This review covers original research focused on the design, synthesis, and pharmacological evaluation of an innovative dimeric dipeptide mimetic of brain-derived neurotrophic factor (BDNF) loop 4 bis-(N-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide (GSB-106). Developed using a proprietary approach for creating low-molecular-weight neurotrophin mimetics, GSB-106 displayed marked antidepressant-like activity following systemic and oral administration. The article details its pharmacological properties in vitro and in vivo, mechanism of action, development of a tablet form of the dipeptide, and findings from toxicological and pharmacokinetic studies.

Aging is the result of combined changes in many biological processes that are associated with impaired functional status in humans and increase the risk of chronic pathologies. Since there are a number of insurmountable difficulties in conducting clinical studies on humans, it is necessary to resort to experimental modeling of key signs of aging and associated pathologies.

However, all the used models of aging are far from perfect, since there are a number of factors that do not allow a full comparison of the mechanisms of the aging process in humans and animals. This article presents the main experimental models of aging and determines their advantages and disadvantages in the context of potential studies.

Background. The domestic antitumor compound 2-[3-(2-chloroethyl)-3-nitrosoureido]-1,3-propanediol (chlonisol) has high antitumor activity on a wide range of experimental tumors.

Goal. To study the content of chlonisol in the blood of rats at different times after intravenous administration and its chemical stability in 0.9 % sodium chloride solution, urine and blood serum.

Methods. The concentration of chlonisol in various media was determined by HPLC. In vivo studies on 10 male rats with a body weight of 180–200 g. the concentration of chlonisol in the blood of rats was determined 2, 30, 60, 90 and 120 minutes after its intravenous administration at a dose of 40 mg/kg. In in vitro experiments, a 0.1 % solution of chlonisol was incubated at 37 °C in three media: 0.9 % sodium chloride solution, blood serum and urine. Aliquots were selected at different intervals and analyzed for the content of chlonisol. The stability of chlonisol was evaluated in relation to its concentration before and after incubation, expressed as a percentage.

Results. When chlonisol was administered intravenously at a dose of 40 mg/kg to rats, its complete disappearance from the blood was observed within 2 hours. The half-life was 27 minutes. Of the three media studied in vitro experiments, chlonisol was the most stable in 0.9 % sodium chloride solution(89 % of the initial level after 10 hours of incubation at 37 °C). Less stable, but for a long time – in urine (60 % of the initial after 1 hour of incubation and 37 % after 2 hours). The lowest resistance of chlonisol was in the blood serum (a decrease in concentration to 11 % after 1 hour and to 0 after 2 hours of incubation).

Conclusion. The results obtained allow us to make assumptions about possible ways of using chlonisol: The high stability of chlonisol in 0.9 % sodium chloride solution will allow its long-term drip intravenous infusions, as well as perfusion intraarterial chemotherapy. Maintaining the concentration of chlonisol in urine at 60 % of the initial level for 1 hour will allow the use of intravesical instillations of chlonisol in superficial bladder cancer.

Background. Methotrexate (MTX) in high doses (1000–5000 mg/m²), occupies one of the leading places in modern programs of therapy of acute lymphoblastic leukemia (ALL) in children. Achievement of high long-term survival rates in children with ALL has become possible thanks to this drug. However, no less important problem is the toxicity of the treatment and prediction of its efficacy and safety, in this regard, the role of pharmacogenetic studies in the identification of polymorphisms in candidate genes affecting the pharmacokinetics of MTX is increasing.

Objective. To determine predictors of delayed elimination of methotrexate using pharmacokinetic biomarkers in children with acute lymphoblastic leukemia.

Materials and methods. We prospectively analyzed the database of pediatric patients with ALL within the framework of an observational (cohort) singlecenter study. The study included 124 children diagnosed with ALL who received therapy according to the ALL-IC BFM 2009 protocol including high-dosed MTX. Real-time PCR method was used to study polymorphisms of ABCB1 and SLCO1B1 genes. The study material was peripheral blood. Statistical analysis ofpharmacogenetic biomarkers influence on toxicity and efficacy of therapy was performed using SPSS Statistics 26.0 program (USA). To form mathematical prognostic models, we used the method of logistic function construction using binary logistic regression with step-by-step selection of factors and, if necessary, additional construction of ROC-curves with subsequent ROC-analysis. Differences were considered significant at p < 0.05; at p ≥ 0.05, differences were considered unlikely and statistically insignificant.

