Opportunities and Prospects for Preclinical Drug Safety Assessment Using Alternative Methods: Experience from the Toxicology in the 21st Century (Tox21) Programme in the USA

Scientific relevance. The Tox21 (Toxicology in the 21st Century) programme was developed by the US Tox21 Consortium with the aim to replace animal-based toxicity assessments of chemicals with a wide range of in vitro and in silico testing approaches and has since been successfully applied in practice.Aim. The study aimed to review information on alternative in vitro models developed as part of the Tox21 programme for testing the toxicity of chemical compounds.Discussion. According to the information provided by the National Toxicology Program, Environmental Protection Agency, National Center for Advancing Translational Sciences, and other Tox21 Consortium members on their official websites and in the literature, the Tox21 Consortium has developed a quantitative high-throughput screening technology for testing the safety of chemicals and created the Tox21 10K library of chemical compounds using this screening technology. The library has been successfully used to create models that predict the toxicity of chemicals prior to preclinical studies. Researchers have proposed new approaches to studying the safety of chemical compounds in human cell lines to replace in vivo studies. Innovative organ-on-chip, multi-organ-on-chip, and organoid models are free from the drawbacks and limitations of cell-line models and offer more accurate representations of complex cell–matrix and organ–organ interactions. Developed under the Tox21 programme to search for new chemical toxicity biomarkers and gene signatures, novel transcriptomics (toxicogenomics) technologies can be used to classify toxicants according to their health risks and to identify potential side effects long before discovering any pathological changes in the body. The Interagency Coordinating Committee on the Validation of Alternative Methods conducts technical evaluation of alternative testing methods and promotes their implementation into regulatory practice.Conclusions. Thus, new tools and technologies provide an opportunity for switching from in vivo toxicity testing of candidate medicinal products to in silico and in vitro methods

The effect of early and late pharmacological correction with GABA derivatives of psychoemotional state of offspring of rats with experimental preeclampsia

Experimental preeclampsia has a negative effect on the psychoemotional state of offspring. Early and late pharmacological correction with derivatives of GABA, such as succicard, salifen and phenibut, reduced anxiety, manifestations of obsessive-compulsive disorder, and depression in offspring of the rats with EP pregnanc

Changes in the respiratory function of the heart and brain mitochondria of animals after chronic alcohol intoxication affected by a new GABA derivative

The compound RSPU-260, and the reference drug Mildronate improve mitochondrial oxidative phosphorylation in heart and brain cells, the functioning of antioxidant enzymes in animals after CAI, and can be used to correct alcoholic damage to these organ

Pharmacological correction of the sequelae of acute alcohol-induced myocardial damage with new derivatives of neuroactive amino acids coupled with the blockade of the neuronal NO synthase isoform

Acute alcohol intoxication (AAI) induces a number of myocardial disorders, which result in mitochondrial dysfunction in cardiomyocytes, oxidative stress, and decreased cardiac contractility. Nitric oxide produced by the nNOS is one of the major modulators of cardiac activity. New derivatives of GABA (RSPU-260 compound) and glutamate (glufimet) can be potentially regarded as such agents as the interaction between the NO system and the GABA and glutamatergic systems has been prove

Autoantibody levels in blood of <i>H. pylori</i>-infected patients with chronic gastritis

Helicobacter pylori (H. pylori) increases the risk of diseases associated with mucous membrane inflammation of gastrointestinal tract, in particular, gastritis, stomach ulcers, and duodenal ulcers. It may also induce a chronic immune response, causing damage to the mucous membrane and development of these diseases. In addition, the role of H. pylori in the initiation of a wide range of autoimmune diseases is discussed. The aim of this study was to assess the level of autoantibodies – markers of various autoimmune diseases in the blood of H. pylori-infected patients with chronic gastritis. We used samples of whole peripheral blood from 267 primary patients with chronic gastritis in the acute stage. The presence of H. pylori in gastric juice from patients was determined using real-time PCR. The level of autoantibodies to double-stranded and single-stranded DNA, autoantibodies to thyroglobulin, thyroid peroxidase, concentration of rheumatoid factor, IgG autoantibodies to the cyclic citrullinated peptide, IgM and IgG autoantibodies to beta(2)-glycoprotein were determined by the enzyme immunoassay. The average level of rheumatoid factor in blood serum was similar for H. pylori-infected and non-infected patients, and did not exceed the normal values. The level of antibodies to cyclic citrullinated peptide, one of the sensitive markers of rheumatoid arthritis, was increased in all patients, being, however, significantly lower in H. pylori-infected patients compared with non-infected persons. Autoantibodies to thyroglobulin, thyroid peroxidase are considered classic markers of autoimmune diseases of the thyroid gland. In blood of H. pylori-infected patients we have found an increased concentration of autoantibodies to thyroglobulin and thyroid peroxidase in comparison with non-infected ones, but the average level of these antibodies did not exceed the normal range. Any differences in the levels of systemic lupus erythematosus serological markers, i.e., autoantibodies to double-stranded and single-stranded DNA, were found between H. pylori-infected and non-infected patients. The levels of thrombosis risk marker in patients with systemic lupus erythematosus (IgG and IgM autoantibodies to beta(2)-glycoprotein) were also within the normal ranges. However, in H. pylori-infected patients, it even turned out to be statistically significantly lower than in non-infected ones. Thus, no data have been obtained on increased levels of the tested markers of autoimmune pathology in blood of H. pylori-infected patients with chronic gastritis at the acute stage. However, this does not allow us to make an unambiguous conclusion that the influence of H. pylori does not affect the development of immunological changes associated with autoimmune diseases

