Aim. A comparative study of the pharmacokinetics and safety of the investigational drug Duonica®, enteric-soluble, film-coated tablets, 10 mg + 10 mg (Valenta Pharm JSC, Russia) and the reference drug Diclectin®, delayed-release tablets, 10 mg + 10 mg (Duchesnay Inc, Canada) was conducted as part of the bioequivalence study in healthy volunteers under fed conditions.Material and methods. An open-label randomized crossover two-period bioequivalence study was conducted with 28 Caucasian female volunteers. The study participants were randomly divided into two groups of 14 people depending on the order of drug administration during Periods 1 and 2. Participants randomized to the first group received 2 tablets of Diclectin® during Period 1 and 2 tablets of Duonica® during Period 2. Volunteers from the second group took the study drugs in the reverse order. During each study Period, the drugs were administered after a high-calorie breakfast. The analytes studied were doxylamine and pyridoxal-5-phosphate (an active metabolite of pyridoxine). Methods were developed and validated using high-performance liquid chromatography with a triple quadrupole tandem mass spectrometric detector (HPLC-MS/MS) to quantify the analytes. Pharmacokinetic parameters were calculated from the obtained concentration values and statistical analysis was performed. To confirm bioequivalence, 90 % confidence intervals (CI) for the pharmacokinetic parameters AUC and Cmax of the studied analytes were calculated. The safety of the investigational drugs was assessed based on the frequency, severity and type of adverse events.Results. The 90 % CI values for the ratio of Cmax and AUC(0-t) values for doxylamine were 94.08–113.71 % and 90.63–102.50 %, and for pyridoxal-5-phosphate were 97.34–123.47 % and 90.30–111.03 %, respectively. The obtained CI values were within the limits set by the regulatory requirements and the study protocol (80.00–125.00 %), which allowed us to confirm the bioequivalence of the studied drugs for both components. No adverse events were reported during the study.Conclusion. The study investigated the pharmacokinetics of drugs containing a fixed combination of doxylamine and pyridoxine under fed conditions. The results obtained confirmed the bioequivalence of the drug Duonica® to the reference drug Diclectin®. Both drugs were well tolerated and no differences in the safety profile of the investigational drugs were observed.

The term "bone marrow edema" (BME) in MRI examination of the knee joint is used to describe areas of decreased signal intensity on T1-weighted images or increased signal intensity on T2-weighted images in the subchondral bone. BME is classified into ischemic (osteonecrosis), mechanical (trauma), and reactive (arthritis) types. In this review, the causes and differences in BME with spontaneous and secondary osteonecrosis and other characteristics of BME transitioning to a syndrome are considered. BME with injuries and bruises is usually reversible and passes after approximately 2–4 months, if accompanied by a cortical fracture, after 6–12 months. A fatigue fracture develops as a result of repeated overloading of normal bone structures, whereas fractures in zones of subchondral bone insufficiency spontaneously occur in pathologically changed bone tissues (for example, osteoporotic bones) without any trauma or overloading. Histological examination of the damaged subchondral bone in ischemic and mechanical BME revealed hemorrhages, microdestruction of bone trabeculae and vascular anomalies, and almost complete absence of direct edema in MRI-positive zones due to increased extracellular fluid content, which can be partially explained by methodological difficulties in detecting increased extracellular fluid by histopathological methods. Prostacyclin and bisphosphonate have been proposed as conservative therapies for ischemic and mechanical BME.In osteoarthritis (OA) of the knee joints, BME is considered a marker of rapid progression. Data on the influence of obesity, therapeutic exercise and diet, and the use of a cane on BME are presented. Analysis of the effectiveness of conservative therapy revealed a weakly positive response to bisphosphonates. Inhibitors of nerve growth factor (NGF) — monoclonal antibodies to nerve growth factor (like tanezumab and fulranumab) — reduced the severity of pain but led to an increase in the frequency of osteonecrosis and endoprosthesis. Two studies have shown a decrease in the intensity of BME with oral chondroitin sulfate. The attention of orthopedists is focused on subchondroplasty using calcium phosphates. Subchondral filling, which strengthens the bone and replaces the lost barrier function of cartilage, has a symptomatic effect and effectively counteracts the development of BME, although the long-term results need to be studied.

