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OBJECTIVE: Clinical and economic evaluation of using the dapagliflozin in addition to standard therapy for patients with CHF (Chronic Heart Failure) and concomitant type 2 DM (Diabetes mellitus).MATERIALS AND METHODS: All adult Russian patients with confirmed diagnosis of CVD and concomitant type 2 DM were considered as the target population. We evaluated the use of dapagliflozin in addition to standard therapy in comorbid patients with CHF and DM type 2 on the indicators of CC death, death from any cause of hospitalization due to CHF, emergency treatment due to CHF, as well as calculated the cost per life year saved and quality-adjusted life year (QALY) saved both when using standard therapy alone and in combination with dapagliflozin.RESULTS: The use of dapagliflozin in addition to standard therapy for the treatment of comorbid patients with CHF and DM 2 per cohort of 1,000 people will prevent an additional 1,3 and 10 years:CHD-related hospitalizations: 40, 99, 195, respectively;Emergency admissions due to CVD: 15, 38, 73 respectively;CC deaths: 9, 19, 25 respectively;Deaths from any cause: 10, 21, 19At the same time, the costs per one year of quality-adjusted life saved were 1,923,509 rubles during the first year, 1,102,680 rubles during the first 3 years, and 560,841 rubles for 10 years, which did not exceed the calculated value of the willingness-to-pay threshold — 3.14 million rubles, and allowed us to conclude that dapagliflozin is clinico-economically feasible in the studied patient population.CONCLUSION: The use of dapagliflozin in addition to standard therapy for the treatment of comorbid patients with CHF and type 2 diabetes is clinically and economically feasible, considering the cost per year of life saved, adjusted for quality of life.

Drug-drug interactions (DDIs) are a major cause of hospital admissions, accounting for 16.6% of ADRs and about 1% of all hospital admissions. Polypharmacy is on the rise, with a Swedish population-based study of people aged ;;;75 years showing that the prevalence of polypharmacy increased from 27% in 1988 to 54% in 2001 and to 65% in 2006. The aim of the study was to analyze the databases on DDI and to assess the possibility of their use in managing the risks of pharmacotherapy in the Russian Federation and the EAEU. Results. The main DDI databases are characterized. The degree of inconsistency in data on the number of DDI, severity and clinical recommendations was determined. The basic requirements for the completeness of information in databases are formulated. The necessity to harmonize approaches to providing information about DDI, as well as the need to create local databases for medical organizations were revealed. A computer program has been created to minimize the risks of DDI in clinical practice, for expert and scientific purposes. Conclusions. Databases and programs for DDI have different goals, a different set of data on DDI with varying degrees of evidence, differences in assessment of severity, likelihood of occurrence, clinical recommendations for treatment and correction of DDI. The variability of information is due to the lack of a unified system for assessing the severity and likelihood of potential negative consequences of DDI; different purposes for creation; difference in budgets at creation. This situation leads to warning redundancy and physician fatigue from insignificant or unproven DDIs. Based on the identified requirements for local databases, a computer program for modeling rational pharmacotherapy for lower respiratory tract infections was created and received a certificate of state registration.

Aim. To evaluate the dapagliflozin as part of various treatment regimens in patients with heart failure (HF) with reduced ejection fraction (HFrEF) ≤40% receiving medications within federal preferential drug program to achieve the "Reduction of cardiovascular mortality" of the State Program "HealthCare Development". To estimate the costs of reducing the cardiovascular mortality rate by 1 death per 100 thousand of population and achieving 1 percentage point of the target indicator "Reduction of cardiovascular mortality".Material and methods. The target patient population was Russian patients aged over 18 years diagnosed with NYHA class II-IV HFrEF (≤40%), included in the federal preferential drug program. We used model developed based on the DAPA-HF study results. We assessed the costs of drugs, the number of lives saved, the impact of therapy on achievement of the target indicator "Reduction of cardiovascular mortality" and other indicators in the Russian Federation (RF) as a whole and in each subject of the Russian Federation while using dapagliflozin as part of various treatment regimens for HFrEF including angiotensin-converting enzyme inhibitors (ACEi)/angiotensin II receptor blockers (ARB) or angiotensin receptor-neprilysin inhibitor (ARNi), beta blockers, diuretics, mineralocorticoid antagonists, cardiac glycosides.Results. In 2024, the treatment cost of 181351 patients with HFrEF included in the federal preferential drug program with dapagliflozin in combination with standard therapy (ST) will be RUB9265,4 million; in combination with ST without ARNi (ST including ACEi/ARB) — RUB8161,7 million; in combination with ST including ARNi — RUB17837,3 million. The additional number of lives saved when using dapagliflozin in combination with standard therapy was 2394, in combination with standard therapy without ARNi — 2340, in combination with standard therapy, including ARNi — 2913. Costs of therapy per patient per year when using dapagliflozin in combination with standard therapy amounted to RUB51090,90; in combination with standard therapy without ARNI — RUB45004,72; in combination with standard therapy, including ARNI — RUB98358,00. In 2024, the percentage (%) of achievement of the federal target for dapagliflozin in combination with ST is 11,22%, while in combination with standard therapy without ARNi (ST including ACEi/ARB) — 10,96%, in combination with ST including ARNi — 13,65%. Achievement of a 1% target reduction in cardiovascular mortality in 2024 reqiored RUB828,1 million for dapagliflozin in combination with ST, while in combination with ST without ARNI (ST including ACEi/ARB) — RUB748,2 million, in combination with ST including ARNi — RUB1293,3 million.Conclusion. Among the 3 options considered for adding dapagliflozin to ST (ARNi or ACEi/ARB, including ACEi/ARB, including ARNi), ST without ARNI (ST including ACEi/ARB) has the lowest cost required to achieve a 1% target reduction in cardiovascular mortality. At the same time, the standard therapy with ARNI has the highest cost required to achieve a 1% target reduction in cardiovascular mortality, which indicates its least cost-effectiveness.

Objective: to assess budget impact of using empegfilgrastim for the prevention of febrile neutropenia in patients with early and locally advanced human epidermal growth factor receptor 2 positive (HER2+) breast cancer who receive neoadjuvant “docetaxel / carboplatin / trastuzumab + pertuzumab” regimen, considering possible subsequent adjuvant therapy with trastuzumab emtansine or trastuzumab within the Russian healthcare system.Material and methods. We searched and analyzed published clinical, epidemiological and pharmacoeconomic studies as well as regulatory and legal documents. A decision tree model was constructed to reflect the probabilities of switching to different adjuvant therapy regimens depending on the achievement of pathomorphological complete response in patients with early and locally advanced HER2+ breast cancer. The budget impact analysis was carried out comparing two primary prophylactic options, empegfilgrastim and filgrastim.Results. Despite the higher costs of prevention with empegfilgrastim compared to filgrastim (249 vs. 134 thousand rubles), due to the higher rate of achieving a pathomorphological complete response and, accordingly, fewer cases requiring adjuvant therapy with the more expensive trastuzumab emtanzine, savings of 916 thousand rubles per 1 patient per 1 year of therapy are possible. In general, prophylaxis in the target population diagnosed with early and locally advanced HER2+ breast cancer using empegfilgrastim will result in a cost reduction of 9.4 billion rubles per 1 year compared to filgrastim.Conclusion. Empegfilgrastim prophylaxis, despite its higher annual cost, is an efficient option within the Russian healthcare system. In addition to reducing the incidence of febrile neutropenia, the frequency and dose of chemotherapy are preserved, resulting in increased efficacy of the primary therapy.

Scientific relevance. Vancomycin and linezolid are the antibacterial agents of choice for severe infections caused by multidrug-resistant pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). However, few studies have been conducted in Russia to analyse the safety of these medicinal products.Aim. The study aimed to compare the safety of vancomycin and linezolid using the Moscow segment of the Russian Federal Service for Surveillance in Healthcare’s database for adverse drug reaction (ADR) reports.Materials and methods. The study used information from the spontaneous reporting database for 2018–2022, which contained 147 ADR reports for vancomycin (122 reports) and linezolid (25 reports). The authors analysed the ADR distribution and assessed the statistical significance of the identified differences by sex, weight, and age of patients, conditions of medical care, route of administration, single dose, daily dose, therapy duration, ICD-10 codes, ADR severity, and ADR outcome.Results. The distribution of adverse reactions to vancomycin and linezolid by patient age was relatively uniform. Outpatient linezolid was associated with a significantly higher rate of ADRs (3 of 5 reports) than outpatient vancomycin (21 of 129 reports; p=0.0408). For ADR severity, 5 of 20 ADRs reported with linezolid required hospitalisation or prolongation of hospitalisation—considerably more than with vancomycin (16 of 94 reports; p=0.528). The average single dose of vancomycin (794 mg) was higher than that of linezolid (467 mg; p=0.007); the same was noted for average daily doses (1273 mg vs 998 mg; p=0.3664). The mean duration of treatment with linezolid before ADR onset was 5.26 days, which was significantly longer than the mean duration of treatment with vancomycin (2.44 days; p=0.0053). Oral linezolid was associated with a significantly higher ADR rate (4 of 19 cases) than oral vancomycin (5 of 96 cases; p=0.0027).Conclusions. The ADRs observed with vancomycin and linezolid were predictable and class-specific. According to the results of the ADR report analysis, adverse reactions to vancomycin and linezolid were associated with different factors. Similar results of the literature analysis confirmed this conclusion. However, according to the results of the linear regression analysis, none of the factors considered in this study had a statistically significant influence on the probability of developing an adverse reaction to vancomycin or linezolid.

