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INTRODUCTION. The increasing prevalence of multidrug-resistant strains of pathogens determines the need for fundamentally new antibacterial agents, including bacteriophage preparations. The consistent implementation of phage therapy is hindered by the lack of generally accepted standardised regulatory documents governing the legal and methodological aspects of the production and preclinical and clinical studies of bacteriophage preparations.AIM. This study aimed to analyse the international experience with the production and lifecycle management of bacteriophage preparations, as well as the main regulatory requirements for the control of their quality, safety, and efficacy.DISCUSSION. It is difficult to develop virulent bacteriophage preparations in accordance with the existing requirements for other medicinal products because of the biological characteristics of bacteriophages, the wide variety of bacteriophage strains, and the potential for rapid changes both in the bacteriophage population and in the pathogen population. Therefore, it is reasonable to develop streamlined marketing authorisation routes for phage therapies and methods for the assessment of their safety and efficacy. As part of these efforts, it is necessary to assess the adverse events specific to this group of medicinal products, such as the risks of lysogeny, resistance to bacteriophages, and antibiotic resistance gene transfer between bacterial strains. The pharmaceutical development of bacteriophage preparations can be based on several approaches. Many countries worldwide, including the United States, are implementing the concept of Quality by Design, considering approaches based on the Biological Master File, and conducting Expanded Access programmes. The Active Substance Master File procedure allows the submission of a separate document package covering only part of the registration dossier for regulatory approval. Expanded Access programmes provide individual patients with access to innovative medicinal products without approved treatment protocols. In the Russian Federation, the commercial production of bacteriophage medicinal products is conducted in accordance with the quality standards specified in the State Pharmacopoeia of the Russian Federation.CONCLUSIONS. There are fundamental differences in the approaches to phage therapy and its regulation around the world and in the Russian Federation. It is reasonable to supplement the current national guidelines for the safety and efficacy evaluation of bacteriophage preparations, in particular, to specify the requirements for conducting preclinical studies.

Scientist relevance. Antibacterials can have nephrotoxic effects because medicinal products of this class are primarily excreted by the kidneys.Aim. The study aimed to analyse literature data on the mechanisms, risk factors and specific features of toxic nephropathy development during antibiotic therapy.Discussion. The article considers mechanisms of development of acute interstitial nephritis, acute tubular necrosis, crystal deposits in the tubules, proximal or distal tubulopathy with electrolyte abnormalities during the use of antibiotics. Nephrotoxicity was shown to be most often associated with the use of aminoglycosides, beta-lactams, and vancomycin. The authors analysed the dependence of nephrotoxicity on antibacterial agent lipophilicity and drug–drug interactions. The main risk factors for developing nephropathy are older age; male sex; black race; hypovolaemia; arterial hypotension; angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, non-steroidal anti-inflammatory drugs or their combinations; and individual genetic characteristics. Nephrotoxicity is associated with genetic characteristics of the systems responsible for metabolism and excretion of antibacterial products: cytochrome P450 isoenzymes, P-glycoprotein, multidrug resistance protein (MRP), multidrug and toxin extrusion (MATE), breast cancer resistance protein (BCRP), and organic anion transporters. Severe generalised infections change pharmacokinetic parameters of antibacterial products. This should be taken into account when prescribing the hydrophilic antibiotics that are excreted by tubular secretion and reabsorbed in the renal tubules.Conclusions. The study demonstrated the effectiveness of the method comprising a combination of dose adjustment based on therapeutic drug monitoring results and renal function monitoring for improving the safety of antibiotic therapy.

Vancomycin is prescribed to patients in serious condition with infections caused by Gram-positive microorganisms; however, if the therapeutic plasma concentration of the medicinal product is exceeded, it can have a nephrotoxic effect.The aim of the study was to demonstrate the possibility of using therapeutic drug monitoring (TDM) to reduce the risk of developing nephropathy in intensive care unit patients with sepsis.Materials and methods: the study comprised a retrospective analysis of four clinical cases of patients with sepsis admitted to intensive care units of I.V. Davydovsky City Clinical Hospital in 2021 and treated with vancomycin. TDM of vancomycin plasma levels was performed by reverse-phase high-performance liquid chromatography with mass spectrometric detection.Results: using the four cases of septic patients, the study demonstrated that vancomycin at adequate case-specific doses may result in plasma concentrations beyond the therapeutic range. TDM of vancomycin concentrations helped to prevent further deterioration of renal dysfunction in one septic patient having developed acute kidney injury and to control the achievement of therapeutic vancomycin concentrations or timely adjust the dose to that effect in the other three cases.Conclusions: a timely correction of vancomycin dosing with plasma TDM allows for achieving high antimicrobial efficacy in patients with sepsis and minimising the nephrotoxic effect of the medicinal product. Studies of the feasibility of using TDM as a treatment personalisation tool for patients in serious condition will continue in the future.