Introduction. Ultra-fast-acting insulin aspart has great potential for improving postprandial glycemia in patients with type 1 and type 2 diabetes mellitus due to its pharmacological characteristics. The development and production of biosimilars are increasing the availability of modern insulins for patients.Aim. To evaluate the comparability of the pharmacokinetics and pharmacodynamics profiles of insulin aspart GP40311 (tested biosimilar of domestic production) and the reference drug (produced in Denmark) under conditions of a hyperinsulinemic euglycemic clamp in healthy volunteers. To evaluate the stability of a new ultrafast-acting biosimilar when used for continuous subcutaneous infusion in insulin pumps.Materials and methods. Double-blind, randomized, crossover study assessing the pharmacokinetics, pharmacodynamics and safety of the tested biosimilar GP40311 of domestic production and the reference drug produced in Denmark, in the form of a solution for intravenous and subcutaneous administration of 100 IU/ml, the study was conducted under conditions of a hyperinsulinemic euglycemic clamp with the participation of 36 healthy volunteers. A study of the stability, dosing accuracy and tendency to catheter occlusion of a domestic drug for continuous subcutaneous infusion was carried out using several types of insulin pumps using the gravimetric method for 72 hours. Dosing accuracy was determined at the minimum and maximum bolus dose, stability was assessed by pH and quantitative insulin content aspart. The quantitative content of insulin and impurities was assessed by high-performance liquid chromatography.Results and discission. The 90% confidence interval for the ratio of geometric mean values of the main parameters of pharmacokinetics (AUCins.0-t and Cins.max) of insulin aspart test and reference drugs corresponded to the acceptable values of 80.00– 125.00%, which indicated their biosimilarity. When assessing PD, the comparability of action parameters is shown. The safety of the study drugs is comparable. Domestic insulin aspart met the specification standards when used for continuous subcutaneous infusion according to physicochemical parameters: pH, quantitative determination of insulin aspart, impurity content. The accuracy of dosing and the absence of occlusions in systems for 72 hours when using the drug in pumps have been established.Conclusion. The study drugs were found to be biosimilar and equally safe. Domestic insulin aspart meets specification standards and can be used in various types of pumps.

Osteoarthritis (OA) of the knee joints (KJ) has a high social significance and is therefore a relevant pathology for scientific research. The authors have proposed an original hydraulic theory for the pathogenesis of OA in KJ. This approach is based on the notion of primary mechanical damage to the internal ligamentous structures and synovial membrane accompanied by posttraumatic edema, synovial hypervolemia, and hypertension. The authors demonstrated that regular physical activity at all stages of the disease is pathogenetically justified and allows the patient to improve lymphatic and venous outflow and thus resist increasing fibrosis. Improved arterial blood flow will reduce tissue hypoxia. Any type of symptom-modifying therapy can be harmful because it reduces the protective role of pain reflexes in protecting the KJ from excessive loads, leading to injury. The necessity of maintaining a walking speed of more than 4.3 km/h with an increase in cadence is emphasized from the perspective of reducing static stress during walking and extending life expectancy.

Introduction. Over the years, insulin therapy has remained an important component of the complex treatment of patients with diabetes mellitus. Ultra-rapid insulin lispro is a DNA recombinant analogue of human insulin, which has a pharmacokinetic (PK) profile that is as close as possible to the endogenous insulin secretion profile, which ensures effective control of postprandial glycaemia. The development of the ultra-rapid insulin lispro biosimilar will expand the range and increase the availability of modern and safe insulin analogues for diabetic patients in Russia.Aim. To compare the PK and pharmacodynamic (PD) profiles of GP40261 (ultra-rapid insulin lispro biosimilar) and the reference Lyumjev® in healthy volunteers.Materials and methods. This was a double-blind, randomised, comparative, crossover study in healthy volunteers who were administered either the test or reference ultra-rapid insulin lispro formulation as a single dose of 0.3 IU/kg. The hyperinsulinaemic euglycaemic clamp technique was used to evaluate the pharmacokinetics and pharmacodynamics of the study products. In order to assess the biosimilarity of the products, 90% confidence intervals (CIs) were calculated for geometric mean ratios of the primary PK parameters AUCins.0-t and Cins.max. The PD parameters of the study drugs were evaluated based on the glucose infusion rate required to maintain the target glycaemic level during the clamp.Results. The 90% CIs for the geometric mean ratios of the primary PK parameters for the test and reference products were 89.41-94.55% for AUCins.0-t and 82.74-92.92% for Cins.max, which complies with the established acceptance limits of 80-125% for both parameters. The study products were also found to have comparable PD profiles of their active substances.Conclusion. This clinical study has demonstrated that GP40261 and the reference ultra-rapid insulin lispro are biosimilar and have a comparable safety profile.

