Triple molybdates one-, one - and three(two)valence metals

The authors thank Ph. D. M. K. Alibaeva, Ph. D. I. A. Gudkova and Ph. D. I. V. Korolkova for participation in the research.The review summarizes experimental data on the phase formation, structure and properties of new complex oxide compounds group - triple molybdates containing tetrahedral molybdate ion, two different singly charged cation, together with tri- or divalent cation. The several structural families of these compounds were distinguished and it shown that many of them are of interest as luminescent, laser, ion-conducting or nonlinear optical materials.The work is executed at partial support of the Russian Foundation for basic research (projects No. 08-03-00384, 13-03-01020 and 14-03-00298)

Comparative evaluation of the mental health problems and their assocoiations with the risk factors of the chronic somatic diseases at the rural and urban populations

The 522 rural and 404 urban respondents were asked using GSAD, GHQ-12, CINDI questionnaires etc to assess prevalence of mental health problems and their associations on the population-based study. Percentage of people with high of depression and anxiety is 42±2,2% and 35±2,1% acc. at the rural population, and 42,6±2,5% and 37,9±2,4% acc. among townspeople, and generally rises with the age. The problems at women are more often, and associated with primary education, marital status peculiarities; high stress level and BMI. some somatic diseases. We obtained high prevalence of alcohol abusing, especially among rural people. It is associated with primary education and low family income. Smoking is more often at rural respondents and associated with male sex, primary education but financial status «more than minimal». We suppose the serious burden of depression, anxiety, alcohol abusing and smocking but low awareness concerning mental health problems at the rural and urban populations.С целью анализа эпидемиологии тревожных и депрессивных расстройств, злоупотребления алкоголем, курения и их ассоциаций, при одномоментном популяционном исследовании проанкетированы 522 жителя села и 404 городских респондента (опросники GSAD, GHQ-12, CINDI и др.). Доля лиц, имевших «50-процентную вероятность депрессии» и «50-процентную вероятность тревожного расстройства на селе 42±2,2% и 35±2,1% , в городе -42,6±2,5% и 37,9±2,4 % соответственно, и нарастает с возрастом. Данные проблемы чаще выявляются у женщин, и ассоциированы с низким уровнем образования, семейным статусом, высоким уровнем стресса, высоким индексом массы тела, наличием ряда соматических заболеваний. Злоупотребление алкоголем широко распространено в популяции и ассоциировано с низким уровнем образования и доходов респондентов. Курение чаще наблюдается среди жителей села, молодых мужчин, лиц с низким уровнем образования, но уровнем дохода выше минимального. Заключение: выявлена высокая распространенность депрессивных и тревожных расстройств, злоупотребления алкоголем и курения среди сельских и городских жителей. Население исследованных районов характеризуется крайне низкой информиованностью относительно проблем в области психического здоровья

Considerations for Permitted Daily Exposure Calculation for Contaminants in Medicinal Products Manufactured in Shared Facilities

The manufacture of different medicinal products in shared facilities creates a risk of cross-contamination. One of the approaches to select the limits for possible contaminants is based on calculating the permitted daily exposure (PDE), i.e. the dose of an active pharmaceutical ingredient or any other substance contaminating a medicinal product that will not be associated with any adverse events in a human in the case of lifetime exposure. The aim of this study was to provide practical guidance on selecting adjustment factors for calculating PDEs to establish limits for potential contaminants in multi-purpose pharmaceutical facilities. The authors analysed the regulatory requirements and literature needed to establish critical effects of contaminants, outlined possible assumptions in the use of quantitative indicators for measuring toxicity, and described the relationship between the PDE and other indicators of the safety of chemical compounds for human health. The article presents an example of PDE calculation for an investigational hypoglycemic medicinal product using a limited amount of open-source literature data. Thus, the article demonstrates the role of information on the primary pharmacodynamic effects of medicinal products in the assessment of their critical effects, which is necessary to implement the most conservative approaches to PDE calculation. The example of PDE calculation presented in the article may be used to assess cross-contamination risks associated with non-dedicated manufacturing facilities

