Therapeutic drug monitoring (TDM) is used to increase the individualization of pharmacotherapy, especially in patient groups with a high interindividual variability in pharmacokinetic (PK) parameters. One of these groups of patients is newborn children, for whom drug therapy, especially drugs with a narrow therapeutic range, causes a few difficulties or cannot be used in principle.

The aim of the work was to develop and validate quantitative HPLC-MS/MS methods for the determination of vancomycin in “dried blood spot” samples using new protocols and comparison of the results obtained with the results in plasma samples using standard sample preparation methods.

Materials and methods. To prepare stock and standard solutions of vancomycin and norvancomycin as an internal standard, dry portions of the corresponding certified standards of vancomycin (Servier, France) and norvancomycin (Augsburg, Germany, purity grade >95.0%) were used. A chromatographic separation of the components was carried out on a Poroshell 120 C18 column (4.6×50 mm, 2.7 µm). When developing conditions for a mass spectrometric detection of the desired substances using the multiple reaction monitoring (MRM) method, precursor ions and their corresponding product ions were determined.

Results. A quantitative HPLC-MS/MS method for the determination of vancomycin in «dried blood spot» samples was developed and validated. A comparison was made between vancomycin concentrations in «dried blood spot» samples and plasma samples. Moreover, more than 95% of the calculated average concentrations are within the limits of d-2s and d+2s, which correspond to the values of –10.2 and 12.2. That confirms the suitability of the developed method for the analysis of patient samples.

Conclusion. The results obtained make it possible for us to recommend the “dried blood spot” method for therapeutic monitoring of vancomycin, additional studies of PK in this group of patients with subsequent use of this drug in newborns and pediatric patients.

Breast cancer (BC) is one of the most common types of malignant tumors, which makes scientific research in this area extremely relevant. The difficulties of breast cancer chemotherapy stimulate the search for new drugs to treat this nosology. Derivatives of imidazotriazine and imidazotetrazine, which are analogues of the antitumor drug temozolamide, can be ones of the promising drugs in this regard.

The aim of the work was to evaluate the antitumor activity of three new azoloazine derivatives in a xenogeneic breast cancer model in mice in vivo.

Materials and methods. A study was conducted on a xenogeneic model of BC. After the immunosuppression with azathioprine, 48 white BALB/c mice were injected with MCF-7 cells, test derivatives, and the reference drug epirubicin at doses of 1/2 IC₅₀ and 1/10 IC₅₀, into the base of the mammary gland once. The body weight of the mice was monitored; on the 15^th day, at the end of the experiment, the relative volume was assessed.

Results and discussion. Among the three compounds studied, imidazotetrazine 1 showed the most encouraging results: stopping the loss of body weight in the mice caused by the administration of tumor cells, and reducing the tumor volume on the 15^th day of the experiment to 50.6% of that in the control when using a dose of 1/10 IC₅₀, up to 39.2% – when using a dose of 1/2 IC₅₀, which significantly exceeded the values of the reference drug epirubicin and the values in the control group. In the histological examination, the signs of spread and preservation of tumor cells viability of the MCF-7 line after its administration were minimal, the value of the histological malignancy index decreased by 9.3% of the control value.

Conclusion. Among the tested azoloazine derivatives, 3-cyclohexyl-4-oxoimidazo[5,1-d][1,2,3,5]tetrazine-8-N-piperidinylcarboxamide is the undisputed leader, causing inhibition of the tumor growth in a xenogeneic model in vivo.

The aim of the work was a phytochemical and pharmacological study of biologically active compounds (BACs) and Populus rubrinervis Hort. Alb. buds preparations of various polarities.

Materials and methods. The object of the study was dry extracts of P. rubrinervis Hort. Alb. buds the samples of which were prepared in January–March 2023 in the Botanical Garden of Samara University (Samara, Russia). The separation of the amount of current substances was carried consecutively by the method of circulating extraction (chloroform), then, by the method of fractional percolation, a tincture was received on 70% ethyl alcohol (1:5). Pinostrobin was used as the standard sample (SS). The analysis of the substances was carried out by the TLC method. The electronic spectra registration was carried out with a spectrophotometer “Specord 40” (Analytik Jena, Germany). The study of the pharmacological (diuretic) activity of P. rubrinervis Hort. Alb. buds dried extracts was carried out on 60 white outbred rats of both sexes weighing 200–220 g in the experiments with aqueous diuresis.

Results. P. rubrinervis Hort. Alb. buds dried extracts of various polarities (extract No. 1 (chloroform) and extract No. 2 (70% ethanol) were received. By the method of thin-layer chromatography, it was determined that the dominant complexes of the lipophilic nature with pinostrobin are isolated in extract No. 1, phenolic substances of the glycoside nature prevail in extract No. 2. Despite various polarities of the extragents, spectral characteristics of extract No. 2 have significant similarities with extract No. 1. When studying the diuretic activity, it was established that when SS pinostrobin was injected at a dose of 1 mg/kg, for 4 h of the experiment, an isolated increase in diuresis was noted (from 1.72±0.11 to 1.97±0.03 ml, p <0.05); at the same time, an isolated increase in creatininuresis (from 1.50±0.29 to 2.39±0.15 mg, p <0.05) was observed during 24 h of the experiment. When extract No. 2 was injected at a dose of 10 mg/kg, there was a moderate significant increase in diuresis (from 1.82±0.02 to 2.07±0.04 ml and from 2.38±0.39 to 3.02±0.11 ml, p <0.05) and a significant increase in creatininuresis (from 0.14±0.01 to 0.19±0.03 mg and from 2.31±0.42 to 2.79±0.51 mg, p <0.05) for 4 and 24 h of the experiment, respectively.

