Prevalence of overweight and obesity among the adult population of the Yaroslavl region

BACKGROUND: Obesity is one of the most common non–communicable diseases. Overweight and obesity negatively affect all spheres of human activity, leading to the development of related diseases and disability. AIMS: to estimate the prevalence of overweight and obesity among the adult population of the Yaroslavl region according to sex and age. MATERIALS AND METHODS: The research included results of comprehensive medical examinations of 13948 persons of both sexes aged from 20 to 79 permanently residing in the Yaroslavl region. Anthropometric examination was performed by standard methods with the measurement of body weight and body length and calculation of body mass index. Overweight was defined as having a BMI to 25.0–29.9 kg/m2, obesity was defined as having BMI grater or equal to 30 kg/m2. The fat compound of body mass was determined by bioimpedancemetry. RESULTS: The prevalence of overweight among the adult population of the Yaroslavl region was 34.2%, obesity was 31.6%. Overweight in men of all ages was at least 1.5 times more prevalent than women, obesity in women was 1.3 times more prevalent than in men. The prevalence of first–degree obesity was 20.9%, grade II and III – 7.9% and 2.8%, respectively. The proportion of overweight and obesity increased with age, reaching a maximum of 50–59 years for men and 60–69 years for women. The gradient of age changes is more pronounced in women. Patients with normal body mass index had excessive fat deposition in 38% of cases. CONCLUSIONS: The study showed a high prevalence of overweight and obesity among adults in the Yaroslavl region

Pharmacokinetic (Bioavailability) Studies of Magnesium Preparations

In order to obtain valid results when studying the bioavailability of medicinal products containing magnesium salts, it is necessary to take into account endogenous levels of the macroelement in the body. The aim of the study was to conduct a systematic review of the results of clinical studies on the bioavailability of medicinal products containing magnesium, to evaluate the methods used for determining the endogenous level of magnesium, and to establish the necessity for adjusting pharmacokinetic parameters according to the identified endogenous magnesium levels. The review includes data from clinical studies of magnesium bioavailability performed with healthy volunteers and published over the past 5 years. According to the literature review results, the most commonly chosen primary endpoint is urinary magnesium excretion analysis, and the most secondary endpoint is plasma or serum magnesium determination. Data sources for the review included Google’s search engine; PubMed, UpTodate®, ClinicalTrials.gov databases; and official websites of regulatory authorities (EFSA, EMA, and FDA). In most studies, endogenous magnesium levels were taken into account at all blood sampling points, and this provided an opportunity to avoid errors and misinterpretations of the results. Adjustments of pharmacokinetic parameters with regard to endogenous magnesium values were performed differently. Some studies treated endogenous magnesium values as independent variables and compared the values obtained after drug administration with them; other studies treated endogenous magnesium values as a covariate influencing the values obtained and requiring mandatory consideration; two studies involved a classical adjustment of pharmacokinetic parameters, the subtraction of endogenous values from the values obtained after drug administration. The evaluation of endogenous magnesium levels as part of bioavailability studies is necessary to adjust pharmacokinetic parameters and to obtain valid study results. It should be planned beforehand at the time of preparation of the study protocol

Recommendations for the Programme of Clinical Trials of Medicinal Products for the Treatment of Influenza

The development of new medicinal products to treat influenza is motivated by the limitations of existing treatment options, the emergence of drug resistance, and the health consequences of influenza epidemics associated with the highly contagious nature of the virus. Proper planning and implementation of clinical programmes providing reliable data on the efficacy and safety of medicinal products under development requires adherence to recommendations of the regulatory authorities. At the moment, the Russian Federation, the Eurasian Economic Union, and the European Union lack documented recommendations on conducting clinical trials of anti-influenza medicines. There is a need in national guidelines that will reflect the procedure for conducting clinical trials and establish the required amount of data to be submitted with marketing applications for new anti-influenza products. The aim of this study was to analyse possible regulatory approaches to planning clinical development programmes for anti-influenza medicinal products. The article pays particular attention to phase III studies, as the main studies confirming efficacy and safety. The authors described a clinical development strategy and the requirements for the volume and quality of efficacy and safety data. This article is based on the current Russian recommendations for the design and development of medicinal products and guidelines on their evaluation, as well as the recommendations by the U.S. Food and Drug Administration (FDA). The analysis results demonstrate the necessity for elaborating Russian recommendations for clinical studies of medicinal products for the treatment of influenza that will take into account the national legislation and clinical development practices. Such recommendations will streamline the implementation of new effective anti-influenza medicinal products

