This article analyzes the regulatory, scientific, and methodological documents of the Eurasian Economic Union (EAEU) and the Russian Federation devoted to conducting preclinical studies on the safety of medicines. Areas for which it is advisable to develop special EAEU guidelines for conducting preclinical safety studies have been identified. Based on an analysis of the international regulatory and methodological framework, elements of foreign experience in preclinical assessment of the safety of medicines for transfer to the practice of the Union are proposed.

Ferroptosis is a regulated form of cell death characterized by iron-dependent lipid peroxidation. Since its initial description, it has garnered significant attention due to its implications in various diseases, including cancer, neurodegeneration, and ischemia-reperfusion injury. The ageing process is characterized by a progressive decline in cellular function and increased susceptibility to oxidative damage, both of which intersect with ferroptosis pathways. This review explores the intricate relationship between ferroptosis and ageing, focusing on molecular mechanisms, the role of iron metabolism, implications in age-related diseases, and potential therapeutic strategies. By understanding the interplay between ferroptosis and ageing, researchers can uncover novel targets for promoting healthy ageing and mitigating age-associated disorders.

Background. The dipeptide TSPO ligand, the compound amide N-phenylpropionyl-L-tryptophanyl-L-leucine (GD-102) was designed and synthesized in the Federal research center for innovator and emerging biomedical and pharmaceutical technologies. It was shown that GD-102 possessed anxiolytic and antidepressant-like activity in behavioral experiments using mice.

The aim of this work was studying the anxiolytic activity and possible side effects of GD-102 in a wide range of doses from 0.01 to 5.0 mg/kg in experiments using rats and mice.

Materials and methods. The pharmacological effects of GD-102 were studied with single intraperitoneal administration. The anxiolytic activity of GD-102 was studied in rats in the elevated plus maze test. The "climbing on the net" test was used to record orientation-exploratory behavior; the muscle relaxant properties were studied in the "rotating rod" and "horizontal bar" tests.

Results. It was found that GD-102 at doses of 1.0 and 0.1 mg/kg (once administration), has a pronounced anxiolytic effect in the elevated plus maze test, significantly increasing the time the rats spent in the open arms of the maze and the number of entries into the open arms of the maze. The study of the sedative/activating effects on various behavior models indicated that GD-102 in a wide range of doses (from 0.01 to 5.0 mg/kg) did not affect orientation-exploratory behavior. In the dose range from 0.01 to 5.0 mg/kg, compound GD-102 does not impair the coordination of movements in the rotating rod test and the pull-up reflex on a horizontal bar, which indicates that compound GD-102 have not side effect on muscle relaxantion.

Conclusion. The obtained results allow us to conclude that the dipeptide ligand of the TSPO translocator protein, compound GD-102, has a pronounced anxiolytic effect and does not have a sedative or muscle relaxant effect in a wide range of doses, which determines the feasibility of its further expanded preclinical study.

Relevance. Metformin is an antidiabetic agent in the therapy of type 2 diabetes mellitus, which has a complex of pharmacological effects that may allow its use as a geroprotector and a means for the treatment of cognitive and behavioral disorders. Metformin when administered orally has low bioavailability (50–60 %), as well as the risk of side effects, which is the rationale for studying the intranasal route of administration of metformin.

Objective. To investigate the behavioral effects of metformin during intranasal administration as a rationale for the development of its intranasal dosage form.

Materials and methods. The object of the study was metformin administered intranasally (i/n) to rats at a dose of 70 mg/kg. The intragastric (i/g) route of administration (70 mg/kg) was used for comparison. After 30-day i/n and i/g administration of metformin, the rats were subjected to behavioral tests: the T-Maze test, Water Maze test, Elevated Plus-Maze test (EPM), and Extrapolation Escape task (EE). The Student's t-test in Graph pad Prism 8.0.1 program was used for statistical processing.

Results. When administered i/n, there was 5.6 times (p = 0.022) decrease in the latent period of arm selection (p = 0.022), and when administered i/g, there was 2.9 times (p = 0.01) decrease in the “T-maze”test compared to the control. No statistically significant result was found in the “EPM”test when applied i/n, in contrast to i/g, in which the duration of stay of rats in the OА of the maze was 3.0 times (p = 0.01) more than the control, and in the CA — 1.3 times (p = 0.01) less. In the “EE” test, i/n administration of metformin contributed to 5.1 times (p = 0.02) decrease in jump duration compared to control. In case of i/g administration metformin, the duration of the jumping period was 2.9 times shorter (p = 0.038).

Conclusion. Intranasal administration of metformin can be considered as an alternative way of its use and be the basis for the development of a system of directed delivery of metformin.

Relevance. Parkinson's disease (PD) is a neurodegenerative disease characterized by motor impairments. The currently used antiparkinsonian pharmacotherapy, despite the symptomatic improvement of patients, is associated with severe side effects. The combination of ladasten with fabomotizole may have a potential neuroprotective effect in the neurodegeneration conditions observed in PD, due to its multitargeting action.

Objective. The study explores the potential antiparkinsonian activity of a combination of ladasten and fabomotizole in paraquat-induced model of parkinsonian syndrome (PS).