Conclusion. The extraction separation of the amount of P. rubrinervis Hort. Alb. buds by the polarity degree was carried out. Pinostrobin SS at a dose of 1 mg/kg and extract No. 2 at a dose of 10 mg/kg had a diuretic activity, in connection with which they are promising in terms of the development of effective drugs.

The aim of our work was to study a pharmacological activity of a selective arginase-2 and thrombin inhibitor from a phenolic compounds group with a laboratory cypher KUD975 on a model of arterial pulmonary hypertension induced by hypoxia.

Materials and methods. To simulate pulmonary hypertension (РН), animals were placed in a normobaric hypoxic chamber and subjected to 5 weeks of hypoxia with an oxygen content of 10% in the air. After 3 weeks of hypoxia, the animals were administered with the test compound KUD975 (intragastrically, at a dose of 2 mg/kg once a day for 2 weeks). L-norvaline (intragastrically, 20 mg/kg) was used as a reference drug. To assess the development and correction of РН, measurements of cardiohemodynamics, analysis of blood gas composition, study of the number of circulating endothelial precursor cells (EPCs), quantitative PCR assessing the expression of mRNA VEGF-R2, SGF-1 (stromal growth factor-1) and MCP-1 (monocyte chemoattractant protein-1). Next, a histological examination of the lungs and heart was performed, the degree of pulmonary edema and the concentration of cardiotrophin-1 and atrial natriuretic peptide were assessed.

Results. The administration of the studied phenolic compound with laboratory cypher KUD975, as well as the reference drug L-norvaline, led to a decrease in the right ventricular systolic pressure against the background of modeling РН. The present study shows a more than twice-fold decrease in the number of circulating (EPCs) in the animals group with modeling a hypoxia-induced circulatory РН (171.3±12.1) in comparison with the group of intact animals (296.1±31.7; p=0.0018). The recovery of EPCs was noted in the animals group administered with KUD-975 and L-norvaline, up to 247.5±34.2 (p=0.0009 compared with a pulmonary arterial hypertension (PAH) and 235.6±36.4 (p=0.008 compared to PAH), respectively. The studied compounds had a protective effect by statistically significantly increasing the expression of VEGF-R2 mRNA and decreasing the expression of SGF-1 mRNA, reducing the lung moisture coefficient and the concentrations of cardiotrophin-1 and atrial natriuretic peptide and preventing vascular remodeling caused by hypoxia.

Conclusion. When studying the pharmacological activity, it was shown that the phenolic compound with the laboratory cypher KUD975 normalizes hemodynamic parameters, reduces the signs of remodeling of the heart and pulmonary vessels and has a pronounced endothelial protective effect on the model of hypoxia-induced РН, and is superior to the activity of the reference drug L-norvaline.

Semaglutide is a representative of analogues of the incretin hormone human glucagon-like peptide-1 (GLP-1) and is currently used in Russia for the treatment of type 2 diabetes mellitus (T2DM; in monotherapy and in combination therapy), including patients with obesity and overweight.

The aim of the work was to conduct a comparative assessment of the physicochemical properties, a biological activity, bioequivalence and safety, including tolerability and immunogenicity, of the drug Quincent® (semaglutide, 1.34 mg/ml, a solution for a subcutaneous administration, Promomed Rus LLC, Russia) and the drug Ozempic® (semaglutide, 1.34 mg/ml, a solution for a subcutaneous administration, Novo Nordisk A/S, Denmark) when administered to healthy volunteers.

Materials and methods. To assess the degree of similarity of the study drug Quincenta® (semaglutide, 1.34 mg/ml, a solution for a subcutaneous administration, Promomed Rus LLC, Russia) with a chemically synthesized active substance to the original (reference) drug Ozempic® (semaglutide, 1.34 mg/ml, a solution for a subcutaneous administration, Novo Nordisk A/S, Denmark), a comparative study of physicochemical properties and a biological activity was carried out. To assess the bioequivalence of the study drug and the reference drug, an open randomized parallel comparative study with the participation of healthy volunteers (n=54), 54 participants of which had been included in the population, was conducted. The volunteers were randomized into 2 groups in a 1:1 ratio, and received a single dose subcutaneously either of the study drug (domestic semaglutide at a dose of 0.5 mg) or the reference drug (foreign semaglutide at a dose of 0.5 mg). The mode of administration was in the morning on an empty stomach. A semaglutide concentration was determined in serum samples using a previously validated enzyme-linked immunosorbent assay (ELISA) method. A quantitative determination of antibodies to semaglutide in the human serum by ELISA was carried out with a microplate photometer using ready-made kits pre-validated by the manufacturer. The conclusion about the bioequivalence of the compared drugs was made using an approach based on the assessment of 90% confidence intervals for the ratios of the geometric mean values of the parameters C_max, AUC_(0–t) of semaglutide in the measurement original units.