Фармакокинетические исследования (исследования биодоступности) препаратов магния

In order to obtain valid results when studying the bioavailability of medicinal products containing magnesium salts, it is necessary to take into account endogenous levels of the macroelement in the body. The aim of the study was to conduct a systematic review of the results of clinical studies on the bioavailability of medicinal products containing magnesium, to evaluate the methods used for determining the endogenous level of magnesium, and to establish the necessity for adjusting pharmacokinetic parameters according to the identified endogenous magnesium levels. The review includes data from clinical studies of magnesium bioavailability performed with healthy volunteers and published over the past 5 years. According to the literature review results, the most commonly chosen primary endpoint is urinary magnesium excretion analysis, and the most secondary endpoint is plasma or serum magnesium determination. Data sources for the review included Google’s search engine; PubMed, UpTodate®, ClinicalTrials.gov databases; and official websites of regulatory authorities (EFSA, EMA, and FDA). In most studies, endogenous magnesium levels were taken into account at all blood sampling points, and this provided an opportunity to avoid errors and misinterpretations of the results. Adjustments of pharmacokinetic parameters with regard to endogenous magnesium values were performed differently. Some studies treated endogenous magnesium values as independent variables and compared the values obtained after drug administration with them; other studies treated endogenous magnesium values as a covariate influencing the values obtained and requiring mandatory consideration; two studies involved a classical adjustment of pharmacokinetic parameters, the subtraction of endogenous values from the values obtained after drug administration. The evaluation of endogenous magnesium levels as part of bioavailability studies is necessary to adjust pharmacokinetic parameters and to obtain valid study results. It should be planned beforehand at the time of preparation of the study protocol.При исследованиях биодоступности препаратов, содержащих соли магния, для получения корректных результатов необходимо учитывать эндогенный уровень этого макроэлемента в организме. Цель работы — провести систематический обзор результатов клинических исследований по изучению биодоступности лекарственных препаратов, содержащих магний, оценить используемые методы определения эндогенного уровня магния и необходимость корректировки фармакокинетических параметров с учетом выявленных эндогенных значений магния. В обзор включены данные клинических исследований по изучению биодоступности магния, выполненные с участием здоровых добровольцев и опубликованные за последние 5 лет. Источниками данных для обзора послужили поисковая система Google, базы данных PubMed, UpToDate®, ClinicalTrials.gov, официальные сайты регуляторных органов (EFSA, EMA и FDA). Анализ литературы показал, что в качестве первичной конечной точки чаще всего выбирают анализ экскреции магния с мочой, а в качестве вторичной точки — определение магния в плазме или сыворотке крови. В большинстве исследований эндогенный уровень магния учитывали во всех точках забора крови, и данный факт позволил избежать ошибок и неправильной трактовки результатов. Корректировку фармакокинетических параметров с учетом эндогенных значений магния проводили по-разному. В одних исследованиях эндогенные значения магния рассматривались как независимые переменные и с ними сравнивали значения, полученные после применения препаратов; в других исследованиях эндогенные значения магния рассматривались как ковариата, влияющая на полученные значения и требующая обязательного учета; в двух исследованиях была проведена классическая корректировка фармакокинетических параметров — вычитание эндогенных значений из значений, полученных после применения препаратов. Оценка эндогенного уровня магния в рамках изучения его биодоступности необходима для корректировки фармакокинетических показателей, получения достоверных результатов исследования и должна быть запланирована заранее при подготовке протокола клинического исследования

Оценка биоэквивалентности воспроизведенных препаратов иматиниба и такролимуса на основе косвенного сравнения результатов изучения их биоэквивалентности

