Relevance. Alzheimer’s disease (AD) is a neurodegenerative disease characterized by cognitive and behavioral disorders. The drugs currently used in clinical practice can slow drug development but are usually associated with lifelong use because of the complexity of pathogenesis. Therefore, to correct AD, a similar approach is needed, which can be CAPAH (2-chloroethoxy-para-N-dimethylaminophenylphosphorylacetohydrazide), a potential drug with a multitarget mechanism of action.Objective. Investigate the effects of CAPAH, memantine, and rivastigmine on the behavior and cognitive functions of rats.Materials and methods. This study identified CAPAH as a potential drug with a multitarget mechanism of action. The comparator drugs were memantine (10 mg/kg) and rivastigmine (2 mg/kg). Animals were divided into 4 groups (control, CAPAH, memantine, rivastigmine), 8 males and 9 females each receiving subcutaneous injections of the respective agents for 30 days. Subsequently, their cognitive functions and behavior were studied on the «Morris Water Maze» (MWM) and «Extrapolation deliverance» (EPI) ("Open Science", Russia) with the help of the "EthovisionXT" program (Noldus, the Netherlands). Statistical processing was performed using one-way ANOVA in the GraphPadPrism 8.0.1 program.Results. In case “MWM” CAPAH increased the swimming time in the platform zone by 1.8 and 1.5 times (p < 0.05) compared with the control in the male and female groups, respectively, exceeding the parameters of the comparison drug. In case "EPI" test, the administration of CAPAH to males reduced the number of jumps by 4.4 times (p < 0.05) and increased the latent period of motor activity by 2.3 times (p < 0.05) compared with the control group, but did not affect these aspects in females.Conclusion. Administration of CAPAH improves cognitive function and memory in healthy male and female rats and reduces anxiety in male rats, whereas it outperforms the effects of memantine and rivastigmine.

Relevance. Drug pollution of the environment is a global environmental problem of our time. Increased consumption of medicines directly affects the level of pollution of various ecosystems, including water resources. The insufficient efficiency of existing methods for treating wastewater from drugs leads to drug pollution of water bodies and requires studying the effect of ultra-low doses of drugs on the human body and animals. A non-steroidal antiinflammatory drug, diclofenac, was detected in surface water samples in Kazan at a concentration of 1×10−9 M.The purpose of this study is to study the presence of specific pharmacological effects of diclofenac detected in water samples in ultra-low doses in experimental models of pathological processes.Methods. The experiment used 21 male white laboratory mice, which were divided into three groups (each with 7 mice). For 4 days, mice were intragastrically injected with distilled water (control group), diclofenac solution 1×10−6 M (experimental group No. 1), diclofenac solution 1×10−9 M (experimental group No. 2). On the fifth day of the experiment, inflammation was induced by injecting carrageenan lambda (1 %, Sigma) subplantarly into the right hind paw in a volume of 0.05 ml. The amount of edema was determined using an IITC Life Science plethysmometer (USA).The results of an experimental study of the specific pharmacological activity of diclofenac showed that diclofenac in ultra-low doses of 0.32×10−3 mg per 100.0 g of weight is able to reduce the severity of acute inflammation caused by subplantar injection of carrageenan and to cause NSAID-associated gastropathy in mice.Conclusion. The obtained data likely indicate a potential risk of adverse effects from drug contamination of the environment with diclofenac, even in ultra-low concentrations.

Introduction. Behavioral methods on laboratory animals are recognized as the main approach in studying the activity of potential psychotropic drugs and allow us to evaluate the main effects of new compounds, increase the possibility of predicting a successful outcome of future clinical trials.Text. This review article analyzes the main modern behavioral models in rodents that are widely used for screening and studying the pharmacological activity of potential psychotropic drugs. The advantages and disadvantages of each test are highlighted and complexes of behavioral methods are demonstrated that most conclusively confirm the reproducibility of the results obtained in clinical trials. The description and evaluation of behavioral methods that characterize the state of anxiety, which are used to screen for new compounds with anxiolytic activity (tests «Open field», «Dark-light chamber», «Elevated plus maze», «Sequence of rays»). The range of tests used to study cognitive functions and memory processes is widely presented (various mazes – T-shaped, U-shaped, radial maze, Barnes maze, E-maze; water mazes – Morris, T-maze) with a description of a comparative analysis and necessary conditions that ensure the reliability of information. An important direction in the field of behavioral pharmacology is the modeling of violations of social behavior and the study of approaches for its correction – the main methods necessary for the study of social behavior are presented in the review by the tests «Three-chamber social test», «Open field» extended test, etc.Conclusion. Behavioral pharmacology dictates the need for close interaction between preclinical and clinical stages of research in the framework of the development of translational medicine and the development of approaches that provide evidence for the reproducibility of the results obtained in clinical trials. It is also necessary to improve existing and develop new behavioral models of mental disorders and to search for new ways to study the mechanisms of formation of behavioral disorders.