Pharmacological correction of the sequelae of acute alcohol-induced myocardial damage with new derivatives of neuroactive amino acids coupled with the blockade of the neuronal NO synthase isoform

Introduction: Acute alcohol intoxication (AAI) induces a number of myocardial disorders, which result in mitochondrial dysfunction in cardiomyocytes, oxidative stress, and decreased cardiac contractility. Nitric oxide produced by the nNOS is one of the major modulators of cardiac activity. New derivatives of GABA (RSPU-260 compound) and glutamate (glufimet) can be potentially regarded as such agents as the interaction between the NO system and the GABA and glutamatergic systems has been proved. Materials and methods: All the studies were performed on female white Wistar rats, aged 10 months, whose weight was 280–320g AAI intoxication was modeled of 32% ethanol (gavage, 4g/kg). Results and discussion: Glufimet and the RSPU-260 compound caused a significant improvement in myocardial contractility, increased oxygen consumption in the V3 state according to Chance, raised the respiratory control ratio and decreased the intensity of LPO intensity. Their effectiveness exceeded that of mildronate, their comparator. nNOS inhibition resulted in a pronounced aggravation of oxidative stress implicated in MDA accumulation in cardiac mitochondria and decreased activity of SOD; myocardial contractility and mitochondrial function indicators did not show a significant difference from the control group. The compounds under study coupled with nNOS inhibition had a cardioprotective effect. Conclusion: Glufimet and the RSPU-260 compound, derivatives of neuroactive amino acids, have a pronounced cardioprotective effect, restrict LPO processes, enhance SOD activity, improve the mitochondrial respiratory function after acute alcohol intoxication when coupled with neuronal NO-synthase inhibition, the expression of which persists after AAI. Graphical abstract