Generic drugs are widely discussed in the scientific literature. Their key advantage is high availability in the medical practice due to the possibility of a significant reduction in developer costs. In most cases the efficacy and safety of generic oral drugs are confirmed based on the acceptable results of pharmacokinetic evaluation of their bioequivalence with the reference drug. However, generic drugs are not directly compared with one another, and this calls into question the validity of the conclusion about the interchangeability of the generic drugs.The aim of this study was to evaluate the results of indirect comparison of generic drugs by the ratios of their AUC0-t and Сmax based on the information obtained in bioequivalence studies involving the reference drug.Materials and methods: the authors performed an indirect comparison of the results of bioequivalence studies of generic drugs containing one active pharmaceutical ingredient. The analysis was based on bioequivalence study reports over the last 7 years dealing with risk/benefit assessment of imatinib and tacrolimus products.Results: the results of indirect assessment of 90 % confidence intervals of the ratios of imatinib products’ geometric means show that in 46.7 % of cases the intervals fall outside the generally accepted limits (80–125 %) for at least one of the estimated parameters. As for tacrolimus products, the intervals did not go beyond the generally accepted limits (80–125 %) for the AUC0-t  ratio, but a discrepancy was found in 10 % of cases for the Cmax ratio. However, when narrower limits of 90–111 % were used to assess the AUC0-t ratio, 90 % of the compared pairs did not meet the recommended standards. Conclusions: thus, conclusions on the acceptable degree of bioequivalence of two generic drugs to the reference product cannot constitute a scientifically sufficient reason for regarding these generic drugs as clinically equivalent.В научной литературе широко обсуждается концепция воспроизведенных препаратов, положительной стороной которой является высокая доступность препарата в практической медицине из-за возможности существенного снижения затрат разработчика. В большинстве случаев для воспроизведенных пероральных препаратов основным условием для признания эффективности и безопасности является приемлемый результат оценки фармакокинетической биоэквивалентности референтному препарату. При этом не проводится прямого сравнения воспроизведенных препаратов между собой, таким образом возникает вопрос об обоснованности заключения о взаимозаменяемости воспроизведенных препаратов.Цель работы: оценка результатов косвенного сравнения воспроизведенных препаратов друг с другом по отношению AUC0-t и Сmax на основании исследований биоэквивалентности в сравнении с референтным препаратом.Материалы и методы: проводилось косвенное сравнение результатов исследований биоэквивалентности воспроизведенных препаратов с одним активным компонентом. Материалом для проведения анализа стали отчеты по изучению биоэквивалентности препаратов иматиниба и такролимуса в рамках оценки отношения ожидаемой пользы к возможному риску применения за последние семь лет.Результаты: результаты косвенной оценки 90 % доверительных интервалов отношений средних геометрических препаратов иматиниба свидетельствуют о том, что в 46,7 % случаев интервалы выходят за общепринятые границы (80–125 %) как минимум по одному из оцениваемых показателей. У препаратов такролимуса ни в одном случае интервалы не выходили за общепринятые границы (80–125 %) для отношения AUC0-t, для отношения Cmax несоответствие обнаружено в 10 % случаев. Однако при оценке соответствия отношения AUC0-t более узким границам 90–111 %, не соответствовали рекомендуемым нормам 90 % пар сравнений.Выводы: таким образом, результат, свидетельствующий о биоэквивалентности двух воспроизведенных препаратов референтному в рамках допустимых границ, с научной точки зрения не может являться достаточным основанием для признания клинической эквивалентности этих воспроизведенных препаратов друг другу

Обоснование возможности проведения исследований терапевтической эквивалентности

The introduction of the «therapeutic equivalence» concept into the Russian legislation is critical for evaluation of medicines interchangeability and for recognising them as generics. It is stipulated by the legislation that therapeutic equivalence has to be evaluated using a special instrument — «therapeutic equivalence study». The aim of this work was to analyse the validity of considering a therapeutic equivalence study as the only study that allows for confirmation of therapeutic equivalence of medicines. The term «therapeutic equivalence» has been adopted by the leading world regulators, but there is no clear concept of what is a therapeutic equivalence clinical study. The key distinctive features of the foreign approach, as compared to the Russian one, are comparison of medicines with one active pharmaceutical ingredient, and additional conditions for the establishment of therapeutic equivalence. The clinical trial methodology, which is based on the use of statistical analysis methods, also imposes constraints on evaluation of «similarity» of properties, efficacy and safety of medicines in a single study. Hence, there are several reasons why the results of comparative clinical trials can not be used as a sole basis for the establishment of therapeutic equivalence. These results have to be substantiated by confirmation of comparable composition and pharmacokinetic parameters of medicines in order for them to be considered therapeutically equivalent. This does not contradict the existing regulatory framework and is consistent with the current scientific methodology for conducting clinical trials.Введение в российское законодательство термина «терапевтическая эквивалентность» имеет принципиальное значение для оценки взаимозаменяемости лекарственных препаратов и признания их воспроизведенными. Регламентируется, что для оценки терапевтической эквивалентности существует специальный инструмент — «исследование терапевтической эквивалентности». Цель работы — анализ обоснованности признания клинического исследования терапевтической эквивалентности в качестве единственного исследования, позволяющего установить терапевтическую эквивалентность препаратов. Ведущими мировыми регуляторными органами закреплен термин «терапевтическая эквивалентность», но отсутствует понятие клинического исследования терапевтической эквивалентности. Ключевыми отличиями зарубежного подхода от отечественного являются сравнение препаратов с одним действующим веществом и наличие дополнительных условий для признания терапевтической эквивалентности. Также ограничение на оценку в рамках только одного исследования «одинаковости» свойств, эффективности и безопасности накладывает методология клинических исследований, основанная на применении методов статистического анализа. Поэтому существует несколько причин невозможности трактовки исключительно результатов сравнительного клинического исследования для доказательства терапевтической эквивалентности лекарственных средств. Без подтверждения сходства состава, сходства фармакокинетических характеристик препаратов результат исследования не может являться единственно достаточным фактором для признания их терапевтической эквивалентности. Это не противоречит существующей нормативно-правовой базе и согласуется с современной научной методологией проведения клинических исследований