Adherence to disease-modifying drugs in rheumatoid arthritis patients, its determinants and influence on clinical outcomes

Adherence to disease-modifying anti-inflammatory rheumatic drugs (DMARDs) in rheumatoid arthritis (RA) patients in Russia and its influence on clinical outcomes have not been studied. The aim of this study was to assess the adherence to DMARDs in rheumatoid arthritis patients. Methods. In cross-sectional study 200 RA patients were interviewed, and their records were analyzed. Inclusion criterion was the duration of follow-up more than a year (mean duration of the disease was 9,2 years). All patients were studied in a tertiary center, and all of them were advised to take different DMARDs. Demographic characteristics and clinical features were assessed, as well as knowledge of patients about RA. Patients were considered to be adherent if they took DMARDs more than 80% of time. Results. 22,5% of RA patients were adherent. The adherence did not influence on clinical features of active inflammation, but it was associated to a less degree of joint destruction: OR=0,32 (95%CI: 0,15-0,67), p=0,003. The main determinants of non- adherence were adverse events of DMARDs, the duration of the disease and the opinion of the patient on the effectiveness of the drug. Conclusion. The adherence to DMARDs in RA patients is low, and it has influence on clinical outcomes.Приверженность больных ревматоидным артритом (РА) рекомендуемому лечению базисными противовоспалительными препаратами (БПВП) и ее влияние на исходы заболевания у российских пациентов не изучалась. Цель исследования — охарактеризовать состояние приверженности лечению базисными препаратами пациентов с РА. Материал и методы В одномоментном исследовании оценены 200 больных РА с продолжительностью наблюдения не менее года (средняя продолжительность заболевания 9,2 г.), обратившиеся на прием в областной ревматологический центр. Всем ранее рекомендовались БПВП. Оценивались демографические и клинические характеристики, рентгенологическая стадия, а также знания пациента о своем заболевании. Приверженными считались больные, принимавшие БПВП не менее 80% времени. Результаты Приверженными рекомендованному лечению были 22,5% больных РА. Приверженность не влияла на клинические признаки активности заболевания, но ассоциировалась с меньшей степенью деструкции суставов по рентгенологическим данным: 0ш=0,32 (95%ДИ: 0,15- 0,67), р=0,003. Важнейшими детерминантами неприверженности были побочные эффекты БПВП, длительность заболевания и мнение пациента о неэффективности лечения. Выводы. Приверженность рекомендованному лечению при РА — низкая, что влияет на исходы заболевания. Необходимы мероприятия по ее повышению

Агонисты тромбопоэтиновых рецепторов: клиническое применение и оценка эффективности терапии