Relevance. It is known that the existing drug therapy for cognitive disorders is characterized by low rates of efficacy and safety, as well as symptomatic orientation. Therefore, the search for new drugs in this area is an urgent issue, the solution of which can be phosphorylated derivatives of thiosemicarbazides (PTC), which have a multitarget mechanism of action. Aim. Study of acute toxicity and behavioral effects of PTC in mice. Methods . The objects of study are 2 new compounds of the PTC series: 2-[2-(Diphenylphosphoryl)acetyl]hydrazinecarbothioamide (T7) and 2-[2-(Diphenylphosphoryl) acetyl]-N-phenylhydrazinecarbothioamide (T8). The reference drug is diphenylphosphorylacetic acid hydrazide (phosenazid). After determining the acute toxicity with a single intraperitoneal injection, the effect of PTK on the behavior of mice was studied in the models "Open field" (OP), "Elevated plus maze" (EPM), "Dark-light chamber" (DLC) and "Behavioral despair" (BD). For statistical analysis, the GraphPadPrism 8.0.1 program was used with the calculation of Student's t-test. Results. It has been established that new PTC are less toxic than fosenazid. Behavioral testing showed that i.m. administration of T8 in test "OP" contributed to an increase in exploratory (6 and 12 mg/kg) and motor (12 mg/kg) activity, the development of an anxiolytic effect in the tests "EPM" (12 mg/kg) and "DLC" (6 mg / kg), and in "BD" (12 mg / kg) antidepressant effect. With the intravenous administration of T7, an increase in motor activity in the “OP” (16 mg / kg) was noted. Conclusion . Compounds of a number of PTC are promising for further synthesis and development as potential drugs with a different spectrum of psychotropic activitys.

Introduction. Orally dispersible dosage forms are one of the new trends in the field of drug delivery systems. One type of such dosage forms is oral lyophilisates that are obtained by freeze-drying a pre-prepared mixture containing the active pharmaceutical ingredient (API) and excipients. This dosage form provides immediate release of the active pharmaceutical ingredient in the oral cavity using a less amount of excipients. Aim. Pharmacokinetic studies of previously obtained lyophilisates based on the polymer-drug complex Eudragit® E PO / ibuprofen (PDC EPO-IB) and the interpolyelectrolyte complex (IPEC) Carbopol® Ultrez 10 / Eudragit® E PO (IPEC C10/EPO) and metronidazole. Materials and methods. Lyophilisates of the following compositions were obtained: 1) 100 mg of metronidazole and 50 mg of IPEC C10/EPO or 2) 100 mg of PDC EPO-IB, the first or second composition of the carrier with API was dispersed in 50 % maltodextrin syrup, Span®80 was added – 1.42 % from the total mass of the mixture. The mixture was poured into blisters for tablets, frozen in a FreeZone 1L laboratory dryer (Labconco, USA) for 24 hours at a temperature of –49 °C, and the main drying was carried out at a pressure of 0.350 mbar. Soviet Chinchilla rabbits were administered one lyophilisate containing PDC EPO/IB or IPEC C10/EPO with metronidazole; the substances ibuprofen (50 mg) and metronidazole (100 mg) were used as reference drugs. The concentration of API was determined by high-performance liquid chromatography (HPLC) on an LC-20 Prominence chromatograph (Shimadzu Corporation, Japan) with UV detection. Pharmacokinetic parameters were calculated using a model-independent method using the Thermo KinetikaTM (version 5.0, Build 5.00.11, Thermo Fisher Scientific, USA) program. Results and discussion. According to the obtained pharmacokinetic profiles, the maximum concentration of ibuprofen from EPO/IB PDC is achieved within the first hour after oral administration. The second peak in the profiles shows the absorption of the remaining portion of the API into the blood from the gastrointestinal tract (GIT), both in the case of EPO/IB PDC and in the case of ibuprofen from the substance. The relative bioavailability of EPO/IB PDC was F rel = 86.06 %. Lyophilisates based on IPEC C10/EPO provide the maximum concentration of metronidazole after 30 minutes (C max = 4.659 μg/ml). Relative bioavailability was F rel = 107.6 %. Conclusion. According to studies, the maximum concentration of ibuprofen and metronidazole is achieved within the first hour after oral administration of lyophilisates containing PDC EPO-IB and IPEC C10/EPO. Absorption of medicinal substances in the oral cavity occurs due to the components included in the dispersible dosage form, as well as due to the presence of a ЕРО copolymer, PDC and an IPEC, which are able to linger on the oral mucosa due to the presence of mucoadhesive properties. Thus, the pharmacokinetic studies of ibuprofen and metronidazole from the obtained lyophilisates prove the suitability of the obtained forms for immediate release systems.