КОНЦЕПЦИЯ СЛОЖНЫХ НЕБИОЛОГИЧЕСКИХ ЛЕКАРСТВЕННЫХ СРЕДСТВ ПРИ РАЗРАБОТКЕ ВОСПРОИЗВЕДЕННЫХ ПРЕПАРАТОВ

Expansion of the range of new medicines leads to a significant increase in healthcare spending and, consequently, to the appearance of more affordable generic drugs. A drug can be recognised as generic if there is sufficient evidence of equivalent structural characteristics of the active substance and therapeutic characteristics of the drug. However, for a number of substances which are multicomponent mixtures of sister compounds it is quite difficult to demonstrate absolute similarity of the chemical structure and to determine a substrate for bioavailability evaluation. Therefore, a separate group of non-biological complex drugs has been singled out. The present article summarises the requirements of the leading regulatory agencies for demonstration of equivalence between the reference product and such medicines as glatiramoids, liposome-encapsulated doxorubicin and iron-based nanosized colloidal products. It has been shown that preclinical and clinical studies are still necessary for these types of products, and the amount of testing will depend on the results of comparability assessment.Расширение спектра новых лекарственных препаратов приводит к существенному повышению затрат на здравоохранение и, как следствие, появлению воспроизведенных препаратов с более выгодными ценовыми характеристиками. Признание препарата воспроизведенным возможно при наличии достаточных доказательств эквивалентности структурных характеристик действующего вещества и терапевтических характеристик лекарственного препарата. Однако для ряда веществ, представляющих собой многокомпонентную смесь близких по строению соединений, появляется сложность доказательства абсолютного сходства химической структуры и, соответственно, определения субстрата для оценки биодоступности. В связи с этим выделяют отдельную группу сложных небиологических препаратов. В данной статье рассмотрены основные требования ведущих мировых регуляторных органов к доказательству сходства с референтным продуктом препаратов глатирамера ацетата, липосомальных препаратов доксорубицина и наноколлоидных препаратов железа. Показано, что для этих препаратов остается необходимым проведение доклинических и клинических исследований, объем которых определяется на основании оценки их сопоставимости

An integrated method for taxonomic identif ication of microorganisms

For accurate species-level identification of microorganisms, researchers today increasingly use a combination of standard microbiological cultivation and visual observation methods with molecular biological and genetic techniques that help distinguish between species and strains of microorganisms at the level of DNA or RNA molecules. The aim of this work was to identify microorganisms from the ICG SB RAS Collection using an integrated approach that involves a combination of various phenotypic and genotypic characteristics. Key molecular-genetic and phenotypic characteristics were determined for 93 microbial strains from the ICG SB RAS Collection. The strains were characterized by means of morphological, physiological, moleculargenetic, and mass-spectrometric parameters. Specific features of the growth of the strains on different media were determined, and cell morphology was evaluated. The strains were tested for the ability to utilize various substrates. The strains studied were found to significantly differ in their biochemical characteristics. Physiological characteristics of the strains from the collection were identified too, e. g., the relationship with oxygen, type of nutrition, suitable temperature and pH ranges, and NaCl tolerance. In this work, the microorganisms analyzed were combined into separate groups based on the similarities of their phenotypic characteristics. This categorization, after further refinement and expansion of the spectrum of taxa and their metabolic maps, may serve as the basis for the creation of an “artificial” classification that can be used as a key for simplified and quicker identification and recognition of microorganisms within both the ICG SB RAS Collection and other collections