Background. The global recommendations for the treatment strategy of community-acquired pneumonia (CAP) include the empirical prescription of antibiotic therapy (ABT) – beta-lactams, fluoroquinolones, macrolides until the results of laboratory tests are obtained to identify the etiological agent responsible for CAP to determine etiotropic therapy. According to the national Russian clinical guidelines, macrolides, fluoroquinolones, cephalosporins and aminopenicillins are recommended for empirical prescription. Meta-analyses found better outcomes in patients treated with a combination of macrolides with beta-lactam compared to beta-lactam alone. At the same time, the clinical benefit of adding macrolides to beta-lactams for the empirical treatment of moderate CAP remains controversial, since the difference in the results of therapy may depend on the age and comorbid conditions of patients.Objective: to analyze the costs of treating CAP with various ABT strategies in order to optimize the cost structure of a medical organization and plan the budget of local healthcare systems.Material and methods. A retrospective epidemiological analysis of extracts from 157 medical records of middle-aged patients in accordance with the World Health Organization classification treated in multidisciplinary medical organizations was carried out. The methods included frequency analysis, cost of illness analysis, cost minimization analysis, and cost-effectiveness analysis. Depth of research was 2 years.Results. Frequency analysis revealed that the initial strategy of ceftriaxone and azithromycin combination (n=74; 47%) prevailed in prescriptions. In terms of the rate of prescriptions, ceftriaxone monotherapy (n=37; 24%) was in the second place. The analysis of the effectiveness of the selected ABT strategies showed that, in general, 113 (72%) of prescriptions were effective. Standard therapy strategies were equivalent in absolute costs and had a similar cost structure.Conclusion. Doctors’ adherence to national clinical guidelines for CAP treatment was found when prescribing the initial empirical ABT, the dominant strategies were identified. Cost of illness analysis demonstrated that the applied strategies were optimal in terms of cost minimization, and cost-effectiveness ratio. The costs structure in therapy with various ABT strategies did not have significant differences. In medical organizations, they adhere to the most rational and cost-effective strategy for CAP treatment and prescribe ABT regimens in each individual case based on risk factors, as well as the results of studies of CAP pathogens sensitivity.

Objective: to evaluate the pharmacoeconomic feasibility of using monoclonal antibodies or their combinations vs standard therapy in patients with mild and moderate-severe COVID-19 in order to prevent the severe course of the disease.Material and methods. The decision tree and Markov models for calculation of costs and outcomes were used for patients with COVID-19 and post-COVID-19 syndrome, respectively. The cost-effectiveness of tixagevimab and cilgavimab was evaluated in persons ≥18 years old not vaccinated against COVID-19 with a high risk of progression to severe COVID-19. Effectiveness and safety of tixagevimab and cilgavimab combination was assessed based on TACKLE phase III study results. The quantities of life years gained (LYG) and quality-adjusted life years (QALY) were calculated. Results were compared with the wiliness-to-pay threshold measured as tripled gross domestic product per capita according the World Health Organization recommendations.Results. Treatment of COVID-19 with tixagevimab and cilgavimab results in additional 0.2657 LIGs or 0.2255 QALYs. The cost of 1 LIG was 213,4 thousand rubles, the cost of 1 QALY was 251,5 thousand rubles. Both costs of LIG and QALY appeared to be significantly less compared to the wiliness-to-pay threshold equal to 3.09 million rubles in 2022.Conclusion. Treatment of mild and moderate-severe COVID-19 is economically feasible and may be recommended for wide use in the Russian healthcare system.

Objective: development of approaches to predict the likelihood of adverse reactions (ARs) when using drugs based on a comprehensive assessment of risk factors.Material and methods. We used a database containing 1,450 drug-related ARs reports from January through December 2021. A list of antibacterial drugs by international nonproprietary name (INN) with 4 or more ARs reports was selected as a reference group to perform various types of statistical analysis. A cumulative multivariate regression analysis was carried out on a database of 187 ARs notifications for 13 INN of antibacterial drugs. The study was performed in two stages. In the first stage, a statistical method was used (classical multiple regression, linear discriminant analysis, factor analysis, principal component regression, partial least squares regression, estimation of variance accuracy); at the second stage a modeling method was used. As part of the modeling stage, the integral score of the risk of ARs was presented as a sum of values for individual risk factors. Two groups of risks were proposed to be assessed: 1) intrinsic risk value for each factor (attribute), which was equal to the sum of risks of all factors (conditions) in which the drug had been used; 2) intrinsic risk value for antibacterial drugs by each INN. The total risk value was defined as the sum of the risk of the drug and all factors (conditions) in which this drug had been used.Results. The results were visualized in the form of a two-level risk-based model matrix, with a “heat map” of the risk level overlaid on it. The maximum total risk of ARs was obtained for ceftriaxone – 404.96 points, depending on patient’s gender. The minimum total risk was calculated for azithromycin and cefotaxime depending on the International Classification of Diseases (10th revision) code – 88.46 points. The proposed methodological approach also allows combining all possible combinations of drugs and conditions of their use. For example, for the use of vancomycin in hospital conditions by intravenous administration: intrinsic risk of use – 42.93 points; risk of use in hospital conditions – 183.68 points; risk when administered intravenously – 209.95 points; the total risk value in the designated situation – 436.56 points.Conclusion. The proposed approach can allow medical organizations to reduce significantly the number of ARs when using drugs by categorizing and preventing risks before they occur. It also has significant prospects of application at the federal level, given its modification on a large volume of data.

Relevance. Cardio-vascular diseases (CVD) are the one of the main reasons of mortality and disability. Hypercholesterinemia is a factor of CVD progression, and thus it should be corrected. Combination of statin + ezetemib is an effective option of a medical technology for this purpose. Pharmacoeconomic analysis of rosuvastatin and ezetemib fixed combination (FC) has been performed in this work in comparison with free combination (FrC) of these drugs.Materials and methods. Modelling of FC vs FrC in groups of CVD risk has been performed on 1–5 years horizon based on the local epidemiologic published data with aim of economic analysis. Efficacy of FC and FrC, direct medical costs, including cost of drugs, hospitalizations etc. were taken into account also. ICER has been calculated and compared with willingness to pay.Results. FC usage instead FrC can prevent 2960–3055 deaths and 8880–9164 admissions to hospital caused CVD. FC decrease of ambulance cost as well as others direct medical expenditures in compare with FrC treatment on 9,3 bln RUR per 5 years. ICER has been calculated and has negative (dominant) result.Conclusion. FC usage is an economic dominant technology in compare with FrC for hypercholesterolemia control.

Aim. To evaluate the contribution ticagrelor compared with clopidogrel therapy in patients with acute coronary syndrome (ACS) and patients with myocardial infarction (MI) to achieving the State Program "Health Development" target "decrease of cardiovascular mortality" in the country as a whole and Russian regions in 2023-2025.Material and methods. In the first year of therapy, all patients over 18 years of age with a confirmed diagnosis of ACS who were indicated for dual antiplatelet therapy (DAPT) were considered as the target population. In the second and third years, therapy was continued by patients at high risk of coronary events after MI. The number of deaths that could be additionally prevented within 1 year after diagnosis using DAPT with ticagrelor compared with DAPT with clopidogrel was calculated based on the PLATO trial. For post-MI patients, the number of deaths that could be prevented in the second and third years of therapy using DAPT with ticagrelor+acetylsalicylic acid (ASA) compared with ASA monotherapy was calculated based on the PEGASUS trial. The proportion of the target "decrease of cardiovascular mortality of the population" in 2023-2025 that can be achieved by using DAPT with ticagrelor instead of clopidogrel or ASA monotherapy was calculated.Results. The use of ticagrelor as part of DAPT for patients with ACS will make it possible (compared to DAPT with clopidogrel or ASA) to contribute to achieving "decrease of cardiovascular mortality" target in the Russian Federation:in 2023 — 8,0% due to expected prevention of 4443 cardiovascular deaths,in 2024 — 30,3% due to expected prevention of 4753 cardiovascular deaths,in 2025, 5366 cardiovascular deaths can be Conclusion. The use of ticagrelor as part of DAPT for patients with ACS will contribute to achieving "decrease of cardiovascular mortality" target in the Russian Federation.

Aim. To assess cost-effectiveness of valsartan+sakubitril, dapagliflosin and empagliflosin for prevention of cardiovascular death and achieving the target indicator "reduction of cardiovascular mortality" of the State Program "Health Development" in patients with heart failure (HF) of the entire profile of left ventricular ejection fraction in 2023-2024Material and methods. The target population was Russian patients who had acute cardiovascular disease (CVD) and a verified diagnosis of HF and received subsidized drug coverage. Parametric modeling was used to predict cardiovascular mortality. In the corresponding comparative pair, the amount of drug costs required to prevent one cardiovascular death (CVD) was calculated, as well as to achieve a 1% target for reducing cardiovascular mortality in the whole country and separately in each region.Results. To prevent one cardiovascular event, the costs of 1-year val-sartan+sacubitril therapy was RUB11,80 million, dapagliflozin — RUB7,07 million, empagliflozin — RUB13,83 million. The costs required to achieve a 1% target for reducing cardiovascular mortality for valsartan+sacubitril, dapagliflozin and empagliflozin were:• in 2023, RUB6534,0 million, RUB3915,0 million and RUB7654,2 million, respectively;• in 2024, RUB1100,6 million, RUB659,5 million and RUB1289,7 million, respectively.Conclusion. The use of dapagliflozin is characterized by the lowest costs for preventing one cardiovascular event and achieving a 1% target for reducing cardiovascular mortality in 2023-2024.

