Planning of clinical trial programmes for medicines for the treatment of obesity

Scientific relevance. Obesity is a significant public health problem. Currently, the Russian Federation and the other Member States of the Eurasian Economic Union (EAEU) do not have regulatory documents and recommendations for planning clinical trials (CTs) of new (original) medicines for the treatment of obesity.Aim. The study aimed to provide recommendations on the basic principles of planning and conducting CTs of medicines for the treatment of obesity.Discussion. The authors reviewed the requirements for conducting CTs of medicines for the treatment of obesity set forth by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). In addition, the authors analysed approaches to CTs providing for a reliable evaluation of the efficacy and safety of medicines for the treatment of obesity. The primary endpoint of such CTs is a statistically significant loss of at least 5% of the baseline weight after 12 months of treatment. Secondary endpoints include assessments of abdominal obesity reduction, subcutaneous and visceral fat reduction, and the medicinal product’s effect on maintaining a reduced body weight.Conclusions. In addition, CTs should investigate the effects of treatment on cardiovascular risk factors and cardiovascular morbidity/mortality. A CT protocol should define the intercurrent events that should be considered in the analysis of trial results. When investigating the safety of medicines for the treatment of obesity, studies should focus on neuropsychiatric safety, the potential for abuse/addiction and withdrawal reactions, and the development of valvulopathy and pulmonary hypertension. These recommendations may be of use to experts evaluating clinical development programmes or marketing authorisation submissions for medicines for the treatment of obesity

Current Approaches to Demonstration of Therapeutic Equivalence of Locally-Acting Gastrointestinal Drugs

Evolution of knowledge about pharmacokinetics and pharmacodynamics of locally acting products, and an increase in the number of generics and medicines under development have laid the ground for the development of new scientific approaches to planning and conducting of therapeutic equivalence studies of medicinal products acting locally in the gastrointestinal (GI) tract. To date, many international guidelines on planning and conducting of bioequivalence (BE) studies of locally acting GI products have been updated, however, there are still no such guidelines in the Russian Federation and the Eurasian Economic Union (EAEU). Therefore, elaboration of common methodological approaches to the planning of clinical studies of these products is of particular relevance for the EAEU. The aim of the study was to analyse foreign approaches to planning, conducting, and evaluation of therapeutic equivalence studies of locally acting GI products. The paper analyses the guidelines of the European Medicines Agency and the US Food and Drug Administration on the planning, conduct, and evaluation of BE studies of locally acting GI products. The analysis demonstrated that BE clinical trials are giving way to in vitro studies providing a sensitive and accurate assessment of the differences between a locally acting GI product and the reference product, based on careful consideration of the medicine’s mechanism of action, dosage form, and site of action. The paper gives examples of test methods applied to medicinal products with a complex biopharmaceutical profile whose bioequivalence assessment is challenging, with a special focus on mesalazine products. The results of the analysis may be used for elaboration of a harmonised methodological approach to planning and conducting therapeutic equivalence studies of locally acting GI products in the Russian Federation and EAEU

Treatment for mixed cognitive impairments and emotional disorders in young and middle-aged patients

Objective: to evaluate the efficacy of Tanakan® (EGB761®) used in young and middle-aged patients with mixed cognitive impairments (CI) and emotional diseases.Patients and methods. An open-label observational study of the efficacy of Tanakan® was conducted in 54 patients aged 18–4 years with CI and psychoemotional disorders. Tanakan® was administered at a daily dose of 120 mg (40 mg t.i.d) for 3 months.Results. Tanakan® therapy resulted in health improvement, as shown by the HAM (Health, Activity, Mood) questionnaire; the mean score of the latter increased from 3.86 at baseline to 4.84 after 3 months of treatment. There were improvements in three HAM questionnaire items: the mean score of the item «Health» increased from 3.69 to 4.79; that of the item «Activity» from 3.65 to 4.58, and that the item «Mood» from 4.25 to 5.14 after the completion of the investigation.Tanakan® therapy also demonstrated improvements in memory (the mean number of correctly repeated words increased from 5.7 to 6.7 at the beginning of a visit and from 4.2 to 5.8 at its end) and in attention (the mean symbol-digit coding test score increased from 48.1 to 55.7%. There were no clinically relevant differences between patients with higher and secondary education in the efficacy of Tanakan®.Conclusion. Tanakan® had a very good safety profile; no adverse drug events were recorded during the investigation. Almost all the 53 (98.1%) of the 54 patients were satisfied with Tanakan® therapy results after 3 months of treatment