The article highlights modern concepts of inflammatory diseases in adults and children in terms of genetic possibilities for diagnosing Crohn's disease and ulcerative colitis. It names the main candidate genes, which, in the presence of their specific polymorphisms, indicate the occurrence of a high risk of inflammatory bowel disease. The principles of modern therapy, the possibilities of pharma-cogenetic testing in predicting the effectiveness or risks of reducing the safety of drug therapy are described. The article focuses on modern trends and perspectives in ulcerative colitis and Crohn's disease treatment.

The study objective is to present current data on various genetic reasons of feminization.Results. Disruption of puberty in males can be associated with genetically determined defects of androgen receptor which cause partial or full insensitivity to the action of these hormones. The article presents a detailed description of the structure and function of these receptors. Additionally, polymorphism of the androgen receptors» gene is described: it consists of different number of CAG-repeats, and elongation of this locus causes hypogonadism.Conclusion. Pathology of androgen receptors can cause insufficient clinical effectiveness of testosterone drugs, therefore treatment of male hypogonadism requires evaluation of androgen receptor sensitivity prior to drug prescription and during evaluation of treatment results.

This article describes basic information about the classification, structure, substrate specificity and expression of organic cation transporters. The pharmacokinetic and pharmacogenetic aspects of transporters are discussed in more detail, as well as their participation in drug-drug interactions. Organic cation transporters are members of the SLC family which include three isoforms: OCT1, OCT2, OCT3. They are similar in structure to other members of this family and have 12 transmembrane domains. OCT1 is expressed predominantly in the liver, OCT2 in the kidneys, and OCT3 is the most common among all transports of this family and is expressed in the liver, placenta, kidneys, skeletal muscles, heart and brain. The regulation of transporter expression is mainly due to the presence of glycosylation and phosphorylation sites in large loops between 1,2 and 6,7 transmembrane domains, respectively. Among the endogenous substrates OCT — catecholamines, neurotransmitters, steroid hormones, etc. Among drugs, substrates of OCT are: metformin, ganciclovir, procainamide, cisplatin, cimetidine, etc. All three OCT genes are located in one cluster with a length of 300,000 bp. on the long arm of the 6th chromosome. For OCT1 the four most studied polymorphisms are known: rs12208357, rs34130495, rs72552763 and rs34059508. For OCT2, the only clinically relevant polymorphism is rs316019. For OCT3 at the moment, there are 4 polymorphisms: A116S, T400I, A439V, and M370I. Drug-drug interactions involving OCT occur when the substrate is inhibitor of the transporter. The effect of cimetidine and platinum drugs on the pharmacokinetics of drugs has been most studied. Organic cation transporters are currently being actively studied. Every year the number of drugs that are substrates of OCT is growing.

This review article describes the classification and mechanism of action of organic anion transporters (OAT). The influence of certain members of this family of transporters on the pharmacokinetics of β-lactam antibiotics.

The article analyses scientific literature on the use of pharmacogenetic testing to optimize sulfonylurea treatment of patients with type 2 diabetes. It describes characteristics of modern sulfonylurea drugs used in the treatment of type 2 diabetes, including their mode of action, and the frequency of associated hypoglycaemia events. The authors analysed the main pharmacokinetic parameters of sulfonylureas (bioavailability, protein binding, metabolites, elimination, etc.), and adverse reactions associated with these drugs. Based on integrated data on Cytochrome P450 isoenzymes role in sulfonylureas metabolism, and determination of the role played by polymorphism of the gene encoding this fragment, the authors demonstrated the usefulness of pharmacogenetic testing combined with phenotypic (losartan) testing in the treatment of patients with type 2 diabetes.

The article reviews scientific literature on C3435T polymorphism in the ABCB1 gene which encodes P-glycoprotein (an ATP-binding cassette transporter which is responsible for energy-dependent transport of substrates across cellular membranes and whose primary role consists in the prevention of penetration of various substances, such as xenobiotics, through biological barriers. C3435T polymorphism in the ABCB1 gene could be regarded as a promising pharmacogenetic biomarker which could be used in diagnostic testing after approval of the corresponding test methods. The authors of the article collected and systematized scientific data available in the electronic media (NCBI PubMed, eLIBRARY.ru) regarding medicines (such as digoxin, fexofenadine, loperamide, amlodipine, statins, etc.) for which there are integrated pharmacogenetic data on the effect of C3435T polymorphism in the ABCB1 gene on pharmacokinetic parameters, as well as on the efficacy and safety of treatment. It was demonstrated that ABCB1 gene polymorphism is of great importance for personalised medicine, however, there is a lack of awareness about all the factors that affect the bioavailability of medicines, and this precludes a significant progress in the use of ABCB1 genotyping in the near future.