Introduction. Obesity is a growing public health issue in Russia, increasing the risk of cardiovascular diseases, type 2 diabetes, and hypertension. Controlling obesity involves lifestyle changes and pharmacotherapy. Semaglutide, an effective obesity treatment, stimulates insulin production and reduces appetite. Developing a generic semaglutide preparation will improve its availability in Russia.Aim. To study the comparative pharmacokinetics, bioequivalence, safety and tolerability of semaglutide products GP40331 and Wegovy using concentrations of 0.68 and 3.2 mg/ml in healthy volunteers under fasting conditions.Materials and methods. Bioequivalence studies, conducted per Good Clinical Practice, were open-label, randomized, and involved healthy male volunteers. Subjects received semaglutide at single doses of 0.25 mg (0.68 mg/ml) and 0.5 mg (3.2 mg/ml) under fasting. Bioequivalence was determined by the 90% CI of the ratios of geometric mean values of the primary pharmacokinetic parameters (AUC0-t, Cmax). Semaglutide concentrations were measured using high-performance liquid chromatography with tandem mass spectrometry.Results. The 90% CI values for the ratios of geometric means of the primary PK parameters of semaglutide were 90.22–110.29 and 86.48–108.98% (0.68 mg/ml) and 90.62–115.71 and 92.86–113.51% (3.2 mg/ml). Comparable safety was proven for both concentrations.Conclusion. GP40331 and Wegovy at 0.68 and 3.2 mg/mL are bioequivalent and equally safe.

The lack of effective and affordable therapies for rare diseases is an important ethical issue. One example is cystic fibrosis (CF), a chronic, progressive disease characterized by an impaired function of all exocrine glands. The combination of ivacaftor and lumacaftor (CFTR potentiator and corrector) should lead to a sufficient level of protein on the cell surface and to an increase in its activity, thereby correcting the impaired function. Development of a generic drug containing ivacaftor and lumacaftor as active pharmaceutical substances will increase the availability of this medication and improve patient survival. To study comparative pharmacokinetics and bioequivalence of drugs containing ivacaftor and lumacaftor in healthy volunteers. It was conducted as an open-label, randomized, crossover bioequivalence study involving a single intake of the drug during each period under fed condition in healthy male and female volunteers. The conclusion about bioequivalence was made if 90% confidence interval for primary pharmacokinetic parameters (Cmax, AUC0-t) fell within the accepted bioequivalence limits of 80–125%. According to the results of the study, it was shown that the values of 90% CI of the geometric mean of the main pharmacokinetic parameters for ivacaftor and lumacaftor fall within the acceptance limits for bioequivalence. According to the applied criteria, the drugs are bioequivalent, which makes it possible to recommend the investigational drug to the Ministry of Health of the Russian Federation for obtaining the registration status.