Multiple myeloma (MM) accounts for 1 % of all cancers and about 10 % of all hemoblastoses. The use of innovative technologies with the inclusion of targeted drugs leads to a significant improvement in the quality of pharmacotherapy and the achievement of overall survival (OS).The aim of the work is to conduct a pharmacoeconomic analysis of the most used MM therapy regimens with the use of targeted drugs and to determine the dominant treatment regimens using a costeffectiveness analysis.Materials and methods. To determine the cost of a course of treatment, we summed up the costs of drugs included in the pharmacotherapy regimen, taking into account taxes, marginal trade markup and duration of the course. Dosing of the targeted drug included in the regimen was determined according to the official instructions for the drug. Progression-free survival (PFS) was adopted as the main criterion for the effectiveness of treatment. Information on PFS of targeted drugs was obtained from data from international phase III RCTs — ASPIRE, TOURMALINEMM1, POLLUX and ELOQUENT2.Results. Based on the results of the pharmacoeconomic analysis, the dominant treatment regimen for MM was determined — daratumumab / lenalidomide / dexamethasone, which has the best cost-effectiveness ratio. The combination of elotuzumab / lenalidomide / dexamethasone was recognized as the least effective technology.

Cephalosporins are the empirical antibiotic therapy (ABT) of choice for patients with community-acquired pneumonia (CAP). When treated with antibiotics, elderly patients, especially those with comorbidities, are at higher risk of developing adverse drug reactions (ADRs).The aim of the study was to analyse data on the safety and efficacy of initial empirical ABT with cephalosporins in elderly patients over 75 years old with CAP admitted to multidisciplinary hospitals in Moscow.Materials and methods. The retrospective study included 305 medical records of patients with CAP admitted to three multidisciplinary hospitals in Moscow in 2017–2019 and prescribed initial mono- and/or combination ABT including a cephalosporin. Initial ABT was considered effective if the body temperature normalised within 48–72 h from the start of treatment. It was considered safe if there were no ADRs during hospital stay.Results. Mostly, patients were prescribed ceftriaxone monotherapy or ceftriaxone and azithromycin combination therapy. These ABT regimens were effective in 69.07% and 78.10% of the cases, respectively. Patients with severe CAP needed their initial ABT adjusted significantly more often than those with non-severe CAP. The initial ABT was changed for a number of reasons, including ineffectiveness, ADRs, abscesses formed as a complication of CAP, sputum culture results enabling causal ABT, secondary hospital-acquired infections, and exacerbated chronic infections. All patients had comorbidities, and the most prevalent were arterial hypertension (83.9%), coronary heart disease (45.6%), chronic heart failure (44.9%), cerebrovascular disease (40.9%), atrial fibrillation (26.9%), diabetes mellitus (21.3%), and chronic obstructive pulmonary disease (19.0%). Initial ABT was significantly more often considered ineffective in patients with chronic heart failure and cerebrovascular disease. The most common causative agent of CAP in the study population was Streptococcus pneumoniae (31.9%). In 16% of patients, the authors identified ADRs associated with the antibiotics used as initial therapy. The most common were diarrhoea, anaemia, leucopenia, and hepatopathy. Ceftriaxone was associated with ADRs in 11% of patients.Conclusions. The study results suggest that initial mono- and/or combination ABT including a cephalosporin is effective and relatively safe; therefore, this treatment option is expedient for elderly patients with CAP. For this population, the safety of ABT may be improved through the wider use of existing markers of ADRs and the identification of new ones.

Despite the fact that the incidence of community-acquired pneumonia (CAP) among young people is significantly lower than among older patients, the frequency of hospitalizations for severe CAP among people under 45 years of age remains high. The effectiveness and duration of treatment directly depend on the rationally selected initial empirical antibacterial therapy (ABT).The aim of the study is to analyze the factors influencing the effectiveness of initial empiric antibacterial therapy for CAP in young people in multidisciplinary medical institutions.Materials and methods. The study was designed as a retrospective observational study; it analyzes 105 medical records of young patients with CAP admitted to one of the multidisciplinary hospitals in Moscow from 2017 to 2019.Results. The empiric ceftriaxone + azithromycin ABT regimen (70% of all prescriptions) was ineffective in 13.7% of cases; monotherapy with ceftriaxone (13% of all prescriptions) was ineffective in 57% cases. Severe CAP, acute respiratory failure, systemic inflammatory response syndrome, and exudative pleurisy were diagnosed with significantly higher frequency in the group of patients with ineffective initial empirical ABT. There was no predominance of any comorbid pathology and Charlson Comorbidity Index in groups where the initial ABT was changed and in groups without a change in initial ABT. The microbiological spectrum of CAP pathogens did not significantly differ in young patients between groups with a changed initial empirical ABT and a group without changing initial ABT.Conclusion. The reasons for the ineffectiveness of the initial empirical ABT could be such factors as: underestimation of the risk of the presence of multidrug-resistant pathogens; underestimation of the risk of viral genesis of CAP; underestimation of the severity of CAP, as well as the severity of CAP complications.

The general toxicity was studied with an assessment of local tolerability, immunotoxicity, and pharmacological safety of the new medicine Dioxidine®, a solution for topical and external use, 0.25 mg/ml (0.025%) for the treatment of acute tonsillopharyngitis (JSC «Valenta Pharm», Russia). The experiment included 48 rabbits (divided in equal proportion by sex) randomized into 3 groups (n=16 in each group), whose back wall of the pharynx was irrigated with the studied substances for 28 days. Group 1 — control (aqueous solution of NaCl 0.9% for infusions at a daily dose of 4.0 ml/animal); group 2 — dioxidine (1.8 ml/animal); group 3 — dioxidine (4.0 ml/animal). The animals were observed for the entire period of drug administration — up to the 28th day of the experiment, as well as during the delayed observation period — up to the 58th day. The following indicators were recorded: lethality, daily monitoring of general condition and behavior, weight, feed and water consumption, respiratory rate, heart rate, blood pressure, electrocardiogram, mass coefficients of internal organs. Immunotoxicity, poisoning symptoms, adrenal insufficiency, as well as animal autopsy results were assessed. Clinical and biochemical blood tests, blood coagulation system analysis, urine analysis, macroscopic and histological examination of internal organs were performed. The absence of statistically significant differences in all evaluated indicators between the group of animals receiving dioxidine solution for topical and external use, 0.25 mg/ml (0.025%) at a dose of 1.8 ml/animal (equivalent to 15 therapeutic doses for humans), the group receiving dioxidine at a dose of 4.0 ml/animal (equivalent to 35 therapeutic doses for humans) and the control group allowed us to draw conclusions concerning the absence of signs of general toxicity, including toxic effects on the adrenal glands, cardiotoxicity, immunotoxicity, and toxic effects on other organs and organ systems, as well as local irritant and toxic effects after repeated irrigation of dioxidine on the back wall of the pharynx in rabbits for 28 days and during the period of delayed observation.

The article presents the results of an in vitro study of the synergetic effect evaluation of the combined preparation based on coordination complex ethylmethylhydroxypyridine succinate and trimethylhydrazinium propionate on energy metabolism and cell respiration.The aim of the study was to evaluate the mitochondria-directed action of the metabolic and antioxidant preparation based on succinic acid coordination complex with trimethylhydrazinium in relation to optimizing the energy metabolism in the cells under the oxidative stress conditions, as well as against the background of ischemic processes.Materials and methods. The study of the hydroxysuccinate complex effect of the drug Brainmax® components was carried out on isolated mouse liver mitochondria. In the course of the study, the potential of mitochondria, the generation rate of hydrogen peroxide during the respiration, the respiration rate were evaluated in the following positions: a) unstimulated by malate and pyruvate, b) stimulated by malate and pyruvate (complex I substrates), by succinate (complex II substrates), c) against the background of the initial section of the electron transport chain blockade by rotenone, d) in phosphorylation blockade by oligomycin, e) against the background of the FCCP-induced uncoupling, and f) in cyanide-blocked complex IV (cytochrome C oxidase).Results. It has been shown that the succinic acid coordination complex with trimethylhydrazinium, which is the active principle of the Brainmax® drug, significantly reduced the transmembrane potential of mitochondria (IC50=197±5 µM), compared with the widely used preparations of ethylmethylhydroxypyridine succinate and trimethylhydrazinium propionate, which facilitates the transfer of the produced ATP into the cell and preserves a vital activity of mitochondria even under stress. In the study of the mitochondrial respiration stimulated by the substrates of complex I (NADP-coenzyme Q-oxidoreductase), pyruvate and malate, the studied drug led to a more pronounced increase in the oxygen consumption with IC50=75±6 µМ. When evaluating the effect of the complex on the production of ATP by mitochondria, the most pronounced effect was observed with the addition of studied complex, which indicated to the uncoupling of respiration and oxidative phosphorylation at the given concentrations of the studied compounds. When assessing the effect of the complex on the production of hydrogen peroxide by isolated mitochondria, a significant decrease in the peroxide production was shown in the samples containing the complex of trimethylhydrazinium propionate and EMHPS.Conclusion. Based on totality of the results obtained, it can be assumed that a favorable conformation of the pharmacophore groups of ethylmethylhydroxypyridine succinate and trimethylhydrozinium propionate coordination complex included in the composition of Brainmax® leads to a synergetic interaction and more pronounced pharmacological effects on target cells. This complex provides stabilization of a mitochondrial function, intensification of the adenosine triphosphate energy production and the optimization of energy processes in the cell, reduces the severity of the oxidative stress and eliminates undesirable effects of an ischemic-hypoxic tissue damage.