Планирование программы клинических исследований препаратов для лечения ожирения

Obesity is a significant public health problem. Currently, the Russian Federation and the other Member States of the Eurasian Economic Union (EAEU) do not have regulatory documents and recommendations for planning clinical trials (CTs) of new (original) medicines for the treatment of obesity.The aim of the study was to provide recommendations on the basic principles of planning and conducting CTs of medicines for the treatment of obesity.The authors reviewed the requirements for conducting CTs of medicines for the treatment of obesity set forth by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). In addition, the authors analysed approaches to CTs providing for a reliable evaluation of the efficacy and safety of medicines for the treatment of obesity. The primary endpoint of such CTs is a statistically significant loss of at least 5% of the baseline weight after 12 months of treatment. Secondary endpoints include assessments of abdominal obesity reduction, subcutaneous and visceral fat reduction, and the medicinal product’s effect on maintaining a reduced body weight. In addition, CTs should investigate the effects of treatment on cardiovascular risk factors and cardiovascular morbidity/mortality. A CT protocol should define the inter-current events that should be considered in the analysis of trial results. When investigating the safety of medicines for the treatment of obesity, studies should focus on neuropsychiatric safety, the potential for abuse/addiction and withdrawal reactions, and the development of valvulopathy and pulmonary hypertension. These recommendations may be of use to experts evaluating clinical development programmes or marketing authorisation submissions for medicines for the treatment of obesity.Нормативные документы и рекомендации по планированию клинических исследований (КИ) новых препаратов для лечения ожирения в Российской Федерации и в других государствах — членах Евразийского экономического союза в настоящее время отсутствуют.Цель работы: представить рекомендации по основным принципам планирования и проведения КИ препаратов для лечения ожирения.Проведен анализ требований к проведению КИ препаратов для лечения ожирения Европейского агентства по лекарственным средствам, Управления по контролю за качеством продуктов питания и лекарственных средств. Рассмотрены подходы, позволяющие достоверно оценить эффективность и безопасность препаратов для лечения ожирения при проведении КИ. Показано, что первичной конечной точкой является демонстрация статистически значимого снижения массы тела по крайней мере на 5% от исходной массы тела после 12 мес. терапии. Вторичные конечные точки: уменьшение степени выраженности абдоминального ожирения; оценка количества подкожного и висцерального жира; оценка влияния препарата на поддержание сниженной массы тела. Должно быть оценено влияние препарата на сердечно-сосудистые факторы риска и сердечно-сосудистую заболеваемость/смертность. В протоколе КИ необходимо представить определение интеркуррентных событий, влияние которых также нужно учитывать при анализе полученных результатов. В отношении безопасности препаратов для лечения ожирения следует сделать акцент на нейропсихической безопасности, потенциале злоупотреблений/зависимости и реакциях отмены, развитии вальвулопатии и легочной гипертензии. Настоящие рекомендации могут использоваться экспертами, осуществляющими оценку программы клинической разработки препаратов для лечения ожирения и экспертизу с целью регистрации

ОСОБЕННОСТИ МИКРОФЛОРЫ КИШЕЧНИКА У ДЕТЕЙ – РЕЦИПИЕНТОВ ДОНОРСКОЙ ПЕЧЕНИ

Aim. The study microecology of the large intestine of children with cirrhosis before transplantation of the share liver. Materials and methods. Studied the flora of the colon 157 children of 1 to 17 years admitted to hospital for liver transplantation fragment from a related donor. Identification was carried out using microbial panels BD Crystal and databases BBL Crystal MIND. Methicillin-resistant staphylococci were determined by their sensiti- vity to oxacillin and cefoxitin. Beta-lactamase activity was tested using discs with ceftazidime and ceftazidime/ clavulanic acid. Results. Microecological revealed deep irregularities in the large intestine transplantation in children up lobe of the liver on a spectrum and composition of the microflora. Among the resident microflora decreased levels of bifidobacteria, lactobacilli and coliform bacteria, especially in children under one year. A sig- nificant portion of the children surveyed (over 60–70%) had an increase of frequency of finding stateally bacteria, especially Klebsiella and enterobacteria in third children – non-fermenting bacteria – Pseudomonas and Acine- tobacter spp. Revealed the spread of strains of gram-negative bacteria with extended-spectrum betalaktamaz.Conclusion. Expressed microecological violations in the large intestine in children with higher levels of bac- teria are conditionally risk factor reeks of infectious complications in the postoperative period and require are complex tools to assist in eliminatsii.s given antibiotic resistance of bacteria. Цель: исследование микроэкологии толстого отдела кишечника детей с циррозами до трансплантации доли печени. Материалы и методы. Изучена микрофлора толстой кишки 157 детей от 1 года до 17 лет, поступивших в клинику для трансплантации фрагмента печени от родственного донора. Идентификацию микробов проводили с помощью панелей BD Crystal и базы данных BBL Crystal MIND. Метициллин-резистентность стафилококков определяли по их чувствительности к оксациллину и цефокситину. Бета-лактамазную активность тестировали с помощью дисков с цефтазидимом и цефтазидим/клавулановой кислотой. Результаты. Выявлены глубокие микроэкологические нарушения в толстом отделе кишечника у детей до трансплантации доли печени, касающиеся как спектра, так и состава микрофлоры. Среди резидентной микрофлоры отмечено снижение уровня бифидобактерий, лактобацилл и кишечных палочек, особенно у детей до года. У значительной части обследованных детей (свыше 60–70%) отмечено нарастание частоты нахождения условно-патогенных бактерий, особенно клебсиелл и энтеробактеров, у 1/3 детей – неферментирующих бактерий – синегнойных палочек, ацинетобактеров. Выявлено распространение штаммов грамотрицательных бактерий с бета-лактамазами расширенного спектра действия. Заключение. Выраженные микроэкологические нарушения в толстом отделе кишечника у детей с повышением уровня условно-патогенных бактерий являются фактором риска развития инфекционных осложнений в послеоперационном периоде и требуют применения комплексных средств, способствующих их элиминации.