We report here studies using an experimental model of autism created by prenatal administration of valproic acid to produce a comparative analysis of behavioral disorders in female and male rats, along with indicators of relative levels of expression of the Drd1 dopamine receptor gene in brain structures playing a significant role in disorders of social behavior and the development of anxiety – the prefrontal cortex, amygdala, cerebellum, and hippocampus. The state of anxiety in the valproate model of autism was found to develop only in males, while disorders of social behavior were typical of rats of both sexes, though the nature of these disorders differed in females and males: in the three-chamber social test, males preferred to spend more time in the compartment with a familiar animal, while females preferred to spend significantly less time with a novel, unfamiliar rat, as compared with control animals. Sex-related differences were found in the relative levels of expression of the Drd1 gene in the prefrontal cortex, amygdala, and cerebellum: the relative level of Drd1 expression was greater in the prefrontal cortex and amygdala in females, while males, conversely, showed significantly lower expression in the cerebellum in relation to both males of the control group and females. Analysis of the results obtained here indicates that there is a need to consider changes in the relative levels of Drd1 expression in all study areas simultaneously, evaluating the overall changes in the expression profiles of this gene, which may underlie sex-related differences in both communication disorders and other possible behavioral changes in the valproate model of autism in rats.

Relevance. Alzheimer's disease (AD) is a neurodegenerative disease, the drug therapy of which can only slow the progression of the disease, due to the variety of existing pathogenetic processes. A possible effective approach to the correction of symptoms can be the use of compounds with a complex mechanism of action — phosphorylacetohydrazides, capable of simultaneously acting on different parts of the pathological process, the most effective representative of which is the compound 2-chloroethoxy-para-N-dimethylaminophenyl phosphorylacetohydrazide (CAPAH). Target. To study the possibility of correcting cognitive and behavioral disorders in rats with a stereotaxic model of AD using the CAPAH compound, which affects different parts of the pathological process. Methods . 24 female Wistar rats were used in the work. AD was modeled in rats by stereotaxic bilateral injection of β-amyloid into the hippocampal region in a phosphate buffer solution, then on day 11, CAPACH (10 mg/kg) was administered intraperitoneally for 10 days, after which tests were performed using the ≪Elevated Plus Maze≫, ≪Open Field≫ and ≪Morris Water Maze≫. Statistical processing was carried out in the GraphPad Prism 8.0.1 program using one-way ANOVA analysis. Results . Multiple administration of CAPAH contributed to a decrease in the level of anxiety in the ≪Elevated Plus Maze≫ method, increasing the time spent in open arms by 4.6 times ( p < 0.05) compared to rats without treatment. In the ≪Morris Water Maze≫ and ≪Open Field≫ tests, normalization of memory and motor activity processes was observed, respectively, the platform search time and the number of crossed lines did not differ from those of control animals. Conclusion . CAPAH reduces anxiety and memory processes in rats with a stereotaxic model of Alzheimer's disease caused by the introduction of β-amyloid into the hippocampus.

