetic polymorphisms and their haplotypes for adverse reaction risk associated with the treatment with phenazepam.

Materials and methods: The study enrolled 102 male patients with non-comlicated alcohol withdrawal syndrome (F10.3 by ICD-10) who entered the study group in 24 hours after the admission to hospital and was administered Phenazepam for 6 days. Therapy safety was evaluated with UKU Side Effects Rating Scale on the 6th day of treatment. 5 ml of venous blood was collected from each participant for genotyping to detect CYP3A5*3, CYP2С9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3, CYP2C19*17, and CYP2D6*4 polymorphisms by real-time polymerase chain reaction. Haplotype analysis was performed by SNPStats online-tool. Statistical analysis was made in SPSS Statistics 21.0.

Results: In overall sample (n=102) CYP2C9*3 increased risk of «Increased duration of sleep» (OR 1.46; 95% CI 1.11−1.9; p=0.037) and «Constipation» (OR 13.1; 95% CI 1.44−119.2; p=0.02). The following results in subgroup «Phenazepam’s monotherapy» (n=64) were observed: CYP3A5*3 increased global severity of adverse drug reactions according to patient’s opinion (OR 2.79; 95% CI 1.26−6.22; p=0.031); CYP2C9*3 led to «Increased duration of sleep» (OR 1.57; 95% CI 1.14−2.17; p=0.034). Haplotype CYP3A5*3-CYP2C19*2-CYP2C19*17 (G-G-T) was associated with increased risk of «Concentration difficulties (OR 2.86; 95% CI 0.96−8.50; p=0.061).

Conclusion: The study findings confirmed that CYP2C9*3, CYP3A5*3, and CYP2C19*2 polymorphisms can decrease the phenazepam safety rate in patients with alcohol withdrawal syndrome. The result of haplotype analysis revealed that only CYP3A5*3-CYP2C19*2-CYP2C19*17 (G-G-T) can be used as a significant predictor of adverse reaction to phenazepam.

Annals of the Russian academy of medical sciences. 2018;73(3):206-214
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