Semaglutide is a representative of analogues of the incretin hormone human glucagon-like peptide-1 (GLP-1) and is currently used in Russia for the treatment of type 2 diabetes mellitus (T2DM; in monotherapy and in combination therapy), including patients with obesity and overweight. The aim of the work was to conduct a comparative assessment of the physicochemical properties, a biological activity, bioequivalence and safety, including tolerability and immunogenicity, of the drug Quincent® (semaglutide, 1.34 mg/ml, a solution for a subcutaneous administration, Promomed Rus LLC, Russia) and the drug Ozempic® (semaglutide, 1.34 mg/ml, a solution for a subcutaneous administration, Novo Nordisk A/S, Denmark) when administered to healthy volunteers. Materials and methods. To assess the degree of similarity of the study drug Quincenta® (semaglutide, 1.34 mg/ml, a solution for a subcutaneous administration, Promomed Rus LLC, Russia) with a chemically synthesized active substance to the original (reference) drug Ozempic® (semaglutide, 1.34 mg/ml, a solution for a subcutaneous administration, Novo Nordisk A/S, Denmark), a comparative study of physicochemical properties and a biological activity was carried out. To assess the bioequivalence of the study drug and the reference drug, an open randomized parallel comparative study with the participation of healthy volunteers ( n =54), 54 participants of which had been included in the population, was conducted. The volunteers were randomized into 2 groups in a 1:1 ratio, and received a single dose subcutaneously either of the study drug (domestic semaglutide at a dose of 0.5 mg) or the reference drug (foreign semaglutide at a dose of 0.5 mg). The mode of administration was in the morning on an empty stomach. A semaglutide concentration was determined in serum samples using a previously validated enzyme-linked immunosorbent assay (ELISA) method. A quantitative determination of antibodies to semaglutide in the human serum by ELISA was carried out with a microplate photometer using ready-made kits pre-validated by the manufacturer. The conclusion about the bioequivalence of the compared drugs was made using an approach based on the assessment of 90% confidence intervals for the ratios of the geometric mean values of the parameters C max , AUC (0–t) of semaglutide in the measurement original units. Results. The results of the comparative analysis of the study drug and the reference drug demonstrate the comparability of their physicochemical properties and biological activity. The results of the clinical study demonstrated the bioequivalence of the test drug and the reference drug. Thus, the pharmacokinetic parameters of the drugs were comparable to each other: the C max value for the study drug was 42.088±8.827 ng/ml, for the reference drug Ozempic® it was 42.2556±7.84. Herewith, the half-life for the study drug and the reference drug was 168.39±39.47 and 157.99±28.57 hours, respectively. The resulting 90% confidence intervals for the ratio of the C max and AUC 0–t values of the study drug and the reference drug were 90.89–109.15 and 91.66–111.27%, respectively. The tolerability of the drugs in the volunteers was notified as good. No adverse events were recorded during the study. No serious adverse events were reported throughout the study. According to the results of the immunogenicity analysis, no antibodies to Russian-made semaglutide were detected in the blood serum of the volunteers, which indicated the lack of Results. The results of a comparative analysis of the study drug and the reference drug demonstrate the comparability of physicochemical properties and biological activity. The results of the clinical study demonstrated the bioequivalence of the study drug and the reference drug. Thus, the pharmacokinetic parameters of the drugs were comparable to each other: the C max value for the study drug was 42.088±8.827 ng/ml, for the reference drug Ozempic® this figure was 42.2556±7.84. At the same time, the half-life for the study drug and the reference drug was 168.39±39.47 and 157.99±28.57 hours, respectively. The resulting 90% confidence intervals for the ratio of the C max and AUC 0–t values of the study drug and the reference drug were 90.89–109.15 and 91.66–111.27%, respectively. Tolerability of the drugs in volunteers was noted as good. No adverse events were recorded during the study. No serious adverse events were reported throughout the study. According to the results of the immunogenicity analysis, no antibodies to Russian-made semaglutide were detected in the blood serum of the volunteers, which indicated the lack of the drug immunogenicity. Conclusion. In the course of the study, the comparability of the physicochemical properties and biological activity of the studied Russian drug with the chemically synthesized active substance Quincenta® to the reference drug Ozempic® was confirmed: the activity range of the studied drugs was within 80–120% in relation to the standard sample of semaglutide. The bioequivalence and a similar safety profile, including the immunogenicity and tolerability of the Russian drug Quincenta® (semaglutide 1.34 mg/ml, Promomed Rus LLC, Russia) were shown in comparison with the foreign drug Ozempic® (semaglutide 1.34 mg/ml, Novo Nordisk A/C, Denmark).

