Risk assessment of the adverse impact of industrial synthesis of benzodiazepine drugs on human health

Among the occupational and work-related diseases of employees in pharmaceutical industry the leading positions belong to the diseases caused by long-term work under the conditions of relatively low concentrations of hazard substances. The study and evaluation of risks will eliminate or reduce the impact, thereby, enhancing the quality of life. Synthetic drugs - benzodiazepine derivatives by the values of middle-lethal doses are substances of the 111 class of hazard and cause slight irritating effect to the skin and mucous membranes of the eyes; skin-resorptive and sensitizing effects have not been identified. For the studied benzodiazepine derivatives the safe exposure levels have been approved in the following values: nozepam -1 mg/m3; mezapam - 0.3 mg/m3; sibazon - 0.2 mg/m3; alprazolam - 0.1 mg/m3. On the base of the toxicological studies the parameters of the hazardous effects on the body have been identified allowing for a final risk characterization. The article presents the results of the calculation of the potential dose that may be received by the employee during the working shift in the synthesis of products of this series. Calculation of safe level of exposure is based on a threshold concentration of substances. Drags risk factors by inhalation have been calculated by comparing the value of the potential dose of a xenobiotic received for one shift by inhalation with its level of safe effect under the same route of exposure. The estimated hazard ratios for the studied substances demonstrate a low probability of adverse effects on the workers during the production of nozepam and alprazolam. High risk of negative impact on the health of workers has been identified during the production of sibazon and mezapam. This information can then be used to control the working environment during the synthesis of drugs - benzodiazepine derivatives, aimed at creating a safe working environment and, consequently, improving the workers' life quality

Biosafety model of adenovirus infection: Effects of bacterial proteases for infection of human cells in vitro

To determine the antiviral activity of various biologically active compounds, the model of adenovirus infection on the basis of cell cultures of human HEK293A and recombinant adenovirus Ad-EGFP, expressing green fluorescent protein EGFP. Adenoviruses have a capsid size of 70-90 nm and are able to infect dividing and nondividing cells in vitro and in vivo. Recombinant adenoviruses are the replicative defect in the cells of humans and animals. The developed model allowed us to determine the effect of bacterial proteases in the infected cell cultures with adenovirus. This model can also be used for screening drugs with potential protivivovirusnoy activity

HBD-2 interactions with erythrocyte membranes in vitro

HBD-2 – a member of β-defensin family of antimicrobial peptides – is known to permeabilize cell membranes of susceptible cells, but the mechanism of such interactions is poorly understood. In our study, we have used a hemolytic model to explore the kinetic properties of HBD-2 interactions with membranes of human erythrocytes. We ran hemolytic assays with a wide range of both HBD-2 and erythrocyte concentrations, as well as varying pH values, incubation times, and osmotic strengths; each in the presence or the absence of inhibitory substances such as proteins and salts. The results show that HBD-2 cell membrane permeabilization is both dose- and time-dependent (with plateau effect observed in each case), and inversely dependent on erythrocyte concentration. HBD-2 interactions with cell membranes highly depend on pH value and the presen­ce of inhibitors but are not affected by tested osmotic strength range. Our findings suggest that interactions of HBD-2 with cell membranes are mainly electrostatic in nature and are limited by released cell content. We have developed a speculative model of such interaction based on our results

Scientific school children's dietology: history, present and future

The article presents the formation and development of the scientific school of Pediatric Dietetics at the Ural State Medical University. The foundations of the scientific direction of the Department of Faculty Pediatrics and Propedeutics of Childhood Diseases were laid more than 80 years ago by the first works of the head of the department, Professor, Doctor of Medical Sciences. T.E. Vogulkina, continued by Professor O. A. Sinyavskaya, professor A.V. Kharitonova, were further developed and recognized in Russia and abroad under the guidance of Professor, Doctor of Medical Sciences. N. Е. Sannikova. Based on large-scale research aimed at establishing new aspects of the pathogenesis of alimentary-dependent diseases, improving their diagnosis, treatment and prevention, the Scientific School of Children's Dietetics puts forward and substantiates fundamentally new paradigms in relation to existing scientific and technical areas, creates conditions for the introduction of innovative technologies in production of baby food. An integral part of the development of the scientific school is the training of highly qualified specialists who possess modern knowledge of children's nutrition and, at the same time, carefully preserve the continuity and experience of previous generations of researchersВ статье представлено становление и развитие научной школы «Диетология детского возраста» Уральского государственного медицинского университета. Основы научного направления кафедры факультетской педиатрии и пропедевтики детских болезней заложены более 80 лет назад первыми работами заведующей кафедрой профессора, д.м.н. Т.Э. Вогулкиной, продолжены профессором, д.м.н. О.А. Синявской, профессором, д.м.н. А.В. Харитоновой, получили дальнейшее развитие и признание в России и за рубежом под руководством профессора, д.м.н. Н.Е. Санниковой. Опираясь на углубленные широкомасштабные исследования, направленные на установление новых аспектов патогенеза алиментарно-зависимых заболеваний, совершенствование их диагностики, лечения и профилактики, научная школа «Детская диетология» выдвигает и обосновывает принципиально новые парадигмы применительно к существующим научно-техническим направлениям, создает условия для внедрения инновационных технологий в производство продуктов детского питания. Неотъемлемой частью развития научной школы является подготовка высококвалифицированных специалистов, владеющих современными знаниями детской нутрициологии и одновременно бережное сохранение преемственности и опыта предшествующих поколений исследователе

Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients

Background Patients with acute medical illnesses are at prolonged risk for venous thrombosis. However, the appropriate duration of thromboprophylaxis remains unknown. Methods Patients who were hospitalized for acute medical illnesses were randomly assigned to receive subcutaneous enoxaparin (at a dose of 40 mg once daily) for 10±4 days plus oral betrixaban placebo for 35 to 42 days or subcutaneous enoxaparin placebo for 10±4 days plus oral betrixaban (at a dose of 80 mg once daily) for 35 to 42 days. We performed sequential analyses in three prespecified, progressively inclusive cohorts: patients with an elevated d-dimer level (cohort 1), patients with an elevated d-dimer level or an age of at least 75 years (cohort 2), and all the enrolled patients (overall population cohort). The statistical analysis plan specified that if the between-group difference in any analysis in this sequence was not significant, the other analyses would be considered exploratory. The primary efficacy outcome was a composite of asymptomatic proximal deep-vein thrombosis and symptomatic venous thromboembolism. The principal safety outcome was major bleeding. Results A total of 7513 patients underwent randomization. In cohort 1, the primary efficacy outcome occurred in 6.9% of patients receiving betrixaban and 8.5% receiving enoxaparin (relative risk in the betrixaban group, 0.81; 95% confidence interval [CI], 0.65 to 1.00; P=0.054). The rates were 5.6% and 7.1%, respectively (relative risk, 0.80; 95% CI, 0.66 to 0.98; P=0.03) in cohort 2 and 5.3% and 7.0% (relative risk, 0.76; 95% CI, 0.63 to 0.92; P=0.006) in the overall population. (The last two analyses were considered to be exploratory owing to the result in cohort 1.) In the overall population, major bleeding occurred in 0.7% of the betrixaban group and 0.6% of the enoxaparin group (relative risk, 1.19; 95% CI, 0.67 to 2.12; P=0.55). Conclusions Among acutely ill medical patients with an elevated d-dimer level, there was no significant difference between extended-duration betrixaban and a standard regimen of enoxaparin in the prespecified primary efficacy outcome. However, prespecified exploratory analyses provided evidence suggesting a benefit for betrixaban in the two larger cohorts. (Funded by Portola Pharmaceuticals; APEX ClinicalTrials.gov number, NCT01583218. opens in new tab.

Менингококковая инфекция у детей в период 2012–2021 гг. Основные итоги ретроспективного многоцентрового исследования, проблемы сегодняшнего дня

