β-Blockers are one of the oldest classes of cardioprotectors used in the treatment of cardiovascular diseases. They reduce the heart rate, have a hypotensive effect, inhibit myocardial contractility and have antiarrhythmic properties. In the series of biaromatic compounds with a linear linker, there is a quite large group of β-blockers, which in addition to two aromatic nuclei contain a 1,2-dihydroxy-3-aminopropane fragment in the linker, that is the key for the presence of β-blocking activity. Among the compounds of this group are widely used drugs nebivolol and carvedilol, which are used in the treatment of chronic heart failure and arterial hypertension.

The pharmacokinetics of dimeric dipeptide mimetic of nerve growth factor GC-2 in the rat blood plasma after different routes of administration was studied. The drug was administered at dose of 150 mg/kg by single and repeatedly. After single intravenous and intraperitoneal injection, GC-2 was detected for 2 h, its half-life was 0.4 h. GC-2 absolute bioavailability after single intraperitoneal injection was 84.62 %, that indicates the prospect of development its injectable (intramuscularly) dosage form. After 4-fold (1.5 h dosing interval) intraperitoneal injection dose-independent pharmacokinetic parameters of GC-2 practically do not change compared to single administration. This indicates that GC-2 is not accumulated in the body of rats. The hypothesis of the linearity of the pharmacokinetics of GC-2 in the rats blood plasma after single intraperitoneal administration at doses of 50, 100 and 150 mg/kg was tested. It was found that the kinetics of GC-2 in the rat blood plasma is linea.

In pharmacokinetics (PK) studies of medicinal products with small laboratory animals models, primarily rodents, the design of the animal-point experiment is often used, involves the selection of biological material after euthanasia of the animal. The question of experimental data processing and the PK parameters calculation method in a situation where all concentration values  are obtained from different individuals is relevant.

Purpose of the study. Comparison of pharmacokinetic parameters calculation methods in studies with the animal-point design.

Materials and methods. For a number of previously conducted studies with male outbred rats test systems, a retrospective data analysis was performed and PK parameters were calculated in three different ways: from the average concentration values at each time point (method 1): from data obtained for animals with the same sequence numbers in subgroups corresponding to time points (method 2); using resempling based on modeling of individual PK profiles (method 3). Pharmacokinetic parameters (maximum concentration — Cmax, time to reach maximum concentration — Tmax, area under the curve "concentration-time" — AUC0-t, average time to stay in the body — MRT, half-life — T1/2) were calculated by non-compartment method of statistical moments using the validated PKSolver application for Microsoft Office Excel.

Results. The comparison of the obtained results did not reveal any patterns and preferences for the use of a particular method of calculating PK parameters depending on the studied drugs, route and administration way. For all evaluated PK parameters (Cmax, Tmax, AUC0-t, MRT, T1/2), similar values and/or intervals were obtained, which indicated the correctness of all considered calculation methods.

Conclusion. Based on advantages and disadvantages of the calculation methods comparison it is shown that it is optimal to use method 2, which is a special case of reception (method 3) with a minimum number of replications. It is important to emphasis the method of PK parameters calculation when describing the methodology of studies to improve their quality.

Relevance. Cyclic 3′,5′-guanosine monophosphate is a secondary intracellular messenger that plays a key role in many physiological processes.

Quantitative determination of the level of c-GMP in the tissues of laboratory animals is an urgent task of experimental pharmacology and physiology.

Purpose of the study. Development of a method for the quantitative determination of cyclic guanosine monophosphate in various tissues of rats using high performance liquid chromatography with mass spectrometric detection.

Methods. The biomaterial was homogenized with deionized water. Extraction of c-GMP from homogenates was performed with methanol, acyclovir was used as an internal standard. Detection of c-GMP and acyclovir was performed using a Sciex QTrap 3200MD mass spectrometer, chromatographic separation was performed using an Agilent Technologies 1260 Infinity II HPLC. The mobile phase was methanol and deionized water.

Results. Detection of c-GMP was performed by MRM transitions m/z 346.2/152.1; 346.2/135.1, chromatographic determination of c-GMP was performed in reverse phase mode on an Agilent InfinityLab Poroshell 120 EC-C18 4.6×100 mm, 2.7 µm column. The retention time of c-GMP and acyclovir was 7.85 and 7.45 minutes, respectively, the total duration of the chromatographic analysis was 12 minutes. The analytical range of the procedure for determining c-GMP in homogenates was 0.5–1000.0 pmol/ml. The content of c-GMP in the tissues of intact Wistar rats was analyzed using the developed method.

Conclusion. The developed bioanalytical HPLC-MS/MS method for the quantitative determination of c-GMP fully complies with the validation requirements. The metrological characteristics of the method make it possible to estimate the content of c-GMP in various tissues of rats with high accuracy.

Relevance. Under the influence of endogenous and /or exogenous factors, the intestinal microflora inhabiting all parts of the gastrointestinal tract may change, which disrupts the normal course of physiological processes, and in some cases leads to severe pathological conditions. One of the reasons for the development of intestinal dysbiosis is the use of antibacterial drugs. Thus, the search and development of means for the prevention and treatment of dysbiosis is an urgent task.