Idiopathic thrombocytopenic purpura (ITP), or primary immune thrombocytopenia, is an orphan disease associated with thrombocytopenia. One of the most recent and promising approaches to ITP treatment is the use of thrombopoietin receptor agonists (TPO-RAs). The scope of TPO-RA use is expanding rapidly, which stimulates the development of both innovator and generic (or biosimilar) medicines. The aim of the paper was to assess TPO-RA role in ITP treatment, methodological approaches to TPO-RA development, and feasibility of using the platelet count as a pharmacodynamic marker in bioequivalence studies of peptide TPO-RAs in healthy volunteers. Clinical development of new medicines for the treatment of thrombocytopenia includes comparative, parallel-group trials lasting about a year. The standard approach to bioequivalence studies, which is based on the results of comparative pharmacokinetic studies, can be used in marketing authorisation applications for generic non-peptide TPO agonists, while peptide TPO agonists have to comply with specific requirements for biosimilar products. The orphan status of ITP does not affect the development strategy and study design, but it limits the number of patients that could be included into the study. In the absence of valid surrogate biomarkers of efficacy, demonstration of comparable clinical efficacy of the biosimilar and reference drug is usually required in a randomised, parallel, preferably double-blind comparative study. On the other hand, clinical comparability of the biosimilar and reference drug can also be demonstrated in comparative pharmacodynamic studies, if the selected biomarker is a well-established and valid surrogate marker which correlates with patient clinical outcome. Platelet count is a key parameter in both diagnosis of diseases associated with low platelet levels and assessment of treatment efficacy. Therefore, it can be used as a pharmacodynamic marker in bioequivalence studies of biosimilar peptide TPO-RAs. It was concluded that such studies could be performed in healthy volunteers, and not in patients, whose participation in clinical trials is limited due to the orphan status of ITP.Идиопатическая тромбоцитопеническая пурпура, или первичная иммунная тромбоцитопения (ИТП), — орфанное заболевание, сопровождающееся тромбоцитопенией. Одним из новых и перспективных методов лечения ИТП в последние годы стало использование агонистов рецепторов тромбопоэтина (ТПО), сфера применения которых стремительно расширяется, что делает перспективной разработку не только оригинальных препаратов, но и воспроизведенных или биоподобных препаратов из данной группы. Цель работы — оценка роли агонистов рецепторов ТПО в терапии ИТП, методологических подходов к их разработке и приемлемости использования показателя количества тромбоцитов в качестве фармакодинамического маркера при проведении исследований биологической эквивалентности лекарственных средств из группы пептидных агонистов рецепторов ТПО у здоровых добровольцев. При изучении новых препаратов для лечения тромбоцитопении проводят сравнительные клинические исследования в параллельных группах длительностью около года. Стандартный подход к исследованиям биоэквивалентности, основанный на результатах сравнительных исследований фармакокинетики, может быть применен при регистрации воспроизведенных лекарственных средств, относящихся к непептидным агонистам ТПО, в то время как для пептидных агонистов ТПО актуальны специфические требования, предъявляемые к биоподобным препаратам. При этом орфанный статус ИТП, существенно ограничивающий возможный размер исследуемой популяции, не влияет на стратегию разработки и дизайн необходимых исследований. В отсутствие общепризнанных суррогатных биомаркеров эффективности, как правило, требуется подтверждение сопоставимой клинической эффективности биоподобного и референтного лекарственного препарата в рандомизированном параллельном, предпочтительно двойном слепом сравнительном исследовании. С другой стороны, подтверждение клинической сопоставимости биоподобного и референтного препаратов возможно в рамках сравнительных фармакодинамических исследований, если выбранный биомаркер является валидным и общепринятым суррогатным маркером и соотносится с клиническим исходом у пациентов. В обзоре показано, что так как количество тромбоцитов является ключевым критерием как диагностики, так и эффективности лечения заболеваний, сопровождающихся снижением тромбоцитов, уровень тромбоцитов может быть использован как фармакодинамический маркер в исследованиях биологической эквивалентности биоподобных лекарственных средств из группы пептидных агонистов рецепторов ТПО. Сделан вывод о том, что подобные исследования можно проводить с участием здоровых добровольцев, а не пациентов с соответствующим заболеванием, возможности по включению которых в клиническое исследование ограничены из-за орфанного статуса ИТП

Insects and molluscs of the Late Pleistocene at the Gornovo site (Southern Ural foreland, Russia): New data on palaeoenvironment reconstructions