ПЛАНИРОВАНИЕ И ОЦЕНКА ИССЛЕДОВАНИЙ БИОЭКВИВАЛЕНТНОСТИ ПРЕПАРАТОВ АТАЗАНАВИРА

The Government of the Russian Federation approved the State strategy of combating the spread of HIV aimed at prevention of HIV epidemic. One of the goals of the Strategy is to increase the coverage of antiretroviral therapy for people infected with HIV, which includes extensive use of generic drugs. In order for a generic drug to be authorised, the applicant has to submit a report on the results of the bioequivalence studies in which the generic product was compared to the reference product. Atazanavir is an antiretroviral drug, which is also the drug of choice for the treatment and prevention of mother-to-child transmission of HIV. The aim of this study was to analyze the protocols and reports of atazanavir products bioequivalence studies, which were submitted for expert examination  to the FSBI “SCEEMP” of the Ministry of Health of the Russian Federation, and to prepare recommendations  for planning of bioequivalence studies of atazanavir products. The analysis of a number of studies revealed significant differences in the study design and number of subjects. The main reason for these differences is the conflicting data on the intrasubject coefficient of variation of atazanavir, which means that atazanavir may be considered a highly variable drug. The analysis helped to formulate  recommendations for the design of bioequivalence  studies of atazanavir products,  including studies of the maximum dose, studies under fed conditions, and consideration  of atazanavir variation when planning the study design.С целью предупреждения развития  эпидемии, связанной с распространением ВИЧ-инфекции,  Правительством Российской Федерации была утверждена Государственная стратегия  противодействия распространению ВИЧ. Одной  из  задач  стратегии  является  увеличение  охвата антиретровирусной терапией  зараженных  ВИЧ-инфекцией, в том числе за счет широкого применения воспроизведенных лекарственных препаратов. Для регистрации воспроизведенного препарата необходимо представление отчета о результатах исследования его биоэквивалентности в сравнении с референтным препаратом. Атазанавир,  используемый в антиретровирусной терапии,  является  приоритетным препаратом при лечении и профилактике вертикальной передачи ВИЧ у беременных.  Был проведен анализ протоколов  и отчетов исследований биоэквивалентности препаратов  атазанавира, поступивших  на экспертизу  в ФГБУ «НЦЭСМП» Минздрава России,  с целью подготовки  рекомендаций по планированию исследований их биоэквивалентности. В результате проведенного анализа  ряда исследований выявлены  существенные отличия  в дизайне  исследований и количестве добровольцев. Основной причиной указанных  отличий  являются  противоречивые данные  о коэффициенте внутрииндивидуальной вариабельности атазанавира, указывающие  на возможное  отнесение атазанавира к высоковариабельным препаратам. На основании анализа сформулированы рекомендации по планированию исследований биоэквивалентности препаратов  атазанавира, включающие  в себя проведение  исследования на максимальной дозировке препарата, проведение  исследования после  еды и учет данных  по вариабельности атазанавира при выборе  дизайна исследования

Collection of microorganisms of ICG SB RAS as a genetic resource for biotechnology

Genetic knowledge of microorganisms plays a critical role in the creation of new biotechnologies, since the effectiveness of any biotechnology is determined by the particular qualities of the structurally functional organization of molecular-genetic systems and their components used for the production of targeted products. Collections of microbial cultures play a decisive role in mobilizing biological resources and make it possible to form a solid base for genetic, molecular biological and biotechnological research. The aim of this work was to assess the key molecular-genetic and phenotypic characteristics of strains of the collection of microorganisms created in the “FRC Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences” as a genetic resource for biotechnology. Thirty strains of microorganisms of the collection were isolated by employees of the FRC ICG SB RAS from extreme natural ecosystems, the key molecular-genetic and phenotypic characteristics were described using modern methods of molecular biology and mass-spectrometry. DNA isolation and the sequencing of 16S rRNA gene sequences were performed. The strains of the collection were characterized by morphological, physiological, moleculargenetic and mass-spectrometric characteristics. The particular qualities of growing of strains on different substrates have been established, the study of cell morphology has been carried out. The physiological characteristics of the strains of the collection have been established: the attitude to oxygen, the type of nutrition, the range of temperature and pH, the attitude to NaCl and others. Different resistance of strains to antibiotics has been established. The creation of personal mass spectra of protein profiles of the studied strains of the collection was carried out. The resulting DNA sequences of the strains are deposited in the GenBank. The chemotaxonomic characteristics of strains have been determined. The biotechnological properties of the strains were assessed, the amount of metabolites (ethanol, lactic and acetic acids) in the culture liquid was determined. The value of the collection of microorganisms of the FRC ICG SB RAS as a genetic resource for biotechnology and bioengineering is determined not only by the species diversity of its strains, but also by a wide range of their area isolation and by the depth of their characterization using the widest arsenal of both classical and modern methods (including methods of genomics, proteomics, transcriptomics and bioinformatics)