Methods. PS was modeled by intraperitoneal administration of paraquat (10 mg/kg) 1 time every 3–4 days for 21 days. The C57Bl/6 mice were divided into 4 groups: 1) passive control, 2) active control, 3) ladasten + fabomotizole combination, 4) levodopa. The animals were tested in the battery of behavioral tests each week of the experiment.

Results. The combination of ladasten with fabomotizole successfully treated all manifestations of PS in the battery of behavioral tests, and the greatest difference compared with the active control was found in most tests on the 3rd week of the experiment. Thus, the combination increased latency to fall in the «rotarod test» by 2,38 (p < 0.0001) and 1.5 times (p < 0.01) at fixed and accelerating speed, decreased the turning and descent time in the «pole test» by 1.4 (p < 0.05) and 1.53 times (p < 0.001).

Conclusion. The combination of ladasten with fabomotizole reduced the severity of paraquat-induced PS in the battery of behavioral tests, and it was comparable with the effects of levodopa.

Relevance. Gestational diabetes mellitus (GDM) is the most common complication of pregnancy. The lack of a biological model of GDM complicates the search for a suitable pharmacotherapy and presents the challenge of developing a valid model of this disease.

Objective. The objective of this study was to develop a biological model of GDM accompanied by metabolic disorders in pregnant rats by using a high-calorie diet in combination with tyloxapol as diabetogenic factors.

Materials and methods. GDM was modeled by keeping pregnant female Wistar rats on a high-calorie diet for at least 7 weeks in combination with intraperitoneal administration of tyloxapol at doses of 200 and 400 mg/kg on various days of pregnancy. In parallel we evaluated the dose dependence of the effects of tyloxapol by its single intraperitoneal administration to non-pregnant female Wistar rats at doses of 200, 300, 400 mg/kg.

Results. The study showed that the optimal combination of a high-calorie diet with the administration of tyloxapol at a dose of 200 mg/kg is optimal for GDM induction. In this case, there is a marked violation of glucose tolerance, an increase in the levels of glucose, total cholesterol, triacylglycerides and low-density lipoproteins in the blood serum. A pronounced embryoletal effect was observed with tyloxapol at a dose of 400 mg/kg. The use of tyloxapol at a dosage of 300 mg/ kg did not lead to a change in the registered parameters.

Conclusion. The proposed biomodel demonstrates the main pathognomonic symptoms of GDM and may be useful in studying the mechanisms of development and searching new treatments for this pathology.

Introduction. Low-molecular-weight mimetics of neurotrophin-3 (NT-3) are considered promising compounds for the development of novel drugs. One of the first stages in the preclinical studies of candidate drugs is the assessment of acute toxicity. The aim of this work was to evaluate the acute toxicity of the novel dimeric dipeptide mimic of the fourth loop of NT-3 (compound GTS-301) after intraperitoneal administration in female and male outbred mice.

Materials and methods. GTS-301 (hexamethylenediamide bis-(N-monosucciny L-asparaginy L-asparagine), substance in 1 % starch solution) was administered acutely intraperitoneally to mice in the maximum possible volume and concentration. The control group received an equivalent volume of 1 % starch solution. The time course of intoxication development in mice was recorded, along with a detailed description of the observed clinical signs. Euthanasia and postmortem examination were performed on the 15th day after GTS-301 administration.

Results. During a 14-day observation of mice that received GTS-301 at doses of 1 and 2 g/kg, caused the death of only one animal after the administration of the GTS-301 to the maximum permissible volume and the maximum possible concentration (2 g/kg) that did not allow calculating the median lethal dose of the compounds for mice. The morphological examination of internal organs during postmortem dissection of all experimental animals did not differ from that observed in controls.

Conclusion. It was determined that dipeptide mimetic of neurotrophin-3 (GTS-301) after acute intraperitoneal administration concerns to be practically non-toxic substance. According to classification by Sidorov K.K. (1973), this compound may be related to 5th toxicity class.

Relevance. Arterial hypertension (AH) is widespread throughout the world. Unfortunately, only a small proportion of patients achieve target blood pressure (BP). One of the possible reasons for the ineffectiveness of AH treatment is the pharmacokinetics of antihypertensive drugs.

Objective. To test valsartan pharmacokinetics in patients with AH.

Material and methods. An open cohort study was conducted. The analysis included 28 patients, including 15 (53.6 %) with uncontrolled AH. All patients regularly took valsartan, amlodipine, indapamide for a month. In the morning before and 2 hours after taking valsartan, venous blood samples were taken from all patients to assess its concentration using high-performance liquid chromatography with tandem mass spectrometry.

Results. Patients of the two groups were comparable in terms of major comorbidities. C_0h and C_2h of valsartan did not statistically differ in patients with controlled and uncontrolled AH. In 39.3 % of patients, C_0h and C_2h of valsartan were within the therapeutic range (TD). In 50 % of patients, C_0h did not reach the lower limit of TD, and in three patients, the concentration of valsartan exceeded the upper limit of TD, in one of them it exceeded the upper limit of TD almost three times. In 13 patients for whom valsartan was not recommended, it was found in trace amounts.

Conclusion. Thus, to improve the efficacy and safety of valsartan therapy, it is advisable to monitor its concentration in the blood serum.