The aim of this study was to investigate the antimicrobial activity of the pyrimidine derivative 3-[2-[(4,6-dimethylpyrimidin-2-yl)amino]-2-oxoethyl]quinazolin-4(3H)-one against Escherichia coli. The study of antimicrobial activity was carried out in vitro by serial dilutions of the pyrimidine compound, followed by determination of the minimum inhibitory concentration of 3-[2-[(4,6-dimethylpyrimidin-2-yl)amino]-2-oxoethyl]quinazolin-4(3n)-one (VMA-13-14) and in vivo on the model of generalized E.coli infection. The study of antimicrobial activity in vivo was carried out on 40 CBA mice weighing 19–20 g. All manipulations with animals were performed in accordance with the requirements of the regulatory documentation governing the maintenance of laboratory animals and work involving them. The antimicrobial activity of the pyrimidine compound 3-[2-[(4,6-dimethylpyrimidin-2-yl)amino]-2-oxoethyl]quinazolin-4(3H)-one against E.coli in vitro was evaluated in terms of mouse survival, contamination of blood and internal organs (liver, spleen, lungs, brain), as well as the total number of leukocytes and leukograms. The experiment determined that the pyrimidine compound 3-[2-[(4,6-di- methylpyrimidin-2-yl)amino]-2-oxoethyl]quinazolin-4(3n)-one demonstrates antimicrobial activity against E.coli: in vitro, it has a bactericidal effect at a concentration of 128 µg/ml; in vivo, it has an antimicrobial effect in conditions of generalized infection with the introduction of 50 mg/kg/day for 10 days. The antimicrobial effect of 3-[2-[(4,6-dimethylpyrimidin-2- yl)amino]-2-oxoethyl]quinazolin-4(3n)-one is comparable to ceftazidime, which is the drug of choice in the treatment of E.coli infection.

Background. One of the main problems of antibiotic therapy is the development of resistance in microorganisms. In this regard, the search for new natural antibiotics, including those of plant origin, is relevant. The aim of the study was the determination of antibacterial action mechanisms of aqueous and alcoholic extracts of medicinal plants collected on the territory of the Republic of Bashkortostan. Methods. The bark, roots, stems, leaves, and inflorescences of medicinal plants were selected as objects of the study. The mechanisms of antibacterial action of plant preparations were determined via high throughput screening using the Dualrep2 double reporter system. Results. The mechanisms of the antibacterial action of certain plant extracts obtained from fresh and dried raw materials were established. It has been shown that the products of alcohol extraction of yarrow inflorescences inhibit protein synthesis, while the products of celandine roots and stems cause the activation of the SOS DNA repair system in Escherichia coli bacteria. Conclusion. The results obtained allow us to consider the studied extracts of medicinal plants as a basis for obtaining new antibacterial agents with a specific mechanism of action.

Background. Currently, it is customary to distinguish two pathotypes of Klebsiella pneumoniae — classical and hypervirulent, which have the ability to cause community-acquired infections in healthy people. It has been shown that an increase in virulence is associated with the acquisition of additional genetic material — a plasmid carrying a cluster of aerobactin genes. Aim. To assess the prevalence of the aforementioned virulent plasmids around the globe and in Russia in particular, as well as to identify their key genetic features. Materials and methods. Plasmid sequences were downloaded from PLSDB and BV-BRC databases, annotated with the Abricate and Kleborate programs; cluster analysis was performed using the mge-cluster program, and phylogenetic analysis was performed using the Parsnp program. Results. 296 plasmid sequences isolated from 23 countries from clinical isolates of K.pneumoniae between 2006 and 2021 with a peak in 2019 were analyzed, with more than half of the plasmids coming from China. More than 30 sequence types were identified, among which ST11 and ST23 were predominant. Replicon genes of the IncFIB group were identified in almost all plasmids studied. The pre dominant type of aerobactin in the studied sequences was the first type (iuc1); sequences with iuc3 and iuc5 were also identified. Salmochelin synthesis genes were identified in only 37.1% of sequences; the yersiniabactin cluster was identified in two plasmids from China. 32.1% of plasmids carried resistance genes, of which 7.4% carried extended-spectrum beta-lactase genes and 5% contained carbapenemase genes. Nine clusters of sequences were obtained; almost all plasmids from Russia were assigned to one cluster and were NDM-positive. Together with plasmids from other European countries (Great Britain, Norway, Czech Republic), they formed a separate branch on the phylogenetic tree. Conclusion. Virulent plasmids carrying the aerobactin synthesis gene cluster are distributed globaly, and almost a third of them also carry antibiotic resistance genes.