The relationship between dissolution and bioavailability is an example of the interdependency between the quality of a medicinal product and its safety and efficacy. The uniqueness of thioctic acid is that it can exist in an oxidised and a reduced form, showing lipophilic (lipoic acid) and hydrophilic (dihydrolipoic acid) properties. Bioavailability studies of thioctic acid are necessary to evaluate the expected therapeutic effect and mitigate side effects of the medicinal product.The aim of the study was to carry out equivalence dissolution testing to compare the release of thioctic acid from medicinal products produced by several manufacturers.Materials and methods: the study used a reference medicinal product and three multisource medicinal products by different manufacturers; more specifically, film-coated tablets containing 600 mg of thioctic acid. The experiment was carried out in dissolution media at pH of 6.8±0.05 and 1.2±0.05. Statistical analysis was performed by calculating the average amounts of the substance dissolved, the standard deviation (SD), and the relative standard deviation (RSD, %) using Microsoft Office Excel 2007.Results: The authors chose the testing conditions (dissolution media pH values of 6.8±0.05 and 1.2±0.05) taking into account the nature and characteristics of thioctic acid. The comparison of thioctic acid release profiles based on the calculation of the similarity factor (f2) showed that the dissolution profiles of multisource medicinal products 2 and 3 at pH 6.8 were equivalent to that of the reference medicinal product (more than 85% of the active pharmaceutical ingredient released within 15 minutes) and the dissolution profile of multisource medicinal product 1 was not equivalent to it (with f2 of 28).Conclusions: the established differences in the rate and degree of active ingredient release from the studied medicinal products may indicate possible differences in their pharmacological effectiveness in vivo.

Background. Drug-drug interactions can seriously affect the safety profile of a drug and are an important problem worldwide. Due to the aging of the population, the increasing frequency of polypharmacy, as well as the spread of self-medication, adverse events that are difficult to identify may occur. It is hard to establish a causal relationship between the administration of a certain drug and the occurrence of an adverse event; it may also lead to the conversion of the adverse event into an adverse drug reaction. The risk of drug-drug interactions increases with combination therapy, as a result of misuse of a drug (off-label use), as well as in the absence of full disclosure from physician and patient about potential drug-drug interactions.One of the ways to detect an adverse reaction to a drug is a method of «spontaneous messages», when notification cards issued according to the regulated form are sent from subjects of drug circulation to the national centers for pharmacovigilance, then to the global database of the World Health Organization VigiBase.The aim of the work was a comprehensive analysis of the content compliance of the information presented in the instructions for the medical use of antibacterial drugs on potential drug-drug interactions with validated signals from the WHO global VigiBase database.Material and Methods. The study used information and analytical comparative non-quantitative, graphical, logical methods of analysis, as well as regression analysis. Objects of the study: instructions for medical use for international generic drugs ampicillin, amoxicillin, azithromycin, clarithromycin.Results. The contents of the instructions for use concerning possible interactions of ampicillin, amoxicillin, azithromycin, clarithromycin upon administration with other drugs were studied. Subsequently, a comparative analysis of the obtained data on drug-drug interactions of antibiotics with other drugs was carried out with signals of drug-drug interactions were validated by VigiBase.Conclusion. The study showed that a detailed description of the risks of potential drug-drug interactions in the instructions for medical use with the aim of informing doctors, patients, and caregivers helps to prevent the use of undesirable combinations, thereby reducing the risk of adverse reactions when drugs are used together. The study found that most of the identified information on the safe use of drugs was missing in the instructions for medical use.

Aztreonam is the only approved monocyclic β-lactam antibiotic for human use that is active against Gram-negative aerobes, primarily Pseudomonas аeruginosa. Aztreonam has been used for more than 35 years, and aztreonam lysine has been on the market for 15 years. Although the medicinal products show clinical and microbiological efficacy in severe infections and are significant for cystic fibrosis patients, little information is published on their safety. In the meantime, new data have accumulated.The aim of the study was to analyse the data on adverse reactions in patients of different age groups receiving aztreonam, collected in the safety monitoring databases VigiBase and Pharmacovigilance.Materials and methods: the data on adverse reactions associated with aztreonam, in any dosage form, from the individual case reports submitted to VigiBase (the database of the Uppsala Monitoring Centre) before 15.09.2021 and to Pharmacovigilance (the database for spontaneous reports in the Automated Information System of the Federal Service for Surveillance in Healthcare of the Russian Federation) before 05.10.2021.Results: the analysis of adverse reactions during the use of aztreonam for approved indications showed differences in frequency, types and severity of the adverse reactions amongst the age groups. The most common adverse reaction with aztreonam was cystic fibrosis referred to in 1828 reports (12.0%). It was recorded more often in patients aged 18–44 years (39.2%).Conclusions: the data obtained allowed the authors to identify a new safety signal for aztreonam, namely an increased risk of inefficacy or insufficient efficacy in cystic fibrosis considered an adverse reaction in the individual reports from the databases of spontaneous reports. Confirmation of the signal requires further monitoring.

β-lactam antibiotics, including cephalosporins, are the drugs of choice for empirical antibiotic therapy (ABT) in patients with community-acquired pneumonia. Unreasonable and irrational use of antibiotics leads to an increased risk of adverse reactions, contributes to the growth of antibiotic resistance.The aim of the study was to analyse data on the efficacy and safety of initial empirical ABT using cephalosporins for community-acquired pneumonia in middle-aged patients of multidisciplinary hospitals in Moscow.Materials and methods: the authors analysed 177 archived medical records of the patients admitted to three multidisciplinary hospitals (I.V. Davydovsky City Clinical Hospital, City Clinical Hospital 52 and City Clinical Hospital 4) in Moscow from 2017 to 2019 and prescribed mono- and/or combination therapy including a cephalosporin antibiotic as a starting therapy for community-acquired pneumonia. The initial ABT was considered effective if a patient’s body temperature normalised within 48–72 h following initiation of treatment and safe if no adverse reactions developed during the period of inpatient treatment.Results: the combination of ceftriaxone and azithromycin was the most frequently prescribed ABT regimen; its effectiveness was 71.9%. Ceftriaxone monotherapy was the second in frequency of prescription; its effectiveness amounted to 77.2%. The third regimen included cefotaxime and azithromycin and was effective in 70% of cases. The patients who needed a change in initial ABT had a significantly higher incidence of developing severe community-acquired pneumonia and complications. The study results indicate that the structure of comorbidity did not affect the effectiveness of initial empirical ABT. Streptococcus pneumoniae was found to be the most common causative agent of community-acquired pneumonia in the studied population (44.8% of cases). Only 13% of the patients faced adverse reactions associated with the use of antibiotics as part of the initial empirical ABT; the most common were leukopenia and diarrhoea.Сonclusions: the results of the study indicate the feasibility of mono- and/or combination ABT including a cephalosporin antibiotic as a starting empirical therapy for community-acquired pneumonia due to its effectiveness and favourable safety profile.

Lower respiratory tract infections, which include community-acquired pneumonia (CAP), are the most common cause of death among all infectious diseases. The presence of a comorbid pathology in a patient with CAP suggests a possibility of mutual influence and changes in the course of both the underlying disease and comorbidities, as well as changes in the effectiveness and safety of ongoing drug therapy. The aim of the study was to analyse literature data on the structure of comorbidity in CAP patients and its impact on the efficacy and safety of therapy with β-lactam antibiotics. It has been established that CAP most often occurs in patients with chronic obstructive pulmonary disease, cardiovascular diseases (ischemic heart disease, arterial hypertension, and chronic heart failure), cerebrovascular disease, chronic kidney disease, diabetes mellitus, bronchial asthma, leukemia, anemia, dementia, neurological disorders, and cancer. The most common causative agent of CAP, regardless of the patient’s age and comorbidity, is pneumococcus (Streptococcus pneumoniae), followed by intracellular pathogens (mycoplasmas, chlamydia) and Haemophilus influenzae, as well as respiratory viruses. With this in mind, the initial empiric therapy for CAP mainly includes β-lactam antibiotics, which are effective against pneumococcus. If patients with CAP have concomitant chronic diseases and conditions, the spectrum of pneumonia pathogens may differ from that in the general population and include rare pathogens and multidrug-resistant strains. The effectiveness of antibiotic therapy in such patients is reduced, which leads to a worsening of the course of both CAP and concomitant diseases. This patient population may require longer treatment with antibiotics, including β-lactams, or the use of antibiotics at doses that provide a higher minimum inhibitory concentration, which is associated with a high risk of adverse reactions and a decrease in the safety of antibiotic therapy.