Goal. The aim of the study was to evaluate the effectiveness of a candidate for a calcium lactate-based drug with repeated intragastric administration on a model of antibiotic-induced dysbiosis in rats.

Methods. The study used 40 male Wistar rats (four groups of 10 animals each). A model of antibiotic-induced intestinal dysbiosis was tested in rats by a course of intragastric administration of a combination of amoxicillin and clavulanic acid for 7 days at a dose of 75 mg/kg. The development of dysbiosis was confirmed by a change in the quantitative composition of representatives of the intestinal microbiota. Similarly, for 7 days, the test drug was administered in doses of 5 mg/kg, 25 mg/kg, 125 mg /kg daily 2 hours after the introduction of the pathology inducer. The control group received a 1 % starch solution.

Results. The peak of dysbiosis development was recorded on the 4th day of pathology induction. The use of calcium lactate at a dose of 5 mg/kg did not have a significant effect, while in the groups receiving calcium lactate at doses of 25 mg/kg and 125 mg/kg, there was a statistically significant (Mann-Whitney criterion, p < 0.05) decrease in the severity of the pathological process compared with the negative control group.

Conclusion. According to the results of this study, it was found that the use of calcium lactate in doses of 25 mg/kg and 125 mg/kg contributed to a faster disappearance of symptoms of dysbiosis and normalization of the intestinal microbiota in comparison with animals that did not receive treatment.

Background. Cyclo-L-prolylglycine (CPG) was designed and synthesized at the V.V. Zakusov as a topological analogue of the classical nootrop piracetam and was further identified as an endogenous compound. Previously, the nootropic effect of CPG was revealed in a model of retrograde amnesia in rats induced by electroconvulsive shock in the passive avoidance test (PAT).

Objective. The aim of the present study was to investigate the nootropic effect of CPG under more physiological conditions in the absence of strong stressors.

Methods. Amnesia in rats was modeled by intraperitoneal (ip) administration of scopolamine at a dose of 2 mg/kg. CPG was administered ip at doses of 0.1 and 1.0 mg/kg 15 minutes after scopolamine. Short- and long-term memory were recorded in the novel object recognition test.

Results. It was found that scopolamine disrupted only the long-term memory of rats. CPG at a dose of 0.1 mg/ kg almost completely counteracted this impairment. CPG by itself had no effect on memory at both doses studied.

Conclusion. Thus, CPG exhibits nootropic activity not only in the aversive conditions of the PAT and electroconvulsive shock-induced amnesia, but also in the neutral situation in the novel object recognition test, when the amnesia was caused by the administration of scopolamine.

Introduction. Cardiovascular diseases (CVD) remain one of the leading causes of death worldwide, claiming over 17 million lives annually. This highlights the urgent need to develop innovative drugs to combat CVD. One potential target for such drugs is type 2 ryanodine receptors (RyR2), as they play an important role in maintaining ion homeostasis in cardiomyocytes, and their abnormal activity plays a key role in the genesis of cardiac arrhythmias.

Research objective is to study the mechanisms underlying the antiarrhythmic action of ALM-802.

Methods. In the first stage, in vivo experiments were performed using models of aconitine, calcium chloride, barium chloride arrhythmia, and reperfusion arrhythmias to evaluate the antiarrhythmic effect of the compound ALM-802. The second stage of the study involved electrophysiological experiments performed on hippocampal cells of newborn rats to evaluate the effect of the compound on voltage-gated transmembrane Na+, K+, and Ca2+ ion channels, as well as its effect on intracellular ion concentration of Ca2+. Experiments performed on an isolated myocardial strip evaluated the effect of the compound ALM-802 on the activity of RyR2.

Results. In in vivo experiments, the compound ALM-802 (2 mg/kg, iv) exhibits significant antiarrhythmic activity comparable/superior to that shown by the reference drugs procainamide, verapamil, and amiodarone on the models mentioned above. In in vitro experiments, it was shown that ALM-802 (69.8 µM) initiates the inactivation of K+ and Na+ ion channels and does not affect the activity of Ca2+ ion channels. The compound ALM-802 effectively prevents the increase of Ca2+ ion concentration in the cytosol during depolarization of contraction. In addition, experiments on isolated myocardial strips showed that the compound ALM-802 (5x10-5 M) blocks RyR2.

Conclusion. Thus, based on the spectrum of its antiarrhythmic activity, the compound ALM-802 combines the properties of antiarrhythmic drugs of class IA or IC and class III according to the E.M. Vaughan Williams classification. In addition, the ALM-802 compound exhibits antagonistic activity towards RyR2. The latter is also considered significant, as it is known that under conditions of myocardial pathology, abnormal activity of RyR2 initiates diastolic leakage of Ca2+ ions from the sarcoplasmic reticulum cysterns, which leads to a decrease in the inotropic function of the left ventricle of the heart and significantly increases the risk of developing malignant cardiac arrhythmias.

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.