The aim of the work is to study the functional characteristics of SLC transporters of organic anions: OAT1 and OAT3 in normal conditions and in model ischemia/reperfusion injury.Materials and methods. The HEK293 cell line was used as a model for the study. Conditions of ischemia/reperfusion injury were created by the previously described method. The activity of the transporters was assessed by the capture of the marker substrate - fluorescein. The concentration of fluorescein was measured using a plate fluorimeter. The results were normalized by the amount of total protein.Results. In condition of ischemia/reperfusion injury, the activity of organic anion transporters decreased in comparison with the norm. The data obtained allow us to conclude that in conditions of ischemia/reperfusion injury, the concentration of dicarboxylic acids in the cell is low, which in turn can lead to a decrease activity of transporters.

Aim. To evaluate the influence of gene СYP2C9 activeness via losartan test on the warfarin dosage management in earlier and long-term post-operational periods.Material and methods. Totally 33 patients included with artificial heart valves. All patients underwent assessment of genes carriage by polymorphic marker СYP2C9 by PCR after preparing of DNA from whole blood. The activeness of СYP2C9 was assessed with losartan concentration and its metabolite (E-3174) in urine after single intake of losartan 50 mg.Results. The level of losartan and its active metabolite (E-3174) in urine was a prognostic marker determining therapeutic dose of warfarin in cardiac surgery patients in long-term post-operation period.Conclusion. The СYP2C9 assessment by losartan concentration and E-3174 in“losartan test” might help to determine warfarin treatment dosage in delayed postoperational period that might improve the efficiency and safety of pharmacotherapy in valve prosthesis patients.

Aim. Carriership of CYP2C19*2 allelic variant and reduced CYP3A4 activity can affect the formation of clopidogrel’s active metabolite and, respectively, its antiplatelet effect. We sought to determine the impact of CYP3A4 isoenzyme activity and CYP2C19 polymorphisms on platelet aggregation.Material and methods. The study included 81 patients with acute coronary syndrome (ACS) and subsequent percutaneous coronary intervention (PCI): 64 males and 17 females, mean age 63.9±10.9 years. CYP2C19 allelic variants were detected by the method of real-time polymerase chain reaction. CYP3A4 isoenzyme activity was estimated by urinary 6-β-hydroxycortisol/free cortisol ratio (6-OHC/FC) using the method of high-performance liquid chromatography. Platelet functional activity was evaluated by a portative aggregometer - the VerifyNow P2Y12 assay.Results. Logistic regression analysis has demonstrated significantly increased risk of clopidogrel resistance in patients-carriers of the CYP2C19*2 polymorphism (p=0.022). CYP2C19*2 non-carriers had significantly higher mean platelet inhibition percentage as compared with the carriers of this allele: 30.7±20.1 in the CYP2C19*1/*1 group vs 18.2±16.4 in the CYP2C19*1/*2 one (р=0.03). Clopidogrel laboratory resistance (P2Y12 Reaction Units (PRU)>208) was found out to be higher in the CYP2C19*2-carriers as compared with non-carriers: 53.8% in the patients with the CYP2C19*1/*2 genotype and 16.2% in subjects with the CYP2C19*1/*1 genotype (odds ratio [OR]=1.8; 95% confidence interval [95% CI]: 1.0–3.2; р=0.0067). Linear regression analysis has revealed that smaller mean diameter of stent slightly reduces the risk of clopidogrel resistance development. No significant distinctions in urinary 6-OHC/FC ratios (the marker of CYP3A4 activity) were observed: 3.4±2.8 in the PRU>208 group and 3.2±3.0 in the PRUConclusion. CYP2C19*2-carriership in ACS patients undergoing PCI significantly increases the risk of clopidogrel laboratory resistance. The urinary 6-OHC/FC ratio (as a marker of CYP3A4 isoenzyme activity) does not correlate with platelett functional activity.

The clinical significance of the patient genetic characteristics in the individual pharmacological response to oral anticoagulants is considered. Possible tactics of warfarin dosing and new oral anticoagulants choice on the basis of pharmacogenetic testing as well as indications for this approach in clinical practice are discussed. It should increase efficacy and safety of anticoagulant therapy.

The number of patients receiving statins increases every year and due to the fact that they should take statins during their lives, the problem of their safety use comes to the forefront. The paper analyzes the safety of using the medications of this group and discusses the diagnosis of myopathies induced by statins and the occurrence of immune-mediated statin myopathies. It considers a personalized approach to prescribing statins, analyzes Russian and foreign experience in using pharmacogenetics to reduce the risk of myopathies, publishes the results of the authors’ experience in clinically introducing pharmacogenetic testing at hospitals, and analyzes the long-term results of determining the polymorphism of the SLCO1B1 gene for the prediction of the risk of adverse events when using statins and estimating patient compliance to prescribed treatment.