Objective: evaluation of the pharmacoeconomic feasibility of using benralizumab in the form of autoinjector (pen-injector device) in outpatient facilities compared with its use in the form of a syringe in hospital settings for the treatment of severe asthma (SA).Material and methods. The cost minimization and budget impact analysis methods were used. The current practice of treating patients with SA with benralizumab in hospital settings at the expense of compulsory medical insurance funds was compared with the simulated practice. The simulated price was calculated as half patients receiving benralizumab in the hospital transferred to outpatient facilities at the expense of regional funds for 3 years. Direct medical costs included drug cost and outpatient patient monitoring services cost.Results. The direct medical costs associated with benralizumab therapy in outpatient facilities were lower than the costs required for benralizumab therapy in the hospital settings and amounted to 0.99 million rubles versus 1.17 million rubles per one patient per year, respectively. Thus, the use of benralizumab in outpatient facilities leads to savings of 185 thousand rubles (16%). In 2021, 93 patients were prescribed benralizumab in hospital settings. The expansion of the application of benralizumab use in outpatient facilities will lead to a reduction in medical costs in the first year of therapy (when switching 16.7% of patients) by 5.9 million rubles (4,9%). The consistent expansion of the practice of benralizumab use in outpatient facilities over a 3-year horizon (when switching 50% of patients) will lead to a reduction in medical costs by 46.6 million rubles (12.1%).Conclusion. Expansion of benralizumab use in outpatient facilities with a new form of autoinjector (pen-injector device) will lead to savings in medical costs and reduce the burden on the health care system, thus it is economically feasible.

Aim. To evaluate the cost-effectiveness of achieving the target indicator "Reduction of the cardiovascular mortality of the population" of the State Program "Health Development" when using drugs valsartan+sacubitril, dapagliflozin and empagliflozin in patients with New York Heart Association (NYHA) class II-IV heart failure with reduced ejection fraction ≤40% s in 2023-2024.Material and methods. The target population was Russian patients who received preferential medicines in the last two years after an acute cardiovascular disease. The population size was determined on the basis of Russian literary and statistical sources. To predict the cardiovascular death, a parametric modeling method was used based on published data from clinical trials. The amount of drug costs required to prevent one cardiovascular death, as well as to achieve a one target for reducing cardiovascular mortality, was calculated using each of the comparator drugs in the whole country and separately in each region.Results. The cost of drugs for the 1st year of therapy to prevent one cardiovascular death in the case of valsartan+sacubitril was RUB 3,99 million, dapagliflozin — RUB 2,63 million, empagliflozin — RUB 4,43 million. There were following costs required to achieve one target indicator for reducing cardiovascular mortality of the State Program "Health Development" for valsartan+sacubitril, dapagliflozin and empagliflozin:in 2023 — RUB 2197,9 million, RUB 1451,5 million and RUB 2435,9 million, respectively;in 2024 — RUB 627,4 million, RUB 407,7 million and RUB 706,9 million, respectively.Conclusion. Among the agents considered, dapagliflozin seems to be the most cost effective for preventing one cardiovascular death and achieving one of the target "Reduction of the cardiovascular mortality" of the State Program "Health Development" in 2023-2024.

Relevance. Ademetionine is a hepatoprotective drug, is included in the draft Russian clinical guidelines for the diagnosis and treatment of non-alcoholic fatty liver disease (NAFLD) and in the clinical guidelines for treating intrahepatic cholestasis (ITH), the cost analysis of treating patients with ITH and NAFLD is topical. Aim. The cost analysis of treatment with ademetionine for ITH and NAFLD in the Russian Federation. Methods. This clinical and economic analysis was conducted in accordance with the requirements of GOST R 57525–2017 and the methodological recommendations of the Center for Expertise and Quality Control of Medical Care. At the first stage, to determine the structure and number of costs, a review of legal acts and publications on the pharmacoeconomic analysis of clinical situations and drugs of interest in the e-Library and ConsultantPlus databases was carried out. The source of prices for medical services was the tariffs of the compulsory medical insurance system and data from the tariff agreement in Moscow within the framework of the compulsory medical insurance system, and in the absence of tariffs, the prices for paid medical services. Prices for drugs were obtained from an open source — the Russian Pharmaceutical Portal (Pharmindex.rf). In the absence of data on the cost structure, a survey of physicians conducted through a questionnaire. Results. Because of the literature review, 34 publications were found in the e-Library database on the use of ademetionine in NAFLD and ITH. Additionally, outside the scope of the literature review, a study was found in 2011, which provides a comparative clinical and economic analysis of the use of ademetionine (Heptral®) and essential phospholipids (Essentiale) in alcoholic liver damage and in infectious hepatitis. A review of legal acts in the ConsultantPlus database initially identified 93 documents, of which 25 turned out to be irrelevant to the current purpose of the study, that is, they didn’t allow analyzing the costs of ademetionine therapy. Of the 20 identified standards of medical care, only 2 are devoted to diseases of the liver and biliary tract. Because of the analysis, it was revealed that the cost per case of NAFLD treatment in a round-the-clock hospital amounted to 24.6 thousand rubles; in a day hospital, the cost per case of both NAFLD and ITH in adults amounted to 19.8 thousand rubles each. The average total cost of treating one patient during the year on an outpatient basis for NAFLD amounted to 65.3 thousand rubles, of which only 14.3 thousand rubles. covered by the compulsory medical insurance system, 16.9 thousand rubles outside the compulsory medical insurance system and 34.1 thousand rubles — drug costs. The average total costs for treating one patient during the year on an outpatient basis from ITH amounted to 65.4 thousand rubles, of which 23.9 thousand rubles. covered by the compulsory medical insurance system, 17.6 thousand rubles outside the compulsory medical insurance system and 23.9 thousand rubles — drug costs. Conclusion. Because of the study, the average costs for treating patients with NAFLD and ITH were calculated, which can later be used to conduct other types of pharmacoeconomic analysis.

Microcirculation dysfunction plays a significant role in the development of post-COVID syndrome caused by SARS-CoV-2. However, there have been no studies on changes in microcirculation parameters during pharmacotherapy in patients with post-COVID syndrome. To date, there are no consensus recommendations for the treatment of post-COVID syndrome in the Russian Federation.The aim of the study was to analyse the pattern of clinical manifestations of post-COVID syndrome and bulbar conjunctival angioscopy (BCA) results in a young patient undergoing treatment after mild COVID-19.Materials and methods: analysis of the clinical case of a patient who was followed up at the Therapeutic Ophthalmology Centre between February and September 2021. BCA was performed in a patient with post-COVID syndrome to compare quantitative and qualitative microcirculation parameters before and after the treatment.Results: the paper summarises clinical observation data on a 23-year-old female patient with post-COVID syndrome with mainly neuropsychiatric manifestations and a microcirculation dysfunction as determined by BCA. The patient received pharmacotherapy with meldonium, ethylmethylhydroxypyridine succinate, and meglumine sodium succinate.Conclusions: the prescribed pharmacotherapy led to a significant improvement in the patient’s condition (regression in neuropsychiatric symptoms) with simultaneous improvement of morphological and functional parameters assessed by BCA, which indicates an improvement in microcirculation processes and supports their role in post-COVID syndrome development. The obtained data suggest that the clinical picture of post-COVID syndrome is directly related to the severity of microcirculation dysfunction in various organs and tissues, and that BCA can be used for diagnosis and assessment of the syndrome’s severity, as well as for assessment of the treatment’s efficacy and safety.

Aim. To assess the outcomes of combination therapy with rivaroxaban and acetylsalicylic acid (ASA) in patients with stable coronary artery disease (CAD) and a high risk of thrombotic events on the set targets of Ministry of Health for reduction of cardiovascular mortality in Russia.Material and methods. The development of the model for analysis in MS Excel included the following stages: calculation of the population of patients with stable CAD who can be treated with combination therapy (rivaroxaban and ASA); calculation of the number of deaths due to cardiovascular disease (CVD), number of strokes and myocardial infarction (MI) in the current scenario (patients receive monotherapy with ASA) and simulated scenario (some patients switch from monotherapy to combination therapy); estimation the impact of the number of avoided cases of deaths due to combination therapy on set target for reducing CVD mortality in 2024 year; sensitivity analysis to assess the sustainability of outcomes.Results. Total number of eligible patients for combination therapy was estimated as 1.08 million patients. Based on the simulation results, it was determined that with the reallocation of patients from monotherapy with ASA to combination therapy with rivaroxaban and ASA, the number of avoided deaths in 2022 will be 973 cases, in 2023 – 1,622 cases, in 2024 – 3,245 cases, which will make it possible to reach 6.7%, 7.4% and 11.1% of the set target for reduction of mortality from CVD in the respective years. In addition, the gradual reallocation of patients from monotherapy to combination therapy might decrease the cases of stroke and MI in 973 and 649 cases by 2022, 1,622 and 1,082 cases by 2023, and 3 245 and 2 163 cases by 2024 year, respectively. Sensitivity analysis showed that outcomes are sustainable.Conclusion. The use of combination therapy of rivaroxaban and ASA in patients with stable CAD and high thrombotic risk will allow to achieve up to 11.1% of the set target for reduction of mortality from CVD by 2024 in Russia and can also potentially impact on another set target for reduction mortality from cerebrovascular diseases by reducing the number of strokes. Thereby, this therapy can be considered for drug provision programmes for patients with stable CAD and high thrombotic risk to fulfill the goals to reduce mortality from CVD.