Психологические дисфункции у женщин с бронхиальной астмой

Background. The importance of psychosocial factors in the management of bronchial asthma (BA) is discussed in clinical guidelines, including in international and national clinical guidelines. However, a specific evaluation of their role as a cause of poor asthma control in susceptible patients is required. Aim. Assessment of psychological health of women with different levels of asthma control.Materials and methods. The study included 108 women with asthma observed in Saratov center for Allergology who were stratified into 3 groups according to the control level (good, partial, uncontrolled, according to GINA). In establishing a diagnosis of asthma, standard methods were used (medical history, symptoms, spirography). To assess the level of control, ACQ-5 (Asthma Control Questionnaire 5 items-self-administered) was used, to assess the quality of life, questionnaires AQLQ-S (Asthma Quality of Life Questionnaire S); SF-36 (36-ltem MOS Short-Form Health Survey), a standardized and validated Russian version of the women’s health questionnaire WHQ (Women’s Health Questionnaire) were used; for psychological diagnosis and evaluation of social and personal competencies that contribute to the preservation and improvement of human health (the intellectual, personal, emotional, physical, social, creative, spiritual aspects), integrated multimodal questionnaire was used. The comparison was conducted with a control group of men with bronchial asthma, comparable in age and level of control.Results. Women with poorly controlled asthma had worse performance of AQLQ-S (combined median score of 3,43 instead of 5,13 in the group of good control; p &lt; 0,05); all scales of the SF-36, including the general condition (43,48 against 55,07), role of physical (25,93 against 57,76) and emotional problems (43,83 against 64,37); at p &lt; 0.05. According to the WHQ questionnaire (the inverse relationship: the higher the score, the lower the quality of life) in the group with poor control there is a high level of depression (mean 0,36 versus 0,24; p &lt; 0,05); physical health problems are marked (0,47 against 0,27; p &lt; 0,05). There is a very low selfestimation of their attractiveness in BA (0,71 and 0,64 for bad and good control, respectively). According to the integrated multimodal questionnaire, in both men and women with asthma almost identical results were obtained on the scales sensitive to manifestations of anxiety-depressive symptoms, emotional balance, scales of emotional skills, correlating with severe alexithymia and low capacity for reflection. Among women the proportion of individuals with high scores of intellectual functioning, strong-willed competence, goal-setting, and ability of making contacts was higher.Conclusion. The severity of asthma and disease control are closely linked with the psychological condition of the patient. Psychological dysfunctions are correlated with suboptimal BA control. It is important to understand psychological differences in women and to educate patients in both effective BA control and in establishing individualized asthma management strategies.There is a need for a multidisciplinary approach aimed at the identification and effective correction of asthma. The study of the psychological characteristics of personality and motivational sphere of the patient can help to optimize therapy, improve monitoring and prognosis of the disease. Введение. Важность психосоциальных факторов в управлении бронхиальной астмой (БА) обсуждается в клинических руководствах, включая международные и национальные клинические рекомендации, однако требуется конкретная оценка их роли в качестве причин плохого контроля астмы в уязвимых группах пациентов.Цель исследования. Оценка психологического здоровья женщин с разным уровнем контроля бронхиальной астмы.Материал и методы. В исследование включены 108 женщин с бронхиальной астмой, наблюдающихся в Саратовском аллергологическом центре, которые были стратифицированы на три группы в соответствии с уровнем контроля (хороший, частичный, неконтролируемый (GINA)). При постановке диагноза бронхиальной астмы использованы стандартные методы (анамнез, симптомы, спирография). Для оценки уровня контроля использовались Asthma Control Questionnaire 5 items-self-administered (ACQ-5), качества жизни – опросники Asthma Quality of Life Questionnaire S (AQLQ-S), 36-ltem MOS Short-Form Health Survey (SF-36), стандартизированная и валидизированная русскоязычная версия опросника женского здоровья Women’s Health Questionnaire (WHQ). Для психологической диагностики и оценки социально-личностных компетенций, способствующих сохранению и развитию здоровья человека (интеллектуальный, личностный, эмоциональный, физический, социальный, творческий, духовный аспекты), применялся мультимодальный интегрированный опросник (МИО). Сравнение проводилось с контрольной группой мужчин с бронхиальной астмой, сопоставимых по возрасту и уровню контроля.Результаты. Женщины с плохо контролируемой астмой имели худшие показатели AQLQ-S (суммарная медиана баллов 3,43 вместо 5,13 в группе хорошего контроля; p &lt; 0,05); всех шкал SF-36, включая общее состояние (43,48 против 55,07), роль физических (25,93 против 57,76) и эмоциональных проблем (43,83 против 64,37); р &lt; 0,05. По опроснику WHQ (обратная зависимость: чем выше балл, тем ниже качество жизни) при плохом контроле отмечается высокая выраженность депрессии (среднее значение 0,36 против 0,24; p &lt; 0,05), проблем физического здоровья (0,47 против 0,27; p &lt; 0,05). Отмечена чрезвычайно низкая оценка собственной привлекательности при БА (0,71 и 0,64 соответственно при плохом и хорошем контроле). По опроснику МИО у мужчин и женщин с БА получены практически одинаковые показатели по шкалам, чувствительным к проявлениям тревожно-депрессивной симптоматики, эмоциональной уравновешенности, шкалам эмотивных навыков, коррелирующих с выраженной алекситимией и низкой способностью к рефлексии. Среди женщин была выше доля индивидуумов с высокими шкалами интеллектуального функционирования, волевой компетенции, целеполагания, контактности.Заключение. Тяжесть астмы, контроль заболевания тесно связаны с психологическим состоянием больного. Существует необходимость в междисциплинарном подходе, направленном на выявление и эффективную коррекцию психофункциональных расстройств при БА. Изучение психологических особенностей личности и мотивационной сферы пациента может способствовать оптимизации терапии, улучшению контроля и прогноза заболевания.

Экскреция лекарственного вещества глутарон - нового производного глутаминовой кислоты

In the study of excretion of the drug was found that glutaron determined in urine for at least 72 hours of the study. Renal clearance is 123 ml/hour, extrarenal - 34.84 ml/hour by intravenous route of administration. Superiority over extrarenal and renal clearance correlates with earlier data on the distribution of glutaron in organs and tissues. The drug was determined in the organs responsible for elimination (liver, kidneys and lungs) at high concentrations.При изучении экскреции препарата было выявлено, что глутарон определяется в моче в течение не менее 72 часов исследования. Почечный клиренс составляет 123 мл/час, внепочечный - 34,84 мл/час при внутривенном пути введения. Превосходство почечного клиренса над внепочечным коррелирует с полученными ранее данными о характере распределения глутарона в органы и ткани. Препарат определялся в органах, отвечающих за элиминацию (печень, почки, легкие) в высоких концентрациях