The heavy burden of meningococcal infection is associated not only with life-threatening complications in the acute period and high mortality in invasive forms of the disease, but also with severe consequences in survivors, who are not recorded in our country.The aim of study: to analyze clinical manifestations, complications of the acute period and outcomes of invasive forms of meningococcal disease in children in various regions of the Russian Federation.Materials and methods: an analysis of data from 1327 inpatient medical records of children with an invasive meningococcal infection from 14 regional centers of the Russian Federation for 2012-2021 was carried out (28.3% of cases of the disease in children in the represented federal districts).Results: it was found that young children predominated among the patients – the median was 27.4 (10.7-70.4) months. Complications of the acute period, often combined, were observed in 47.6% of cases. The development of septic shock was noted in 30.4%, Waterhouse-Friderichsen syndrome in 6.6%, carditis in 2.9%, cerebral edema in 15.7%, arthritis in 1.4% of cases; the formation of hydrocephalus, subdural effusion, sensorineural hearing loss in 1.8%, 0.6%, 1% of children, respectively. The presence of soft tissue necrosis requiring surgical intervention was noted in 3.5% of cases. Mortality rate was 10.1%. At the time of discharge from the hospital, 30% of children had complications associated with meningococcal infection: organ dysfunction/ failure in 13.2% of patients (severe in 1.3%), cerebral insufficiency in 19.6%; severe psycho-neurological deficits, sensorineural hearing loss, problems associated with the need for orthopedic/surgical interventions accounted for 0.7%, 0.6% and 0.8%, respectively.Conclusion. Considering the epidemiological features of meningococcal infection – the risk of a sharp increase in morbidity in short periods of time, the life-threatening nature of the disease itself, it is necessary to remain alert to these risks and take all possible measures to prevent the disease using all available means, the most effective of which is vaccine prevention.Тяжелое бремя менингококковой инфекции связано не только с жизнеугрожающими осложнениями острого периода и высокой летальностью при генерализованных формах заболевания, но и с тяжелыми последствиями у выживших, учет которых в нашей стране не ведется.Цель: проведение анализа клинических проявлений, осложнений острого периода и исходов генерализованных форм менингококковой инфекции у детей в различных регионах Российской Федерации.Материалы и методы: проведен анализ данных 1327 медицинских карт (форма 003/у) детей с генерализованной формой менингококковой инфекции из 14 региональных центров Российской Федерации за 2012– 2021 гг. (28,3% случаев заболевания у детей в представляемых федеральных округах).Результаты: установлено, что среди больных преобладали дети раннего возраста – медиана составила 27,4 (10,7–70,4) месяцев. Осложнения, часто сочетанные, в остром периоде заболевания наблюдались в 47,6% случаев: септический шок в 30,4%, синдром Уотерхауза – Фридериксена в 6,6%, кардит в 2,9%, отек головного мозга в 15,7%, артриты в 1,4%, гидроцефалия в 1,8%, сенсоневральная тугоухость в 1%, субдуральный выпот в 0,6% случаев. Наличие некрозов мягких тканей, требовавших хирургического вмешательства, отмечено в 3,5% случаев. Летальность составила 10,1%. На момент выписки из стационара у 30% детей выявлялись осложнения, в том числе выраженная органная дисфункция в 1,3%, грубый психоневрологический дефицит, сенсоневральная тугоухость; осложнения, требующие проведения ортопедических/хирургических вмешательств, составили 0,7%, 0,6% и 0,8% соответственно.Анализ полученных данных позволил вскрыть существующие проблемы, касающиеся клинической и этиологической диагностики заболевания, возможностей выявления осложнений острого периода и учета последствий генерализованных форм менингококковой инфекции.Заключение. Учитывая эпидемиологические особенности менингококковой инфекции (риск резкого подъема заболеваемости в короткие временные промежутки, жизнеугрожающий характер самого заболевания), необходимо сохранять настороженность в отношении данных рисков и предпринимать все возможные меры для профилактики заболевания с использованием всех доступных средств, наиболее эффективным из которых является вакцинопрофилактика

COMBINATION OF TAXOL WITH CARBOPLATIN IN THE TREATMENT OF PATIENTS WITH STAGES IIB-IV OVARIAN CANCER (FIRST MULTI-CENTER EXPERIENCE IN RUSSIA)

Taking into account the fact that the treatment of advanced ovarian cancer includes cytoreductive surgery and chemotherapy, it is important to take advantage of contemporary highly effective agents. In 2003 the Regional program for optimization of ovarian cancer treatment in Cancer centers of Russia was initiated: 100 patients from 22 Cancer dispensaries received combination chemotherapy with Taxol at the dose of 175 mg/m2 as 3 hours intravenous infusion, then Carboplatin at the dose to obtain AUC=5,0 (TCb scheme). As a result of this multi-center study, the effectiveness of TCb scheme as first line chemotherapy was confirmed. The scheme can be successfully implemented in Cancer Centers

Biosafety model of adenovirus infection: Effects of bacterial proteases for infection of human cells in vitro

To determine the antiviral activity of various biologically active compounds, the model of adenovirus infection on the basis of cell cultures of human HEK293A and recombinant adenovirus Ad-EGFP, expressing green fluorescent protein EGFP. Adenoviruses have a capsid size of 70-90 nm and are able to infect dividing and nondividing cells in vitro and in vivo. Recombinant adenoviruses are the replicative defect in the cells of humans and animals. The developed model allowed us to determine the effect of bacterial proteases in the infected cell cultures with adenovirus. This model can also be used for screening drugs with potential protivivovirusnoy activity