High variability of influenza viruses requires the development of agents for nonspecific resistance stimulation, along with the development of new drugs for prevention and treatment. Among the antiviral drugs, interferons and their inducers are known to exhibit a universally wide spectrum of action. The Institute of Medical Biotechnology, a branch of SRC VB «Vector», Rospotrebnadzor, has developed the technology and obtained pharmaceutical compositions containing an interferon inducer — double stranded ribonucleic acid (dsRNA) from the killer strain of Saccharomyces cerevisiae yeast and recombinant human interferon-alpha-2b (IFN- alpha-2b). The specific antiviral activity of the preparations and synergistic effect of the components within the compositions were shown in L-68 and L-929 cell cultures. The aim of this work was to study antiviral activity of intranasal forms of the pharmaceutical compositions containing yeast dsRNA and recombinant human interferon-alpha-2b in a model of lethal influenza infection in mice. The outbred ICR/CD1 mice were intranasally infected with influenza A/Aichi/2/68 (H3N2) virus. The study compositions were intranasally administered 3 hours before infection with influenza virus, as well as 1 and 3 days post infection. The doses of active components in the administered compositions were as follows: for dsRNA — 2.5 mg/kg, for IFN-alpha-2b — 500 IU/kg, 2500 IU/kg, or 5000 IU/kg. The antiviral activity of the drugs was assessed based on the mortality rate and the average life expectancy of mice. It was shown that a three-time intranasal administration of the composition of dsRNA (2.5 mg/kg) and IFN-alpha-2b (2500 IU) into the infected mice according to therapeutic-prophylactic regimen led to an increase in the rates of survival and average life expectancy of animals, which were comparable to the effect of Tamiflu. The comparison preparations — dsRNA and IFN-alpha-2b — administered intranasally at the same doses and regimen exerted no antiviral effect in this mouse model of viral infection. The data obtained confirm the prospects for further development of new dosage forms of dsRNA and interferons for intranasal application as agents for prevention and treatment of influenza.

Background. Previously, genetic markers rs11385942 G>GA and rs657152 C>A of disease severity were identified for COVID-19. The study of the prevalence of clinically significant genetic markers may be useful for the development of region-specific approaches to disease control, considering, among other things, the ethnic composition of the territory, which is especially relevant for Russia. Based on the ethnic heterogeneity of the population of the Republic of Dagestan, this region was chosen as an example to study the distribution of COVID-19 severity markers of interest. Objective. Investigation of the prevalence of rs11385942 G>GA and rs657152 C>A markers among five ethnic groups residing in Dagestan. Methods. The study included 605 healthy volunteers (158 men and 447 women) from five different autochthonous ethnic groups living in the Republic of Dagestan: 118 Avars, 121 Dargins, 116 Laks, 127 Kumyks, and 123 Lezgins. Blood served as a material for determining polymorphisms. Carriage of polymorphic markers was determined by real-time polymerase chain reaction method. Results. The prevalence of rs11385942 G>GA marker ranges from 10.17% among Avars to 15.04% among Lezgins; significant differences were found in comparison with Russian ethnic group from literature sources. The second marker – rs657152 A>C — is distributed relatively homogeneously in the studied groups, without significant differences, and correlates with the data on the frequency of marker detection among Russians, as well as among European populations and worldwide — 50–60%. Conclusion. No differences were found within the ethnic groups of Dagestan in the carriage of both studied COVID-19 severity markers. At the same time, the rs11385942 G>GA marker detection frequency in the analyzed groups was on average higher in comparison with Russians and the average values for European populations.