The aim of the study is to evaluate the clinical efficacy, safety, and impact of the complex metabolic neuroprotector on the patients’ quality of life (CMN) Cytoflavin in tablets, as well as in the course of stepwise pharmacotherapy of patients with chronic cerebral ischemia (CCI) of various etiologies, followed by meta-analysis, on the basis of a systematic review of published clinical studies.Material and methods. A selection of randomized controlled trials was carried out over the past 15 years, in which CMN Cytoflavin was used in the tablet dosage form or in a stepwise course of therapy in at least 25 patients diagnosed with chronic cerebral ischemia with a total course of therapy of at least 25 days. The assessment of CMP clinical efficacy and the analysis of formalized indicators of clinical efficacy (relative risk, odds ratio, frequency of outcomes, values of absolute and relative benefits, etc.) was carried out.Results and conclusion. 403 publications for 2000–2017 describing the use of CMN Cytoflavin were analyzed. 16 studies were selected for the systematic review, the meta-analysis included 6 randomized clinical trials and one non-randomized study of the use of CMN in patients with CCI. The data of the systematic review and meta-analysis showed a sufficient efficacy of complex metabolic neuroprotector use in patients with chronic cerebral ischemia. However, the meta-analysis revealed significant heterogeneity between the studies. The drug has a beneficial effect on the quality of life of patients, increases the likelihood of a positive outcome in relation to the relief of asthenic and vestibular-atactic syndromes, in relation to complaints of increased fatigue, headache, dizziness, noise in the head, impaired coordination. It improves cognitive functions, exhibits sufficiently high tolerance and safety.

According to the World Health Organisation, pneumonia and other lower respiratory tract infections are one of the leading causes of death all over the world. Simultaneous treatment of pneumonia with antibacterial drugs and concomitant medicines may result in adverse drug reactions (ADRs). The aim of the study was to analyse ADRs resulting from drug-drug interactions in different empiric antibiotic treatment regimens used for mild community-acquired pneumonia (CAP), taking into account the concomitant symptomatic non-antibacterial treatment and chronic disease treatment. Materials and methods: the authors analysed spontaneous reports in the VigiBase global database (starting from the date the database was created and until 15 February 2021) on ADRs resulting from interactions of medicinal products included in the Russian clinical guidelines for CAP.Results: the authors compiled a list of antibacterial drugs (amoxicillin+clavulanic acid, amoxicillin, ampicillin, azithromycin, clarithromycin, levofloxacin, moxifloxacin, cefotaxime, ceftriaxone, linezolid), as well as lists of medicinal products for symptomatic and concomitant treatment, based on the approved guidelines for management of CAP and frequent comorbid chronic diseases. They searched VigiBase for ADRs that may have resulted from drug-drug interactions involving these medicinal products. Conclusions: the analysis of adverse reactions used for mild CAP treatment demonstrated that the largest number of ADRs were associated with drug-drug interactions involving azithromycin, while the smallest number of ADRs were associated with cefotaxime and ceftriaxone. Further study of drug-drug interactions will help to prevent potential ADRs, identify rational drug combinations, and improve the existing patient management strategies.

The frequency of adverse drug reactions (ADRs) in older patients is approximately 11.0%, according to scientific literature. Antibiotics are the third largest group (19.5%) of medicinal products in terms of ADR frequency in geriatric patients. Beta-lactam antibiotics are the empiric treatment of choice for older outpatients and inpatients with community-acquired pneumonia. The mortality in this group of patients accounts for 85% of the overall mortality from community-acquired pneumonia. The aim of the study was to analyse scientific data on risk factors and characteristics of adverse drug reactions associated with the use of beta-lactam antibiotics in older patients. Specificity of ADRs to beta-lactam antibiotics in this group of patients is due to age-related changes in pharmacokinetics and pharmacodynamics as well as polymorbidity and polypharmacy. The analysis of scientific literature demonstrated that there have not been so many pharmacoepidemiological studies in this group of patients, and their results have been inconsistent. The frequency, causes, and clinical manifestations of ADRs in geriatric patients are diverse and differ considerably from those in younger patients. Of the most widely used antibiotics, ceftriaxone and cefaclor exhibited a statistically lower risk of ADRs in older patients than in younger patients. At the same time, ceftriaxone was associated with a relatively higher frequency of serious ADRs in older patients as compared to younger patients, whereas the frequency of serious ADRs was lower with cefaclor. The likelihood of nephrotoxic, neurotoxic, and hepatotoxic ADRs associated with the use of beta-lactam antibiotics is becoming more and more obvious but it is still underestimated in clinical and geriatric practice. Safety monitoring, therapeutic drug monitoring with due consideration of ADR risk factors in older patients, and inclusion of older patients in clinical trials of antimicrobial drugs, would improve efficacy and safety of antibiotic treatment.

Aim: To study cases of bacteremia caused by multidrug-resistant (MDR) and extremely-resistant (XDR) gram-negative bacteria in the departments of a multidisciplinary hospital.Material and Methods. Since 2017, a retrospective epidemiological study has been conducted to investigate cases of infections with bacteremia caused using gram-negative bacteria with multiple or extreme antibiotic resistance. The pathogens were identified using the MALDI-TOF MS method, the sensitivity to antibacterial drugs was determined using the automatic Phoenix system, the beta-lactamase genes were detected using real-time PCR on a GeneXpert analyzer.Results. In 2017, bacteremia caused by MDR and XDR pathogens was detected in 42 and 76 patients, in 2018 — in 57 and 81 patients, in 2019 — in 65 and 111 patients, respectively. During three years of observation, the most frequent XDR microorganisms were, in descending order, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa. In 2019, among 11 K.pneumoniae strains, class D carbapenemase (OXA-48) was detected in 5 cases (45.5%), 3 strains produced NDM metallo-carbapenemase, and 3 strains had a combination of NDM and OXA-48 enzymes. Infections caused by MDR and XDR pathogens were characterized by high mortality. Thus, the relative risk of death in patients with XDR infection was 1.33 times higher than in patients from the MDR group (95% CI 1.04-1.69, P

Widespread use of cephalosporin antibiotics in clinical practice calls for greater attention to the risk of adverse drug reactions. Information on serious or unexpected adverse events reported during post-marketing experience is submitted to national and international pharmacovigilance databases. Analysis of these reports helps to identify new adverse drug reactions.The aim of the study was to analyse the safety profile of cephalosporin antibiotics based on spontaneous reports in the international VigiBase database.Materials and methods: the analysis of the adverse reaction profile of cephalosporin antibiotics was based on MedDRA system organ classes and included spontaneous reports submitted to VigiBase from the moment of its creation until August 2020.Results: the authors identified the most clinically significant adverse reactions for different cephalosporin generations. They compared and analysed information on adverse events in VigiBase and in patient information leaflets of medicinal products authorised in the Russian Federation. It was demonstrated that some serious events described in VigiBase spontaneous reports for V-generation cephalosporins are not included in the “Side effects” section of the patient information leaflets. According to VigiBase, the use of ceftaroline was associated with the development of generalised exfoliative dermatitis, Stevens–Johnson syndrome, tubulointerstitial nephritis, while the use of ceftolozane was associated with acute kidney injury, renal insufficiency, sepsis, pneumonia, and respiratory insufficiency.Conclusion: reporting of unexpected and serious adverse drug reactions to cephalosporin antibiotics is an important task of healthcare practitioners. Availability of information on class-specific and generation-specific serious adverse reactions will help predict and prevent their development.

Clinical guidelines have long been one of the working tools of the modern doctor, helping him quickly navigate the most effective proven methods of treatment and prevention of various diseases, and also to adapt these methods to the specific tasks of their patients and to achieve maximum personalization of treatment. Clinical practice guidelines are drawn up by professional non-profit associations and are approved by the Scientific Council of the Ministry of Health of the Russian Federation, while often one recommendation is prepared by two or even three associations. The peculiarity of the recommendations offered to your attention is that not only endocrinologists, but also therapists, cardiologists, gynecologists, gastroenterologists, and experts of many other specialties are involved in the prevention and treatment of obesity. The Multidisciplinary Working Group presents this a project in a multidisciplinary journal to bring together the efforts of several professional associations that associated with the need to pay attention not only to obesity itself but also to comorbid conditions. We are looking forward to constructive criticism and a comprehensive discussion of the problem on the pages of our journal.

The introduction of local programs for the rational use of antibiotics in a multidisciplinary hospital is aimed at reducing the level of antibiotic resistance and the frequency of healthcare associated infections (HAI). The aim of the study was to analyze the frequency of infectious complications caused by pathogens with multidrug resistance and the level of resistance at the B.V. Petrovsky National Research Center of Surgery based on the implementation of the SCAT program. Material and methods. A retrospective analysis of the SCAT program implementation results on the basis of the B.V. Petrovsky National Research Center of Surgery was carried out. 1850 case histories of the surgical profile for 2018 were analyzed (male —1095, average age 56.2±14.9 years; female — 755, average age 53.7±11.9 years) and 1502 case histories for the January–October period for 2019 (male — 1114, average age 58.3±12.1 years, and female — 388, average age 55.4±12.6 years). Results. The incidence of HAI in 2018 and 2019 was 354 and 159 cases, respectively. Of these, the incidence of nosocomial pneumonia (NP) was 64 cases (61.5%) and 40 cases (38.5%); skin and soft tissue infection (SSTI) — 93 cases (57.4%) and 69 cases (42.6%); surgical site infections (SSI) — 69 cases (82.1%) and 15 cases (17.9%) in 2018 and 2019, respectively. The drug resistance index (DRI) for the most clinically significant strains of the causative agents of HAI was: Klebsiella pneumoniae — 0.14, Acinetobacter baumannii — 0.22, Klebsiella spp. — 0.11, Enterobacter cloacae — 0.15, Enterococcus faecalis — 0.18, Enterococcus faecium — 0.21. Conclusion. The proposed measures for the implementation of the SCAT program at the level of a medical organization reduce the incidence of HAI and the local level of the drug resistance index.