The paper presents new data on the subfossil insects and molluscs, as well a new radiocarbon date for the Gornovo site in the Southern Fore-Urals. As a result, the stratigraphic interpretation of the sediments of the lower part of the first above floodplain terrace of the Belaya River is corrected and they are assigned to the Tabulda Horizon (MIS 3) of the Upper Pleistocene in the regional scheme of the Fore-Urals Quaternary. The malacofauna of the locality is represented by 27 species of terrestrial and freshwater molluscs. The composition of molluscs in the deposits of MIS 3 indicates the succession of deposit accumulation in the river valley from the stage of reservoirs that periodically connecting with the river to the stage of the overgrown oxbow lake. Single occurrence of mollusc shells in the loams of MIS 2 is a result of sharp climate change. New insect material includes 136 species of Coleoptera from 17 families, as well as Heteroptera and Hymenoptera representatives. 29 species of beetles (Carabidae, Histeridae, Scarabaeidae, Elateridae, Tenebrionidae, Chrysomelidae, Brentidae and Curculionidae) are recorded for the Pleistocene for the first time. The insect assemblages from Gornovo site are assigned to periglacial and humid boreal faunal types. The entomofauna of the periglacial type has no analogues in the recent fauna; it corresponds to the deposits assigned to the middle of MIS 3. This entomofauna is characteristic to the MIS 2 and MIS 3 insect assemblages from the south of West Siberian Plain. Based on entomological data, the climate of the middle of MIS 3 of the Southern Fore-Urals is reconstructed as dry and cold, extracontinental, with mean July temperature not exceeding +15 °C. Steppe landscapes likely prevailed in open areas and coniferous forests were restricted to river valleys. Beetles from deposits dated to end of MIS 3 are assigned to the fauna of the boreal humid type. These insect assemblages are significantly poorer in diversity than periglacial type assemblages and are represented mainly by near water and forest Coleoptera. Based on these species, meadow and forest landscapes were reconstructed. The reconstructed mean air temperature of July ranged from +16 to +19 °C. This suggests a trend towards more mild conditions in the region connected to the climate warming at the end of MIS 3. It is likely that humidification during this period was regional, determined by the proximity of the site to the Southern Urals Mountains. © 2021 Elsevier Ltd and INQU

Estimate of prevalence of chronic widespread pain syndrome and its association with mental status in rural population

Chronic widespread pain syndrome (CWPS) affects about 10% of adult population and is associated with several chronic conditions, including mental, according to foreign literature. CWPS in Russia is virtually undiagnosed, although the results of a single pilot study allow to conclude that CWPS in prevalent in Russia and is a medical and social problem. Study aim: examine the prevalence of CWPS in rural population of Russia, activity of pain coping strategies and mental status of such patients. Material and methods. Data of 520 respondents aged 25 and older who were randomly chosen by PC from the rural population of Nizhne-Serginsky district of Sverdlovsk region were analyzed. Responded completed questionnaire by themselves comprised of four parts: a) general pain characterictics; b) body manikins to draw pain; c) questionnaires related to subject attitude to pain; d) mental health questionnaires. Results: Prevalence of CWPS was 8,5% (95% Cl: 6,2-11,2). Prevalence increased with age (OR=1,54, 95% Cl: 1,11-2.16), p=0,007. Analysis of levels of mental distress and somatization showed that CWPS respondents had reasonably higher levels of parameters compared to general population (OR=2,3 (95% Cl: 1,2-4,3) for distress and 0R=7,1 (95% Cl: 3,4-14,8) for somatization). Comparison of CWPS subjects and subjects with non-generalized chronic pain showed that CWPS group has higher intensity of both active pain coping (19,4 vs 17,1, p=0,03) and passive pain coping (33,1 vs 29,5, p=0,005). Conclusion. CWPS in rural population is prevalent and is associated with higher levels of somatization and distress, and high intensity of pain-coping behavior that suggests active seeking of medical and social support. CWPS screening is simple but allows decreasing burden of CWPS on rural healthcare system.Синдром хронической генерализованной боли (СХГБ) по данным зарубежной литературы поражает около 10% взрослого населения, и ассоциирован с рядом хронических состояний, в том числе психических. В России СХРБ практически не известен, однако результаты единственного пилотного исследования позволяют предполагать, что СХРБ распространен и в РФ, и является медико- социальной проблемой. Цель исследования — изучить распространенность СХГБ у сельских жителей России, активность борьбы с болью и психический статус таких пациентов. Материал и методы Изучены данные 520 респондентов в возрасте 25 лет и старше, выбранных методом компьютерной рандомизации из популяции жителей Нижне-Сергинского района Свердловской области. Респонденты самостоятельно заполняли анкету, состоявшую из четырех частей: а) общая характеристика боли, б) схемы тела для обозначения боли, в) опросники отношения пациента к боли; г) опросники на психический статус пациента. Результаты Распространенность СХГБ составляет 8,5% (95% ДИ: 6,2-11,2). Отмечен статистически значимый рост распространенности СХГБ с возрастом (0Ш=1,54, 95% ДИ: 1,11-2,16), р=0,007. При оценке уровней психологического дистресса и соматизации выявлено, что у респондентов с СХГБ они существенно выше, чем в остальной популяции (ОШ=2,3 (95% ДИ: 1,2-4,3) для дистресса и 0Ш=7,1 (95% ДИ: 3,4-14,8) для соматизации). При сравнении группы СХРБ и группы хронической негенерализованной боли выявлено, что в группе СХРБ выше уровень как активной (19,4 против 17,1, р=0,03), так и пассивной борьбы с болью (33,1 против 29,5, р=0,005). Выводы СХГБ у жителей сельской местности — распространенное состояние, сопровождающееся повышенным уровнем соматизации и дистресса, а также высокой интенсивности болезненного поведения, что предполагает активный поиск медицинской и социальной поддержки. Скрининг на СХГБ несложен, но позволит существенно снизить нагрузку на сельское здравоохранение