Introduction. Diabetes mellitus is a chronic disease that can impact all aspects of metabolism. Incretin mimetics, such as semaglutide, are a promising group of drugs to treat type 2 diabetes mellitus both through the improvement of glycemic control and additional effects on the cardiovascular system and body weight. The development of a generic semaglutide-containing drug is a burning issue which settlement will increase the availability of semaglutide in the Russian FederationAim. To study the comparative pharmacokinetics, bioequivalence, safety and tolerability of a semaglutide containing GP40221 and Ozempic® in healthy volunteers.Materials and methods. This open-label, randomized, single-dose, parallel group study assessed the bioequivalence of a single dose of 0.5 mg of the study drugs in healthy male subjects under fasting conditions. The conclusion about the bioequivalence of the brand name drug versus the generic drug was made using the classical approach based on the assessment of 90% confidence intervals of the ratios of geometric means of the primary pharmacokinetic parameters (AUC0-t, Сmax) for the active substance of the study drugs.Results. The results of the study showed that the 90% CI values of the ratios of geometric means of the primary PK parameters of semaglutide were 85.96–109.01% and 89.14–111.40% for AUC0-t и Cmax, respectively, and are well within acceptable limits 80.00–125.00%. The comparable safety of the study drugs containing semaglutide has been proven.Conclusion. Thus, GP40221 (GEROPHARM LLC, Russia) and Ozempic® (Novo Nordisk A/S, Denmark) can be considered bioequivalent and equally safe based on the results of this clinical study. The results of this study allow us to recommend a drug developer to submit specific data on their study drug GP40221 to the Ministry of Health of the Russian Federation to obtain marketing authorization.

Introduction. Citicoline is an endogenous nucleoside consisting of cytidine and choline linked by a diphosphate bridge that is involved in the synthesis of membrane phospholipids. Drugs containing citicoline have neuroprotective and neurometabolic effects and are used for the treatment of a wide range of neurological disorders. In its turn, bioequivalence study is a pathway to register a generic citicoline drug in Russian Federation. Aim. The aim of the study was to investigate the comparative pharmacokinetics (PK) and bioequivalence of two citicoline-containing drugs GP30121 and Ceraxon® in healthy male volunteers when taken on an empty stomach. Materials and methods. We evaluated the pharmacokinetics of citicoline-containing drugs corrected for endogenous analyte (uridine) level using an adaptive design. We determined uridine concentration by high-performance liquid chromatography with mass spectrometric detection. We used R Project software, version 3.6.3. for performing statistical analysis for the study. Results and discussion. GP30121 and Ceraxon® exhibited similar PK profiles. It was shown that the values of 94.12 % confidence interval (CI) at α = 0.0294 for the geometric mean ratios for the primary PK parameters of the main metabolite of the active ingredient of the investigated drugs were fully contained within the predefined equivalence limits of 80.00–125.00 %. Conclusion. The study demonstrates bioequivalence of GP30121 and Ceraxon® proving the approach with the correction for endogenous analyte could be considered in studies of other drugs.

Liraglutide is one of the analogues of the incretin hormone human glucagon-like peptide-1 (GLP-1) and is currently a priority treatment for diseases such as type 2 diabetes mellitus (mono- and combination therapy), obesity and overweight in the presence of at least one concomitant disease. The aim of the work was to assess the bioequivalence and comparability of the safety and tolerability profile of the drug Enligria® (liraglutide 6 mg/ml, Promomed RUS LLC, Russia) and the drug Saxenda® (liraglutide 6 mg/ml, Novo Nordisk AS, Denmark) after a single dose in healthy volunteers. Materials and methods. This study was an open-label, randomized, crossover comparative study to evaluate pharmacokinetic parameters, safety, tolerability and immunogenicity. The study comprised 26 healthy volunteers, 26 of whom were included in the bioequivalence assessment population. The study consisted of 2 periods, in each of which the volunteers received either the test drug (liraglutide at a single dose of 0.6 mg) or the reference drug (liraglutide at a single dose of 0.6 mg) once. The washout period between each dose was 7 days. Blood plasma samples were taken to determine the concentration of liraglutide in the range from 0 to 72 hours in each study period. Liraglutide concentrations were determined using a previously validated enzyme-linked immunosorbent assay (ELISA) method. A quantitative determination of antibodies to liraglutide in the blood serum samples was carried out using a microplate photometer and ready-made ELISA kits pre-validated by the manufacturer. The conclusion about the equivalence of the compared drugs was made based on the ratio of the parameters C max , AUC 0→t and AUC 0→t of the studied drug in relation to the reference one. Results. The pharmacokinetic parameters of the drugs were comparable to each other. The resulting 90% confidence intervals for the ratio of the values of C max , AUC 0-t and AUC 0-∞ of the Russian test and reference drug were 87.18–110.46, 84.40–104.11 and 86.69–103.22% respectively, which satisfied the criteria for assessing bioequivalence. The tolerability of the drugs in the volunteers was notified as good. The incidence of adverse events was comparable for the test and reference drugs. No serious adverse events were reported throughout the study. According to the results of the immunogenicity analysis, no antibodies to russian produced liraglutide were detected in the blood serum of the volunteers, which indicated the lack of the drug immunogenicity. Conclusion. During the study, the pharmacokinetic equivalence of the test and reference drugs was confirmed. The Russian drug Enligria® (liraglutide 6 mg/ml, Promomed RUS LLC, Russia) in comparison with a foreign drug Saxenda® (liraglutide 6 mg/ml, Novo Nordisk AS, Denmark).