During last few years, the approaches to the management of patients with severe asthma have been revised. Monoclonal antibodies (MABs), inhibitors of interleukin-5 (reslizumab, mepolizumab, benralizumab) have been recently introduced for the treatment of severe eosinophilic asthma. The mentioned drugs were approved in Russia and included into the list of Vitally Essential Drugs. Aim.The aim of this study was to compare the clinical and economic consequences of the use of biological agents that antagonize IL-5 in the treatment of severe eosinophilic asthma in adults. Materials and methods.Two methods of clinical and economic research were used: assessment of the cost-effectiveness ratio and analysis of the budget impact. The effectiveness of the drugs was assessed using indirect comparison; special attention was paid to comparability of the patient groups in the studies chosen for such an assessment. Two approaches were used for calculation of the cost of therapy for severe asthma: using DRGs (applicable to most regions of Russia), and without the use of DRGs, which is relevant only for few Russian regions. Results.Basing on the data obtained from a budget impact study without the use of DRG, it was shown that reslizumab was dominating for patients with body mass of up to 70 kg, while for the patients with body mass of 70 to 110 kg, mepolizumab was dominating, while utilization of reslizumab appeared to be somewhat more expensive. In the group of patients with body mass over 110 kg, mepolizumab also was dominating. The calculation of the cost-effectiveness ratio (CER) showed that reslizumab appeared to be dominating over two other MABs, The results of the study using the DRG demonstrated that the cost of an annual course of benralizumab in most cases in Russia would exceed the amount that can be compensated by Territorial Funds for Mandatory Medical Insurance to a healthcare institution for therapy of bronchial asthma in one adult patient with genetically engineered drugs. Therefore, further comparisons were made for reslizumab and mepolizumab only. Analysis of the impact on the budget demonstrated that treatment with reslizumab and mepolizumab would represent a similar burden for the budget. When applying cost-effectiveness analysis, reslizumab was more cost-effective than mepolizumab (regardless of patient body mass). Conclusion.Thus, the results of the clinical and economic study suggested that, basing on the cost-effectiveness analysis, reslizumab appeared to be the dominant IL-5 antagonist (regardless of body mass if DRG approach was used and in patients with body mass up to 110 kg, if such an approach was not used). Basing on budget impact analysis, calculations without use of DRG approach showed superiority of reslizumab over mepolizumab and benralizumab for the patients with body mass up to 70 kg and the DRG-based approach showed equal burden for the budget for reslizumab and mepolizumab for the patients with any body mass.

Herbal medicines make up a large part of all medicinal products in the Russian market. Complex combinations of biologically active substances that are used as components in herbal medicines not only determine their therapeutic efficacy, but can also cause adverse reactions. The aim of this review was to analyse data on adverse effects of herbal medicines, and reasons and mechanisms behind their development. Special attention should be given to hepatotoxic and nephrotoxic effects of biologically active substances that are used as components in herbal medicines, because liver and kidney failure may lead to life-threatening conditions. The paper addresses hepatic adverse effects, including sinusoidal obstruction syndrome, caused by toxic biologically active substances of the pyrrolizidine alkaloids group. The paper summarises data on herbal medicines and toxic biologically active substances causing acute kidney injury and chronic kidney disease. It analyses potential clinically significant interactions that may occur during co-use of herbal and other types of medicines due to their pharmacokinetic and pharmacodynamic interactions. Further research involving collection, systematisation, and analysis of adverse effects of herbal medicines used alone or in combination with other medicinal products is needed to improve the safety of pharmacotherapy.

The development of globalization processes requires the provision of scientific and technological leadership of economies. In solving this goal, universities are called upon to play a special role, which can ensure the competitiveness of engineering education. Among the main indicators of academic leadership are ensuring the world level of training content, increasing academic mobility, growing demand and efficiency of master's and postgraduate studies, increase in the number of online educational programs, increase in the number of competitive courses and programs taught online, development of a targeted training system. The key condition for increasing the competitiveness of engineering education is the strengthening of its integration with science and the industrial sector. This is due to the possibility of solving a set of tasks for the development of content, organization and management of the educational process. The effectiveness of their solution is determined by the composition of partners involved in joint activities. The analysis shows that there are trends in the expansion of partnerships and the intensification of international cooperation. This facilitates the development of various formats of interaction to improve the training of engineers. Among the most developing integrated forms of training are networked educational programs. A distinctive feature of their implementation is the growth in the number of participants in network partnerships, among them are universities (as a rule more than one), industry institutes, enterprises (more than one). The network format is being implemented and remains promising in the organization of student practices. The basic departments created at enterprises are the main instrument of targeted training. With the development of the system of professional standards, the role of integration of universities with enterprises in organizing and conducting procedures for assessing the qualifications of personnel has increased. The need to solve the problem of increasing the global competitiveness of education reinforces the requirement to develop the integration of universities with academic science in the form of scientific and educational centers, with foreign universities, enterprises and high-tech businesses.

Current guidelines for the management of patients with dyslipidemia define low-density lipoprotein cholesterol (LDL-C) as the primary target in addressing lipid-lowering therapy. The target level of LDL-C in real clinical practice is achieved in no more than a third of patients who have undergone a coronary event and receive high-intensity lipid-lowering therapy. Achieving the goals of lipid-lowering therapy in a significant proportion of patients with atherosclerotic cardiovascular diseases (ACVD) is impossible with the use of even high doses of statins, which requires its enhancement by other drugs. The article considers the place of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in the prevention of cardiovascular diseases in patients with ACVD in accordance with the latest Russian and international guidelines. A modern decision-making algorithm for the initiation of PCSK9 inhibitors therapy in patients with ACVD is presented. The authors provide a clear understanding about the patient populations that will benefit most from the taking of PCSK9 inhibitors. Particular attention is paid to Guidelines for the management of dyslipidemias developed by European Society of Cardiology and European Atherosclerosis Society in 2019. The issues of patients provision with PCSK9 inhibitors with reference to Russian conditions are described in details in accordance with the requirements for territorial programs of state guarantees. Further improvement in the provision of PCSK9 inhibitors to patients with indications for this therapy is necessary, considering the potential of these drugs in reducing cardiovascular morbidity and mortality in patients with ACVD.

Modern tactics of treatment of arterial hypertension (AH) involves the use of both monotherapy and combination therapy. Monotherapy is recommended primarily for low-risk patients with systolic blood pressure (BP)< 150 mm Hg. Monotherapy should also be preferred in very high risk patients with high normal BP and frail elderly patients. However, combination therapy is recommended for most hypertensive patients as initial therapy. Starting combination therapy is more effective in lowering BP than monotherapy. Even at low doses, it is usually more effective than maximum dose monotherapy. The most commonly prescribed combinations today contain a renin-angiotensin system blocker (angiotensin converting enzyme inhibitors or angiotensin II receptor blocker) with a calcium antagonist or diuretic. The combination of lisinopril with amlodipine not only proved its high efficiency in various international and Russian studies, but also turned out to be pharmacoeconomically more profitable. Fixed combinations of lisinopril and amlodipine are the optimal choice in the treatment of hypertensive patients, due to all the advantages of both components: higher efficacy and safety rates compared to monotherapy and better patient adherence to treatment.

It Is shown that the preliminary administration of drugs that promote the flow of antibiotics into the lymphatic system increases the clinical effectiveness of treatment. Currently, there is a need for experimental justification of this approach to antibacterial therapy. In this study, the effect of drugs with hyaluronidase activity on the rate of lymphatic tissue drainage and the pharmacokinetics of cefotaxime was studied. We determined the time of the removal of lymphotropic blue dye evans of the mesentery of mice when administered on the background of hyaluronidase and bovhyaluronidaze azoximer, the concentration of cefotaxime in the dynamics during the day in blood plasma of rabbits and in the blood plasma, the intestinal tissues and the liver of mice after 1.5 and 24 h after the co-administration of antibiotic with hyaluronidase and bolgelerinde anoxemia. It is found that the hyaluronidase, and bovhyaluronidaze azoximer are equieffective stimulants of lymphatic drainage of tissues. The data obtained indicate the presence of endolymphatic properties of the conductor not only on hyaluronidase, but at bovhyaluronidaze azoximer, additional properties which allow to consider it as a priority of the drug when conducting lymphotropic therapy.