Results. Based on the results of the conducted complex analysis of efficacy and safety of high-dosed MTX therapy, a reliable (p < 0.001) prognostic model with high sensitivity, specificity and efficacy (>70 %, respectively) was developed, demonstrating the interrelationships of clinical and genetic factors influencing the delay of MTX elimination in children with ALL, which confirms the necessity of implementing pharmacogenetic testing in real clinical practice.

Conclusion. Determination of polymorphisms of genes providing transport and metabolism of cytostatics should be used in practical work of oncohematological clinics for individualization of therapy and ensuring its safety.

Introduction. It is known that the allosteric effector of cAMP, in addition to protein kinase A, is the Epac regulatory proteins, which in cardiomyocytes play a key role in the electromechanical coupling control and their rhythmic activity. However, under pathological conditions, abnormal activity of Epac proteins is responsible for the hypertrophy and fibrosis of cardiomyocytes and the initiation of cardiac arrhythmias. Objective. To study the cardiotropic activity of the compound N,2,4,6-tetramethyl-N-(pyridin-4-yl)benzolsulfonamide (code ZMEI-3), which potentially has the properties of Epac protein antagonists, in models of cardiac arrhythmias and alcoholic cardiomyopathy ( ACMP).

Materials and methods. Experiments were carried out on outbred male rats. The antiarrhythmic activity of the ZMEI-3 compound was assessed in models of aconitine and reperfusion arrhythmias, and the cardioprotective activity in a translational model of ACM, which is formed after 24 weeks of forced intake of 10 % ethanol.

Results. Using a model of reperfusion arrhythmias in rats, it was shown that the ZMEI-3 compound (2 mg/kg/day for 7 days i.p.) reduces the incidence of life-threatening arrhythmias, including ventricular fibrillation. In conditions of formed ACMP, the studied compound (2 mg/kg/day for 28 days i.p.) increased the inotropic function of the heart, which was judged by the value of the left ventricular ejection fraction. Histological analysis showed that in conditions of formed ACMP, the ZMEI-3 compound reduces the severity of morphological signs of alcoholic heart damage.

Conclusions. Compound ZMEI-3, when used in a course, has a pronounced antiarrhythmic effect and reduces the severity of alcohol-related heart failure.

Lithium ascorbate is a lithium salt with normothymic and neuroprotective properties. In an experimental model of non-alcoholic fatty liver disease with multiorgan pathology caused by combined consumption of excessive amounts of saturated fats, carbohydrates and inorganic iron salt, the use of lithium ascorbate showed pronounced hepatoprotective effects. The introduction of lithium ascorbate reduced the level of ferritin and transferrin saturation, the content of serum iron, AST, ALT, serum creatinine, leukocytes and normalized the level of serum protein and the rate of glomerular filtration. Lithium ascorbate reduced the increased content of reticulocytes and platelets to control values, restored the levels of vitamins C, B₁₂ in the blood and reduced the number of Kupffer cells in the liver, which were overloaded with iron. The hepatoprotective effect of lithium ascorbate was confirmed histologically. The ability of the neuroprotector lithium ascorbate to reduce the level of hemosiderosis can be used in the treatment of patients with hepatic encephalopathy.

Background. The neuropeptide cycloprolylglycine (CPG) is an endogenous dipeptide analogue of the nootropic piracetam. It has been experimentally shown that CPG (designed and synthesized at the Federal State Budgetary Scientific Institution «Federal Research Center of Original and Promising Biomedical and Pharmaceutical Technologies») has a spectrum of pharmacological effects characteristic of piracetam. In studies aimed at studying the mechanisms of action of CPG, it was found that glutamate AMPA receptors and neutrophin Trk receptors are involved in the anxiolytic, neuroprotective and antihypoxic effects of CPG. However, the mechanism of nootropic action of CPG has not been studied.

Objective. To test the hypothesis about the involvement of Trk receptors in the nootropic effect of CPG in a model of amnesia in mice induced by the administration of scopolamine.

Material and methods. The nootropic activity of CPG (1 mg/kg, i.p.) was studied in a model of amnesia in mice induced by scopolamine (0.75 mg/kg, subcutaneously). A pharmacological inhibitory assay was used with the Trk receptor blocker K252a (5 μg/kg, i.p.). The severity of amnesia was assessed using the Novel Object Recognition (NOR) test.

Results. Scopolamine was found to impair novel object recognition in mice in the NOR test. CPG prevents the development of amnesia induced by scopolamine, and Trk receptor blocker K252a blocks this effect.

Conclusion. Trk receptors are involved in the nootropic effect of the neuropeptide CPG.