Direkord is an original drug containing the active substance of dicholine succinate, which enhances neuronal insulin sensitivity. In this work, we study the tolerability, safety, and pharmacokinetic parameters of dicholine succinate when administered intramuscularly in a phase I clinical trial in healthy volunteers. In total, 18 healthy volunteers –11 men and 7 women – with a mean age of 30.4±7.8 years, were recruited into a randomized study. At stage I, 6 volunteers (group 1) received dicholine succinate intramuscularly every other day with a dose escalation from 0.16 mg/kg/day to 600 mg/day. At stage II, 12 volunteers (group 2) received dicholine succinate intramuscularly at a single dose of 200 mg, and then, at stage III, the same 12 volunteers received dicholinesuccinate at a dose of 600 mg/day (3 x 200 mg at an interval of 8 hours) for seven days. The safety population in this study included all randomized volunteers. Data from 12 volunteers (group 2) were included in the calculation of the pharmacokinetic parameters. All volunteers completed all procedures of the three research stages in accordance with the protocol. According to clinical and laboratory monitoring data, no adverse events were registered during the study. The drug was well tolerated, with no signs of hyperemia, edema, and bruising being observed at the injection site. The volunteers did not complain of pain, itching, and burning. After a single injection of dicholine succinate, the concentration of choline in the bloodstream reached its maximum value after an average of 0.375±0.365 hours with the half-life of 1.271±1.071 hours. After repeated administration at a dose of 600 mg per day, no cumulation of the active substance was observed. The data obtained have confirmed a good safety profile of Direkord; therefore, the drug can be recommended for further investigation in a study involving patients.

The article presents the data from an open, two-stage, multicenter study on the efficacy and safety evaluation of a combined drug (a fixed combination of nirmatrelvir 300 mg and ritonavir 100 mg) in the complex therapy in COVID-19 patients.The aim of the study was to assess the safety, tolerability and pharmacokinetic parameters of the fixed combination of nirmatrelvir 300 mg and ritonavir 100 mg in healthy volunteers, the efficacy and safety assessment of the drug in the combination therapy compared with the standard therapy in COVID-19 patients.Material and methods. An open two-stage multicenter clinical study to assess the main pharmacokinetic parameters, safety, and efficacy against COVID-19 of the drug nirmatrelvir 300 mg and ritonavir 100 mg combination (Skyvira® PROMOMED RUS LLC, Russia) in the adult population, included 2 stages. At stage 1, safety, tolerability and pharmacokinetic parameters were evaluated in healthy volunteers (over 18 years of age) in order to confirm their comparability with the literature data known for a set of active substances. Phase 2 assessed efficacy and safety in COVID-19 patients. As a part of the second stage, the study involved 264 patients (men and women aged 18 to 80 years), who had been divided into two groups. The first group patients (n=132) received the study drugs (nirmatrelvir 300 mg and ritonavir 100 mg) – 1 tablet twice a day with an interval of 12±2 hours for 5 days in combination with pathogenetic and symptomatic therapy. The second group patients (n=132) received standard therapy in accordance with the approved Temporary Guidelines for the Prevention and Treatment of Novel Coronavirus Infection (Version 15 dated February 22, 2022).Results. During the study, none of the patients from the (nirmatrelvir + ritonavir) group experienced a transition of the COVID-19 course to a heavier severity level, in contrast to the patients in the standard therapy group. The study participants included patients with comorbidities (68% of the general population), with risk factors for COVID-19 progression to a heavier severity level and the risk of hospitalization (75% of the general population). There were no cases of COVID-19 progression to a heavier severity level in the study drug group. By the 6th day, in the nirmatrelvir + ritonavir group, the proportion of the patients who had achieved a complete recovery was twice more and amounted to 35.61% (p=0.0001), and the proportion of the patients with a negative RNA analysis to SARS-CoV-2 was 20% higher than in the comparison group, and amounted to 82.58% (p=0.0001). The fixed nirmatrelvir + ritonavir combination therapy has a favorable safety profile comparable to the standard therapy. The identified adverse reactions were transient in nature and did not require discontinuation of therapy or changes in the treatment regimen.Conclusion. The fixed nirmatrelvir + ritonavir combination has a favorable safety profile in COVID-19 patients, comparable to the standard therapy. The data obtained demonstrate a clinical and pharmacoeconomic feasibility of including the fixed (nirmatrelvir + ritonavir) combination in the COVID-19 treatment regimen.