In this article, we discuss the expression levels of Sert, Htr4a, and Bdnf genes in the blood of Wistar rats exposed to the following types of chronic stresses for 270 days: swimming with a load and immobiliza-tion, as well as the combination of these two stresses. On day 180 of the experiment, the stresses described above triggered an increase in Sert expression in both females and males of all the groups, except the control group. The immobilization stress induced for 270 days caused an increase in the level of Sert expression in females and reduced it in males. In response to the stresses under study, the expression of Htr4a decreased in males, but not females, on day 270. The expression of Bdnf decreased on day 270 in males after the combined stress and in females subjected to immobilization. Thus, the expression levels of some genes involved in the peripheral transmission of serotonin are greatly influenced by chronic stresses and depend on gender, duration of exposure to stress, and type of stress factors.

One of the most widespread experimental models for studying the development of autism spectrum disorders (ASDs) and methods of their therapy is the valproic acid-induced rodent model. Individuals born to females who received injections of valproic acid during pregnancy demonstrate a number of ASD-specific impairments. It was previously found that valproic acid affects neuromuscular transmission and, moreover, alters the expression of a set of genes during the development of neuromuscular junction. However, until recently it was unknown whether neuromuscular transmission changes in animals with fetal valproate syndrome and, if so, how? Using the "rotating rod" functional test, we found that in rats with a developed valproate syndrome, the coordination of movements did not differ from control animals. Using the methods of microelectrode electrophysiology, we analyzed (i) the amplitude-time parameters of single postsynaptic signals; (ii) the frequency of spontaneous release of acetylcholine quanta, (iii) the number of acetylcholine quanta released in response to the stimulus, (iv) the amplitude of evoked responses during rhythmic stimulation. We did not reveal any changes in the processes of acetylcholine release from the nerve ending and its reception on the muscle fiber membrane, both at rest and during nerve stimulation. Thus, it can be concluded that in rats with a developed fetal valproate syndrome, peripheral cholinergic neurotransmission does not undergo any functionally significant changes.

Stress response is a multifactorial condition which is formed under extreme environmental exposure due to various neuroendocrine systems interactions. Dopaminergic system plays a key role in stress response through the dopamine which effect is realized after binding with special dopamine receptors types D1-D5. Expression of these receptors varies in different tissues, organs and specific brain structures but there is a special interest in their genes expression level in peripheral blood that can be served as additional marker to evaluate the chronic stress degree. Herein we determine the influence of various types induced chronic stress exposure during 6 months (such as exhausting physical activity (forced swimming), immobilization stress, and their combinations (swimming with immobilization)) on Drd1, Drd2 and Drd3 genes expression level in Wistar rats’ peripheral blood. According to our results, no activity for Drd2 and Drd3 genes is shown; however significant overexpression of Drd1 gene was detected in all studied groups after 3 months exposure compared to the data before experiment beginning, whereas after 6 months the relative expression level significantly decreased in the group with immobilization stress, which proves the negative effect of this type of chronic stress on the production of dopamine receptors of the D1 type. Thus, Drd1 gene activity in the blood can serve as a marker for assessing the severity of chronic stress in rats.

One of the most widespread experimental models for studying the development of autism spectrum disorders (ASD) and methods of their therapy is the pre-natal valproic acid exposure model in rodents. Individuals born of females who received injections of valproic acid during pregnancy demonstrate a number of ASD-specific impairments. It was previously found that valproic acid affects neuromuscular transmission and, moreover, alters the expression of a set of genes during the development of neuromuscular synapse. However, until recently it was not known whether neuromuscular neurotransmission changes in animals with fetal valproate syndrome and, if so, how? Using the functional test "rotating rod", we found that in rats with a developed valproate syndrome, the coordination of movements did not differ from control animals. Using the methods of microelectrode electrophysiology, we analyzed (i) the amplitude-time parameters of single postsynaptic signals; (ii) the frequency of spontaneous release of acetylcholine quanta, (iii) the number of acetylcholine quanta released in response to the stimulus, (iv) the amplitude of evoked responses during rhythmic stimulation. We did not reveal any changes in the processes of acetylcholine release from the nerve ending and its reception on the muscle fiber membrane, both at rest and during nerve stimulation. Thus, it can be concluded that in rats with developed fetal valproate syndrome, peripheral cholinergic neurotransmission does not undergo any functionally significant changes.