Results. The results of the comparative analysis of the study drug and the reference drug demonstrate the comparability of their physicochemical properties and biological activity. The results of the clinical study demonstrated the bioequivalence of the test drug and the reference drug. Thus, the pharmacokinetic parameters of the drugs were comparable to each other: the C_max value for the study drug was 42.088±8.827 ng/ml, for the reference drug Ozempic® it was 42.2556±7.84. Herewith, the half-life for the study drug and the reference drug was 168.39±39.47 and 157.99±28.57 hours, respectively. The resulting 90% confidence intervals for the ratio of the C_max and AUC_0–t values of the study drug and the reference drug were 90.89–109.15 and 91.66–111.27%, respectively. The tolerability of the drugs in the volunteers was notified as good. No adverse events were recorded during the study. No serious adverse events were reported throughout the study. According to the results of the immunogenicity analysis, no antibodies to Russian-made semaglutide were detected in the blood serum of the volunteers, which indicated the lack of Results. The results of a comparative analysis of the study drug and the reference drug demonstrate the comparability of physicochemical properties and biological activity. The results of the clinical study demonstrated the bioequivalence of the study drug and the reference drug. Thus, the pharmacokinetic parameters of the drugs were comparable to each other: the C_max value for the study drug was 42.088±8.827 ng/ml, for the reference drug Ozempic® this figure was 42.2556±7.84. At the same time, the half-life for the study drug and the reference drug was 168.39±39.47 and 157.99±28.57 hours, respectively. The resulting 90% confidence intervals for the ratio of the C_max and AUC_0–t values of the study drug and the reference drug were 90.89–109.15 and 91.66–111.27%, respectively. Tolerability of the drugs in volunteers was noted as good. No adverse events were recorded during the study. No serious adverse events were reported throughout the study. According to the results of the immunogenicity analysis, no antibodies to Russian-made semaglutide were detected in the blood serum of the volunteers, which indicated the lack of the drug immunogenicity.

Conclusion. In the course of the study, the comparability of the physicochemical properties and biological activity of the studied Russian drug with the chemically synthesized active substance Quincenta® to the reference drug Ozempic® was confirmed: the activity range of the studied drugs was within 80–120% in relation to the standard sample of semaglutide. The bioequivalence and a similar safety profile, including the immunogenicity and tolerability of the Russian drug Quincenta® (semaglutide 1.34 mg/ml, Promomed Rus LLC, Russia) were shown in comparison with the foreign drug Ozempic® (semaglutide 1.34 mg/ml, Novo Nordisk A/C, Denmark).

Modern approaches to the treatment of type 2 diabetes mellitus (T2DM) are aimed not only at glycemic control, but also at reducing cardiovascular risks. The increasing prevalence of the disease and the need for effective treatment options highlight the importance of glucagon-like peptide-1 (GLP-1) receptor agonists in the pharmacotherapy structure.

The aim of the work was to review the literature regarding the physiology of GLP-1 and the therapeutic potential and development trends of its agonists.

Materials and methods. The search for the review materials was carried out using the abstract databases of PubMed, Google Scholar and e-Library. The search was carried out for publications from 2000 to 2023, using the following keywords: “GLP-1”; “GLP-1R agonists”; “GIP”; “exenatide”; “liraglutide”; “dulaglutide”; “semaglutide”; “lixisenatide”; “albiglutide”; “taspoglutide” taking into account various spellings.

Results. The interaction of almost all food components with enteroendocrine cells of the intestine leads to the secretion of incretins (primarily GLP-1) into the blood, triggering a complex of physiological reactions aimed primarily at the rapid utilization of incoming glucose (regulation of insulin and glucagon secretion), as well as the central regulation of dietary behavior (slowing gastric emptying and the formation of a feeling of satiety). A wide distribution of the GLP-1 receptor in various tissues and organs, its connection with intracellular signaling cascades aimed at launching energy-consuming remodeling (recovery) processes in endothelial cells, heart, neurons, beta cells, etc., is the basis for a wide range of pleiotropic effects of GLP-1 unrelated to its hypoglycemic effect. The discovery of synthetic GLP-1 receptor agonists with a long period of action has made it possible not only to therapeutically influence various parts of carbohydrate metabolism disorders, but also to increase the functional reserves of the target diabetes organs, reducing the risk of developing complications of the disease. Incretin-like drugs are well tolerated, with nausea being the most common side effect. The factors limiting a wider use of the drugs include their high cost and the preferred form of a subcutaneous solution. The current research is focused on the development of long-acting, oral, dual and triple agonists, fixed-dose combinations, and small molecule drugs.

Conclusion. GLP-1 receptor agonists are a class of effective and safe drugs for the treatment of diabetes and obesity, which is rapidly developing in the most advanced areas of pharmacy. A further development of this group and the solution of the identified problems will open up new opportunities for the treatment of diabetes and its complications.