The changes of standard DXA measurements and TBS depending on outcomes of neurosurgical treatment in patients with Cushing's disease

BACKGROUND:Patients with endogenous hypercortisolism have reduced bone mineral density (BMD) and trabecular bone score (TBS) that are the causes of secondary osteoporosis and low-traumatic fractures. It is well known that radical treatment (neurosurgery or radiosurgery) of Cushings disease leads to a decline of cortisol levels in all body fluids to normal values. However, it is still uncertain whether bone tissue structure, and particularly its microarchitecture, does recover in remission of the disease. AIMS:To evaluate an influence of hormone activity (presence or absence of remission) in patients with Cushing's disease on changes of bone structure measurements in accordance with DXA values (TBS, BMD, T- and Z-scores), as well as significance of such changes in 12 and 24 months after neurosurgical treatment. MATERIALS AND METHODS:In patients with confirmed active Cushing's disease (ACTH-producing pituitary adenoma) (n = 44) and in control group of healthy volunteers (n = 40), BMD in lumbar spine (L1-L4) and simultaneously TBS, in cut-off points before neurosurgical treatment (in both groups) and in 12 and 24 months after it (only in patients), were assessed. We diagnosed presence or absence of disease remission at cut-offs. All measurements were performed using a GE iDXA device (GE Healthcare Lunar, Madison, Wisconsin, USA). The TBS was calculated simultaneously from taken BMD scans, blinded to clinical outcome using TBS iNsight software v2.1 (Medimaps, Merignac, France). The activity of Cushings disease was evaluated using late-night salivary cortisol (LNSC, at 23:00). To determine the differences in DXA and TBS values before and after neurosurgical intervention depending on remission occurrence, covariate analysis (ANCOVA) was applied. RESULTS:There were found significant changes in TBS, BMD and T-score values in 12 months after neurosurgical treatment associated with presence or absence of disease remission (p = 0.039, 0.046 and 0.048, respectively). No differences in Z-score as well as in all measurements in 24 months, that might be associated with remission occurrence, were revealed. The gain in all DXA measurements (including TBS) during 24 months of observation period was statistically significant when analyzing data using Students paired t-test. However, the values corresponding to the age references had not been achieved for the specified time interval. CONCLUSIONS:Patients with Cushings disease have lower TBS values. In remission conditions TBS is getting significantly higher. The increase in BMD and TBS occurs during 24 months after achieving remission of Cushings disease but doesnt lead to a full restoration of normal bone mass and microstructure throughout observation period of 24 months