Introduction. Intranasal drug delivery from nose-to-brain is one of the promising approaches for the treatment of brain diseases including neurodegenerative diseases, stroke, brain tumors, etc.Text. Delivery of drugs through the nose has a number of advantages, including the rapid onset of a pharmacological effect, the ability to bypass the blood-brain barrier, avoidance of some side effects and fast and non-invasive route of administration. However, the significant disadvantages of this route are rapid elimination of the drug from the surface of the mucosal membrane, poor penetration of the drug through the nasal mucosa, mucociliary clearance and effects of proteolytic enzymes. Currently, to overcome the above limitations, various approaches are used, including the development of delivery systems from nose-to-brain, which are mucoadhesive, mucus-penetrating and gel-forming systems that facilitate the retention or penetration of drugs through the mucosal membranes. At the same time, high-molecular weight compounds play a significant role in the design of these systems. In particular, mucoadhesive systems can be prepared from cationic and anionic polymers. Recent studies have also shown that interpolyelectrolyte complexes also exhibit mucoadhesive properties. An improvement in mucoadhesive properties of polymers can also be achieved by conjugating various functional groups such as thiols, maleimides, acrylates, methacrylates, catechols, etc. Mucus-penetrating systems can be prepared by PEGylation of nanoparticles, as well as functionalization with some poly(2-oxazolines), polyvinyl alcohol, etc. The mucus-penetrating ability of these polymers has been shown in other mucosal membranes in the body. Finally, increased penetration can be achieved by using mucolytic agents in combination with non-ionic surfactants. Another approach to increase the efficiency of drug delivery from nose-to-brain is the use of in situ gelling systems. Initially, this type of formulation exists as a solution; then a phase transition to gel is observed in response to chemical and physical effects. Depending on the external stimulation of the phase transition, thermo-, pH-, ion-reversible and other systems are known. These systems have shown effectiveness for delivery to the brain by intranasal administration.Conclusion. Effective intranasal delivery of drugs and therapeutic agents to the brain can be achieved by using mucoadhesive, mucus-penetrating, gelling systems and/or their combinations.

В статье рассматривается взаимодействие врачей различных специальностей и родителей детей с расстройствами аутистического спектра (РАС) в контексте теории социального конструкционизма. Основное внимание уделено анализу опыта родителей по взаимодействию с врачами и медицинскими организациями в процессе диагностирования у ребенка РАС. Эмпирическую базу исследования составляют материалы 42 индивидуальных интервью с родителями, проживающими в городах Казань, Санкт-Петербург, Йошкар-Ола, и 3 фокус-групп; анализ 350 историй болезни (за 2015–2018 гг.) стационарных пациентов с диагнозом «детский аутизм» в Республиканской клинической психиатрической больнице им. В.М. Бехтерева Минздрава Татарстана. На основе анализа полученных данных показано, что участковые педиатры не имеют настороженности по отношению к РАС даже в тех случаях, когда родители активно выражают беспокойство в связи с особенностями поведения ребенка. Врачи-неврологи первоначально применяют медикаментозное лечение и только после прохождения всего курса направляют ребенка к врачу-психиатру. Средний возраст ребенка на момент установления заключительного клинического диагноза F84.0 составил 4,5±2 года. Время, когда можно применить весь арсенал методов раннего вмешательства, оказывается упущенным. Такая ситуация может привести к ухудшению социального функционирования пациентов с РАС и к институциональным конфликтам между медицинскими работниками и родителями пациентов. Полученные результаты необходимо учитывать при организации диагностики и лечебно-коррекционной помощи пациентам. In the article, there is discussed the interaction of doctors of various specialties and parents of children with autism spectrum disorder (ASD) in the context of the theory of social constructionism. The main attention is given to the analysis of parents’ experience in interacting with doctors and medical organizations in the process of diagnosing ASD in children. The empirical base of the study comprises the material of 42 individual interviews with parents living in the cities of Kazan,Saint Petersburg, Yoshkar-Ola, and 3 focus groups; the analysis of 350 case histories (for the period of 2015–2018) of in-patients diagnosed with child autism at the Bekhterev Republican clinical psychiatric hospital of the Ministry of Health of Tatarstan. On the base of the analysis of the obtained data, it was showed that the district pediatricians are not alert in relation to ASD, even when parents clearly express concern about their child’s behavior. Neurologists initially prescribe medication and only after completing the entire course refer the child to psychiatrist. The average age of the child at the time of the final clinical diagnosis of F84.0 was 4.5±2 years. The time of using the entire arsenal of early intervention methods is passed. This situation can lead to social malfunctioning of patients with ASD and to institutional conflicts between medical professionals and parents of patients. The obtained results should be taken into account when organizing events and providing medical and correctional assistance to patients.