Liberal oxygen therapy for COVID-19 causes hyperoxemia in most patients and reduces their survival rate. Even moderate hyperoxemia reduces oxygen delivery, and high levels of oxygen in central venous blood increase mortality in COVID-19 patients. These facts occur due to the manifestation of toxic effects of oxygen (vasoconstriction, bronchoconstriction) requiring the use of medications that reduce toxic effects. The aim of the study was to assess the ability of succinate preparations to eliminate the toxic effects of oxygen affecting central hemodynamics and blood oxygenation in patients with COVID-19. Material and methods. The effect of medicines containing succinates (Cytoflavin and Reamberin) in stopping the manifestations of hyperoxia in 51 surviving patients with the novel coronavirus infection who received high-flow oxygen therapy (HFOT) was analyzed in a retrospective study. Results. Monitoring of heart rate, respiratory rate, SpO₂, PaO₂ and PaO₂/FiO₂ during HFOT within 12 hours from the start of oxygen therapy showed an indirect, but statistically significant effect of stopping the toxic effects of oxygen. This was expressed in a decrease in tachycardia and tachypnea [to 86.7–115.0 (at P<0.001) and 22–24 (P<0.001), respectively] against the background of concomitantly administered succinate preparations, that provided effective oxygen absorption and contributed to the effective elimination of hypoxia and hypoxemia (an increase in PaO₂/FiO₂ to 196.0 [(184.2–249.0) at P<0.001], which was confirmed by a dynamic decrease in the level of lactate (to 2.6±0.8 mmol/l at P<0.001). Conclusion. The results obtained indirectly confirm the protective effect of succinates, which are more pronounced in Citoflavin, but require additional confirmation of the hypothesis of succinate effectiveness in stopping the toxic effects of oxygen in further studies.

The combination of two or more medications is increasingly more common in the development of new treatment guidelines for common diseases. Thus, the use of combinations of histone deacetylase inhibitors with chemotherapeutic agents is a current trend in solid tumor treatment. The aim of this study was to investigate an effective vorinostat (SAHA) to doxorubicin (DOX) ratio for the treatment of different subtypes of breast cancer. The survival of HCC-1954, SKBR-3, MCF-7, MCF-7/ADR, MDA-MB-231 cell lines was assessed under incubation conditions with 64 variants of SAHA and DOX combinations using the MTT assay. This made it possible to determine the effect of interactions of SAHA/DOX combinations (antagonistic, additive, synergistic), as well as calculate the SAHA/DOX synergy index using the Loewe additivity model. The effect of SAHA/DOX ratios with the highest synergistic index for each tumor cell line was confirmed using the Chou-Talalay method. It was shown that the SAHA/DOX combination exhibited the greatest synergism in relation to HCC-1954, MCF-7/ADR and SKBR-3 cell lines belonging to the HER2-positive subtype. The average value of SAHA/DOX ratio with the highest synergy against breast cancer cells was 30:1 (SAHA to DOX, respectively). The ability of SAHA/DOX combination to effectively trigger apoptosis was confirmed in the most sensitive to SAHA/DOX therapy HCC-1954 cells. Thus, the Loewe model made it possible to identify the drug combination with the highest synergistic anticancer effect, which was confirmed using Chou-Talalay method. The data obtained demonstrates great potential of SAHA/DOX combination (30:1) for the treatment of HER2-positive breast cancer.