The antidepressant activity of pyrrolo[1,2a][1,4]diazepines (GMAL-24, GMAL-27, GMAL-31, GMAL-32 and GMAL-33) synthesized at the V.V. Zakusov Research Institute of Pharmacology in a forced swimming test on male outbred mice was studied. The compounds were tested in the dose range from 1.5 mg/kg to 20 mg/kg, the reference group received tricyclic antidepressant amitriptyline at a dose of 10 mg/kg, and the control group received 0.5 ml of saline solution. All injections were performed intraperitoneally. After GMAL-27 administration immobilization time was decreased of 1.78, 1.64 and 1.74 times, respectively, compared with the control in all three studied doses (1.5 mg/kg, 5 mg/kg and 10 mg/kg), without significant differences from the control (p = 0.1340; p = 0.2748; p = 0.2214, respectively). The compound GMAL-31 in doses from 1.5 mg/kg to 20 mg/kg had no effect on the duration of immobilization compared to the control group of mice. It was established that the compound GMAL-24 at doses of 5 mg/kg and 10 mg/kg significantly reduced the periods of immobilization compared to the control group and did not differ in this parameter from the comparison drug, which indicates an antidepressant effect comparable to the effect of amitriptyline.

Background. Earlier, on the translational model of alcoholic cardiomyopathy (ACMP) developed by us in outbred white rats, which reproduces the main clinical diagnostic signs of this disease, it was shown that in rats of both sexes under conditions of constant 24/7 alcoholization for 24 weeks, AСMP is formed.

This study purpose is a comparative assessment of the features of the ACM formation in male and female rats depending on the level of ethanol consumption in model experiments simulating "domestic drunkenness" with periodic alcoholization 24/2 for 24 weeks.

Materials and methods. Experiments were performed on outbred white rats randomized into 4 groups: group 1 — control male rats (n=18), group 2 — control female rats (n = 18), group 3 — alcoholized male rats (n = 39) and group 4 — alcoholized female rats (n = 19). Control animals received a normal diet and free access to water. Animals of the 3rd and 4th groups weekly, for 24 weeks, from Friday 22.00 to Monday 8.00, received a 10 % ethanol solution as the only source of liquid with unlimited access to standard food, and the usual diet on the remaining days.

Results. In animals of both sexes, after 24 weeks from the consumption start of the ethanol solution, ACM is formed, as evidenced by an increase in the end-systolic and end-diastolic sizes of the left ventricle of the heart (p = 0.0001) and a decrease in its ejection fraction (p = 0.0001), while the degree of pathological myocardial remodeling is more pronounced in females. According to cluster analysis, by the consumption of ethanol (CET), animals of both sexes are divided into 3 subgroups: low, medium and high CET, however, in males, the subgroup with an average CET prevails — 56 %, and in females with a high CET — 47 % (p = 0.0286), the low CET subgroup is minimal (16 %). At the same time, if in males in all subgroups, starting from the 8th week of alcoholization, CET dynamically decreases, then how in females in subgroups with medium and high CET, starting from the 16th week, it increases. It was found that the degree of left ventricular remodeling in females with high and moderate CET was almost 2 times higher than in males (p < 0.05).

Conclusion. In model experiments imitating “domestic drunkenness”, it was shown that in females the intensity of the left ventricle heart remodeling is significantly higher than in males, which, apparently, is determined by the identified gender-dependent multidirectional trends in the formation of alcoholic behavior characterized by dynamic growth. consumption of ethanol in female rats as the duration of alcoholization increases.

Aim. The primary aim of this study was to evaluate the pharmacokinetic parameters and confirm the bioequivalence of drugs containing gidazepam, namely Gidazepam® (Valenta Pharm, Russia) and Gidazepam VIC (VIVA Pharm, Republic of Kazakhstan), after a single administration of 1 tablet (50 mg) to healthy volunteers under fasting conditions. The secondary aim was a comparative analysis of safety profiles (adverse events) after a single administration of the studied drugs.

Materials and methods. An open, randomized, crossover, two-period comparative study of pharmacokinetics and bioequivalence with adaptive design was conducted in healthy volunteers. Blood sampling was performed 15 minutes before and 20 min, 40 min, 1 h, 2 h, 3 h, 3.5 h, 4 h, 4.5 h, 5 h, 6 h, 8 h, 12 h, 24 h, 48 h, and 72 h after drug administration. High-performance liquid chromatography-tandem mass spectrometry was used for the evaluation of gidazepam and its metabolite (desalkylgidazepam) concentration with the subsequent calculation of pharmacokinetic parameters.

Results. From both formulations, gidazepam was quickly absorbed and biotransformed into an active metabolite. Studied drugs had similar pharmacokinetic profiles, as 90% confidence intervals for the ratio of geometric means for Cmax and AUC(0-72) were within the bioequivalence acceptance range of 80.00–125.00 %. No adverse events were recorded as a result of clinical, laboratory or instrument evaluations during the study.

Conclusion. Study drugs are considered bioequivalent and show comparable tolerability after a single administration under fasting conditions.