ИССЛЕДОВАНИЕ АНТИБИОТИКО- И ФАГОЧУВСТВИТЕЛЬНОСТИ НОЗОКОМИАЛЬНЫХ ШТАММОВ МИКРОБОВ, ВЫДЕЛЕННЫХ ОТ ПАЦИЕНТОВ ТРАНСПЛАНТОЛОГИЧЕСКОЙ КЛИНИКИ

Antibiotic and fagosensitivity most etiologically important nosocomial strains of bacteria – Pseudomonas aeru- ginosa, Klebsiella pneumoniae, E. coli, Proteus spp., Staphylococcus spp. were studied. Multiple drug-resistant bacteria as gram-positive and gram-negative, isolated from 8 substrates, had been demonstrated. With regard to the sensitivity of Pseudomonas aeruginosa >40% was observed in 40–50% of the strains to aminoglycosides – aztreonam, amikacin, netilmicin, and only 23–25% of the strains – to gentamicin and levofloxacin (an average of antibiotic susceptibility was 27%). All strains of ESBL Klebsiella drew up and were sensitive only to imipenem, meropenem and aminoglycosides. Specific phages lysed 43–48% of the strains Pseudomonas aeruginosa and Klebsiella pneumoniae, E. coli, Pro- teus spp., multidrug resistant strains of Staphylococcus spp. It is proposed to introduce the use of phages in clinical practice. Исследована антибиотико- и фагочувствительность наиболее этиологически важных нозокомиальных штаммов микробов – синегнойных палочек, клебсиелл, кишечных палочек, протеев, стафилококков. Установлена множественная резистентность штаммов бактерий как грамположительных, так и грамотрицательных, изолированных из 8 субстратов. В отношении синегнойной палочки чувствительность >40% отмечена у 40–50% штаммов к аминогликозидам – азтреонаму, амикацину, нетилмицину и только у 23–25% штаммов – к гентамицину и левофлоксацину (в среднем антибиотикочувствительность составила 27%). Все штаммы клебсиелл вырабатывали БЛРС и были чувствительны только к имипенему, меропенему и аминогликозидам. Специфические бактериофаги лизировали 43–48% штаммов синегнойных палочек и клебсиелл, кишечные палочки, протеи, множественно резистентные штаммы стафилококков. Предлагается внедрять использование бактериофагов в клиническую практику трансплантологических клиник.

Fractional Order Integrals for the Sustainable Development Model

© Published under licence by IOP Publishing Ltd. Sustainable development is now engaged in many leading countries. The notion is connected with the activity of countries, their economies, social and political institutions. One of the criteria of sustainability is the economic sphere, the study of which will allow you to control and predict its activity. It is known that the description of continuous processes that arise in economic problems, using definite integrals. In the case when the studied continuous development is carried out in small jumps, when it is the description of the use of fractional integral and differential equations. However, their exact solution is possible only in special cases. Therefore, the construction of approximate methods for solving fractional integral and differential equations is of great importance. In this paper, we give an approximate solution of fractional integral equations of the first kind, where the fractional integral is constructed using the Weyl fractional integral. It turns out that the constructed operator of fractional integration is symmetrical and positively definite. These properties are built by the operator enables to introduce the scalar product on the basis of the specified operator and the corresponding energy space. Next, using the same methodology that is used in the finite element method, approximate solution is constructed, constructed a rough scheme of the method and rationale of the proposed method to construct the energy space. The integral equation of the standard form is given as a specific example, as well as an example solution to illustrate the effectiveness of the proposed method

Numerical methods of the decision differential the equations for continuous models of economy

© 2015, Mediterranean Center of Social and Educational Research. All rights reserved. The review of some models of economy based on application of the ordinary differential equations is provided in article linear and nonlinear, and also the review of approximate methods of their decision. Expediency of use of this or that numerical metods of the solution of the differential equations is shown. For some equations of continuous models of economy in work the approximate method is offered and reasonable. Estimates of convergence of approximate methods are given in the corresponding functional spaces. Results of the numerical solution of these equations in the form of tables and schedules are also received. The comparative analysis of the received results is carried out

Numerical methods of the decision differential the equations for continuous models of economy

© 2015, Mediterranean Center of Social and Educational Research. All rights reserved. The review of some models of economy based on application of the ordinary differential equations is provided in article linear and nonlinear, and also the review of approximate methods of their decision. Expediency of use of this or that numerical metods of the solution of the differential equations is shown. For some equations of continuous models of economy in work the approximate method is offered and reasonable. Estimates of convergence of approximate methods are given in the corresponding functional spaces. Results of the numerical solution of these equations in the form of tables and schedules are also received. The comparative analysis of the received results is carried out