Currently, a decrease is seen in the effectiveness of treatment in patients with tuberculosis due to the appearance of adverse reactions to anti-tuberculosis drugs. Hepatotoxic reactions play an especially important role in anti-tuberculosis therapy, and phthisiologists often have to deal with the cancellation of a number of anti-tuberculosis drugs. The aim of the study was to investigate the relationship of polymorphic gene variants of xenobiotic biotransformation metabolizing enzymes (NAT2 (590G>A (rs1799930), CYP2E1 (9896C>G (rs2070676), ABCB1 (3435T>C (rs1045642), GSTM1 (E/D), GSTT1 (E/D) with the risk of hepatotoxic reactions in patients with pulmonary tuberculosis. Material and methods. The logistic regression analysis method was used to predict the probability of hepatoxic reactions during specific anti-tuberculosis therapy. Results: 1 statistically significant model was obtained, which reflects the association with hepatotoxic reactions to anti-tuberculosis drugs of the TS genotypes or the TS gene (T allele) ABSV1 (rs1045642). Conclusion. Pharmacogenetic testing used in the study allows us to identify risk groups of patients with pulmonary tuberculosis according to the likelihood of hepatotoxic reactions, which may provide an individualized approach to the treatment of these patients in the future.

The article presents an analysis of studies assessing the effectiveness of new nonspecific medications against hemorrhagic fevers caused by arenaviruses. The possible targets for nonspecific medications, classes of researched antiviral preparations, methods of preclinical investigation of antiviral preparations in vitro and on laboratory animals, as well as prospects for their use in healthcare at present are considered. It has been shown that the level of development of nonspecific medications against hemorrhagic fevers caused by arenaviruses is significantly inferior to those against filovirus infections. Favipiravir should currently be considered as the most effective nonspecific medication against hemorrhagic fevers caused by arenaviruses.

Infective endocarditis in children is a rare disease, which often has an extremely serious prognosis. The most common risk factor for infective endocarditis in this category of patients is the history of congenital heart disease. At the same time, currently, the disruption of the integrity of the peripheral vascular bed is increasingly noted, among the predisposing causes, due to invasive diagnostic and therapeutic medical procedures, as well as severe somatic diseases. In accordance with the developed recommendations, the appointment of antibacterial therapy for infective endocarditis should be based on etiotropic orientation. Taking these circumstances into account, the article presents an overview of the data reflecting the issues of etiology and choice of antibacterial therapy for infective endocarditis in pediatric practice.

Spiramycin is a natural 16-membered macrolide antibiotic that has been used in clinical practice for about 70 years. Despite long-term use, spiramycin retains its position in clinical practice; the resistance of the main respiratory and urogenital pathogens is lower to spiramycin than to 14- and 15-membered macrolides. The interest in spiramycin is due to the fact that its physico-chemical and pharmacokinetic properties are similar to the last semi-synthetic macrolides, and it lacks the disadvantages of erythromycin. Special biological properties of spiramycin explain its consistently high clinical efficacy that has lasted for 70 years of clinical use in various infections. It is necessary to emphasize the uniqueness of spiramycin as an antibiotic with not only the direct effect on microbes, but also non-antibiotic properties. This allowed the experts at the time to declare the «paradox» of spiramycin — the presence of a higher real clinical efficacy than expected according to in vitro studies. Such properties of spiramycin include pro-antibiotic and post-antibiotic effects, immunomodulatory effect, as well as high intracellular and extracellular concentrations of the antibiotic. The review discusses antimicrobial, pharmacokinetic, and pharmacodynamic characteristics of spiramycin and its place in the treatment of various infections — respiratory, ENT, urogenital, gynecological, and dental.

The article presents an overview of specialized medical information systems that perform ABC/VEN analysis. It provides a comparison of specific examples, describes their advantages and disadvantages, as well as the possibility of automating the processes of searching for information on the proven effectiveness of drugs, selecting alternative drugs within one ATC group, selecting alternative drugs within the framework of the current clinical recommendations of the Ministry of Health of the Russian Federation, assessing drug-drug interactions, as well as the reference information from the instructions for use of the drugs.