Thiosemicarbazides of diphenylphosphorylacetic acid and their cyclic derivatives have been synthesized. Functionalization of the obtained 1,2,4-triazole-3-thiones with ethyl 2-bromoacetate at the sulfur atom has been carried out, the obtained esters have been transformed into the corresponding hydrazides via hydrazinolysis. Preliminary pharmacological tests of the synthesized compounds have been performed.

The structures of the molecular complexes based on calix[4]resorcinol bearing a p -tolyl moiety at the lower rim with phosenazid (2-(diphenylphosphoryl)acetohydrazide) and CAPAH (2-{[4-(dimethylamino)phenyl](2-chloroethoxy)phosphoryl}acetohydrazide) were studied by NMR, IR, and UV spectroscopy and X-ray powder diffraction. The results of the screening of neurotrophic activities of the molecular complexes are presented.

We report here a comparative study of the release of model drug diclofenac sodium from samples of interpolyelectrolyte complexes (IPEC) in in vitro conditions on a rotating basket apparatus and in vivo in experiments in rabbits. The study IPEC were prepared using different grades of Carbopol ® polymer (C71g, C2020) and Noveon ® AA-1 and oppositely charged polyelectrolytes – Eudragit ® EPO or the natural polysaccharide low-viscosity chitosan. These studies demonstrated the potential for IPEC samples based on Carbopol ® as a new modified-release drug delivery system. At the same time, assessment of bioadhesive properties provided evidence of the potential for using IPEC based on C2020/EPO as a mucoadhesive carrier.

У крыс, перенесших острую перинатальную гипоксию, при достижении 2 мес были отмечены мнемотропные нарушения на модели условной реакции пассивного избегания, развитие депрессивноподобного состояния на модели «поведенческое отчаяние», повышение активности МАО Б в головном мозге. Введение препарата КАПАХ (2-хлорэтокси-пара-N-диметиламинофенилфосфорилацетогидразид) в дозе 10 мг/кг подкожно в раннем постнатальном периоде (с 8 по 12 дни жизни) в течение 2 недель предупреждало развитие этих нарушений, исследуемые показатели у них не отличались от таковых у интактных животных. Мнемотропное действие КАПАХ сходно с эффектом лиганда нейрокининовых NK1 рецепторов субстанции Р. Учитывая наличие аффинности у КАПАХ к нейрокининовым рецепторам, высказано предположение, что мнемотропный эффект КАПАХ, как и субстанции Р, реализуется через нейрокининовые NK1 рецепторы. В механизме предупреждения развития депрессивноподобного состояния препаратом КАПАХ играет роль способность угнетать активность фермента МАО Б.

С целью оптимизации скрининга новых психотропных соединений с использованием компьютерной программы PASS был осуществлен прогноз психотропной активности 47 новых соединений, относящихся к ряду арил(гидразинокарбонилметил)фосфиновых кислот, из которых были выделены 16 наиболее перспективных. Психотропная активность этих веществ была изучена на лабораторных животных с использованием поведенческих моделей. Для этих соединений была прогнозирована мнемотропная активность (Pa = 0,742 – 0,840), антидепрессивная активность (Pa = 0,543 – 0,663) и анксиолитическая активность (Pa = 0,330 – 0,642). Результаты экспериментального изучения психотропной активности производных арил(гидразинокарбонилметил)фосфиновых кислот показали, что соединения оказывают мнемотропное, антидепрессивное и анксиолитическое действие в дозах, составляющих 1/100 и 1/1000 от ДЛ50. Результаты экспериментального изучения мнемотропной, антидепрессивной и анксиолитической активности в целом совпадают с данными компьютерного прогноза по программе PASS.