Modern therapy, aimed at eradication of H.pylori, includes a set of antisecretory and antibacterial drugs and sometimes bismuth preparations. A feature of modern eradication schemes is the 14-day use of antibiotics, prescribed in high daily doses and selected mainly based on microorganism resistance to clarithromycin and metronidazole in the respective region. However, each component of eradication scheme can have rather serious sode effects, as well as affect the bioavailability, biotransformation, excretion, and the potentiation of the effects of the drugs that the patient can take simultaneously with anti H.pylori therapy. The article lists the most serious and common variants of drug-drug interactions of the eradication schemes' components, it gives a description of the mechanism of their development, when applicable. Before the approval official of practical recommendations for the prevention of drug-drug interactions of drugs included in the eradication schemes, commonly available databases containing information about such interactions should be used.

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 growing level of resistance of microorganisms requires a critical reduction in cases of unreasonable use of antibiotics and a reduction in the overall duration of antibiotic therapy. Controlled clinical trials conducted in recent years have confirmed the high effectiveness of the use of the procalcitonin test (B-R-A-H-M-S PCT™) in reducing the occurrence of unjustified prescribing of antibiotic therapy and reducing its duration.In this regard, procalcitonin test promotes the personalization of approaches to antibiotic therapy. It is possible to significantly reduce the frequency of empirical antibiotic therapy in low-risk situations (bronchitis, exacerbation of COPD) by determining the level of procalcitonin (B-R-A-H-M-S PCT™). Monitoring the concentration of procalcitonin allows shortening of the duration of antibiotic therapy in more severe clinical situations (pneumonia, sepsis).

Urinary tract infection (UTI) is a frequent infectious disease or complication of hospital stay. The effectiveness and the recovery speed of the patient depends on the correct choice of antibacterial drug for the treatment of UTI. The choice of antibacterial therapy in the treatment of UTIs should be dictated by the predicted uropathogen flora. Since it is necessary to start treatment before obtaining the results of urine culture, UTI therapy uses empirical treatment with broad-spectrum antibiotics. However, this leads to a very rapid increase in the resistance of microorganisms to antibiotics. To reduce this effect, as well as to impove the effectiveness of treatment, it is necessary to put forward a hypothesis about the proposed microorganism which caused the UTI as precisely as possible and to try to prescribe the most suitable antibiotic. The clinical situation in which the UTI occurred may determine a probable pathogen, which will be the basis for the choice of antibiotic therapy. The article offers various therapeutic strategies for treatment of UTI, depending on the proposed bacterial flora, the clinical situation, and the characteristics of the patient.

Despite the evidence of the effectiveness of modern medicines, which are included in modern schemes of eradication therapy, against Helicobacter pylori, the problem of growth of microorganism resistance to them is relevant not only for various regions of the Russian Federation; it also has an international and even intercontinental spread. The article presents modern information on Helicobacter pylori pathogenicity, the prevalence and development mechanisms of its resistance to antibiotics widely used for eradication, the contradictions in the information on indications, duration of use, anti-Helicobacter pylori treatment regimens and dosage in modern clinical guidelines and instructions for medical use.

The article deals with the problem of the reader and reading among the urban population, which is little studied in Russian history. Based on the analysis of the materials of the state archive of the Irkutsk region, the author characterizes the readership and the reader’s interests of certain social and professional groups of the Irkutsk population in the late XIX–early XX centuries. A distinctive feature of the Irkutsk readership is shown: the social composition of active readers of the city is revealed, the circle of the most popular domestic and foreign authors is designated, the most popular all-Russian, regional and local periodicals are marked. The obtained data can help to characterize the mechanism of influence of reading on the formation of socio-political views, moral education and artistic tastes of Irkutsk residents

Objectives. Obesity is a chronic relapsing disease that requires long-term and lifelong treatment. The development of diseases associated with obesity may cause the additional need for prescribing drug therapy. The main aim was to analyze the structure of preferential drug prescriptions for patients with obesity for the period 2015-2018 in Moscow. Methods. A pharmacoepidemiological retrospective analysis of the structure of drug prescriptions for the period 2015-2018 in Moscow according to the chosen nosology — obesity (code ICD-10 — E66) was performed. The total number of patients receiving medications, the total number of prescribed prescriptions and packages were analyzed. The results are processed using the MS Excel 2013 package and are presented in the form of absolute values, shares (%). Results. For the period from 2015-2018 there is a 3.5-fold increase in the number of obese patients receiving preferential drugs — from 259 people up to 899 people. Over the entire analyzed period, there is a gradual increase in the proportion of drugs for the treatment of diabetes (from 43.1 to 51.6 %), mainly due to metformin, and for the treatment of the gastrointestinal tract (from 6.7 to 18.7 %). The total costs of drug therapy for obese patients over the analyzed period increased by 3.6 times. The largest share of the costs was attributed to drugs for the treatment of diabetes mellitus (from 38.1 to 62.5 %). Conclusions. Analysis can help to improve the system of rational distribution of financial resources for the drug provision of obese patients through the development of clinical and economic approaches that allow choosing the most effective and less costly approaches to providing medical care to patients.

Aim. To evaluate the effect of the use of the double antiplatelet therapy (DAT) with ticagrelor compared to DAT with clopidogrel and antithrombotic therapy with acetyl salicylic acid (ASA) in patients with acute coronary syndrome and patients with high coronary risk on the target indicator (CP) of the state program (GP) “Development of Healthcare” and the federal project “Fight against cardiovascular diseases” — reducing mortality from diseases of the circulatory system (BSC).Material and methods. All adult Russian patients with a diagnosis of ACS eligible for DAT were considered as the target population; in the second and third years, only patients with high coronary risk continued treatment. The calculation of the number of deaths that can be prevented using DAT ticagrelor 90 mg + ASA vs DAT of clopidogrel + ASA within 1st year from the date of diagnosis was based on the clinical efficacy data of the PLATO study. The number of deaths that can be prevented with the use of DAT ticagrelor 60 mg + ASA — instead of ASA monotherapy patients with a history of myocardial infarction was made based in the clinical efficacy results of the PEGASUS study. It was calculated what proportion of the target indicators could be achieved in 2022-24 years by using DAT with ticagrelor instead of clopidogrel or ASA monotherapy.Results. The use of DAT with ticagrelor vs DAT with clopidogrel or ASA for the treatment of patients with ACS will prevent additional 5389, 5704 and 6012 deaths in 2022-2024, that will ensure the implementation of the CP “reduction of mortality from BSC” GP “Development of healthcare” in the Russian Federation by 36,9%, 26,0% and 20,6% respectively.Conclusion. The use of DAT with ticagrelor for the treatment of patients with acute coronary syndrome ensure the implementation of the CP “reduction of mortality from BSC” GP “Development of healthcare” in the Russian Federation in 2024 by 20,6%.

Aim. To assess the effect of therapy with sodium glucose co-transporter type 2 inhibitor dapagliflozin in patients with heart failure with reduced ejection fraction (CHrEF) on the state cardiovascular mortality target indicators.Material and methods. All adult Russian patients with NYHA class II-IV HFrEF (left ventricular ejection fraction ≤40%) were considered as the target population. The characteristics of patients in the study corresponded to those in the Russian Hospital HF Registry (RUS-HFR). The study suggests that the use of dapagliflozin in addition to standard therapy will be expanded by 10% of the patient population annually in 2022-24. Cardiovascular mortality modeling was performed based on the extrapolation of DAPA-HF study result. The number of deaths that can be prevented was calculated when using dapagliflozin in addition to standard therapy. Further, the contribution of prevented deaths with dapagliflozin therapy to the achievement of federal and regional cardiovascular mortality target indicators (1, 2 and 3 years) was calculated.Results. The use of dapagliflozin in addition to standard therapy for patients with NYHA class II-IV CHrEF with the expansion of dapagliflozin therapy by 10% of the patient population annually will additionally prevent 1729 cardiovascular death in the first year. This will ensure the implementation of cardiovascular mortality target indicators in Russia in 2022 by 11,8%. In the second year, 3769 cardiovascular deaths will be prevented, which will ensure the implementation of target indicators in 2023 by 17,2%. In the third year, 5465 cardiovascular deaths prevented, which will ensure the implementation of implementation of target indicators in 2024 by 18,7%.Conclusion. The use of dapagliflozin in addition to standard therapy for patients with NYHA class II-IV CHrEF will ensure the implementation of implementation of target indicators in 2024 by 18,7%.

Since 2010, Russia has been developing new drug legislation, internal quality control and safety of medical organizations, and has developed algorithms for submitting Individual Case Safety Reports (ICSR) using an automated information system. On April 1, 2019, Russia launched an updated national database of ICSR, which uses the international ICH E2B data standard, which may increase the amount of reporting to the Uppsala monitoring center. This publication covers the key aspects of pharmacovigilance system development in the Russian Federation. The analysis of pharmacovigilance structure in the Russian Federation is carried out, its main problems are designated. Presents methods to identify causal relationships between adverse reaction and drug, evaluation of its degree of validity (questionnaires, algorithms, and scale), as already recommended by the WHO, and the new modifi ed versions. The expediency of using a scale for determining the degree of reliability of a causal relationship «an undesirable reaction — drug interaction» when analyzing spontaneous reports of undesirable reactions that may be caused by drug interactions is noted. An effective method of detection and prevention of adverse reactions is presented — the Global Trigger Tool (GTT). The question of the need for motivation and training of medical personnel in the correct design of spontaneous messages, as well as methods of identifying the causal relationship between adverse reactions of drugs. The directions of optimization of pharmacovigilance system are proposed, including methods of more effective active surveillance in the identifi cation and prevention of adverse reactions.