The use of magnetic resonance imaging (MRI) for osteoarthritis made it possible to simultaneously detail the state of cartilage, subchondral bone, menisci, ligaments, and synovial membrane. In some studies, a correlation was found between bone marrow edema (BME) and the intensity of the pain syndrome, the progression of OA and the risk of total knee replacement. In other studies, these data were not confirmed. It has been suggested that BME in OA, leading to debilitating pain, is not associated with trauma and is determined by an increase in extracellular fluid. Analysis of MRI images of 80 patients with 1-3 stages of knee osteoarthritis revealed a statistically significant relationship between the presence of bone marrow edema and the thickness of the cartilage of the femur and tibia, rupture and degradation of the medial menisci, the presence of Baker cysts and thickening of the synovial membrane. No reliable relationship was found with the presence and severity of synovitis. A review of data on the effect of various methods of conservative therapy on bone marrow edema in osteoarthritis is presented. The effect of anti-osteoporotic drugs, prostacyclin, Pentosan polysulfate sodium chondroitin sulfate is considered. Thus, OKM is of interest both in terms of the pathogenesis of OA and as an indicator of the effectiveness of the treatment of OA. Our data demonstrate a high incidence of OKM in the late stages of OA. The effect of pharmacological therapies on OKM requires further study.

The use of magnetic resonance imaging (MRI) for osteoarthritis made it possible to simultaneously detail the state of cartilage, subchondral bone, menisci, ligaments, and synovial membrane. In some studies, a correlation was found between bone marrow edema (BME) and the intensity of the pain syndrome, the progression of OA and the risk of total knee replacement. In other studies, these data were not confirmed. It has been suggested that BME in OA, leading to debilitating pain, is not associated with trauma and is determined by an increase in extracellular fluid. Analysis of MRI images of 80 patients with 1-3 stages of knee osteoarthritis revealed a statistically significant relationship between the presence of bone marrow edema and the thickness of the cartilage of the femur and tibia, rupture and degradation of the medial menisci, the presence of Baker cysts and thickening of the synovial membrane. No reliable relationship was found with the presence and severity of synovitis. A review of data on the effect of various methods of conservative therapy on bone marrow edema in osteoarthritis is presented. The effect of anti-osteoporotic drugs, prostacyclin, Pentosan polysulfate sodium chondroitin sulfate is considered. Thus, OKM is of interest both in terms of the pathogenesis of OA and as an indicator of the effectiveness of the treatment of OA. Our data demonstrate a high incidence of OKM in the late stages of OA. The effect of pharmacological therapies on OKM requires further study.

Osteoarthritis is a frequent, age-associated disease affecting >10% of world's population over 60 years of age. This study intended to compare intra-articular whole blood clot secretome (autologous conditioned serum [ACS], recently re-named blood clot secretome [BCS]) to platelet-rich plasma (PRP) in knee osteoarthritis (OA). A clinical, nonrandomized open-label comparison of ACS versus PRP in knee OA with subclinical or moderate synovitis symptomology was performed. One hundred and twenty-three patients with knee OA, Kellgren and Lawrence grade II-III, were each treated with six i.a. injections of ACS or PRP. The clinical efficacy was measured by visual analog scale and Western Ontario and McMaster Universities Arthritis Index (WOMAC) score. The biochemical effects measured include synovial fluid (SF) viscosity, cytokines interleukin (IL)-1Ra and IL-1b, radical footprint NO3, and conjugated dienes (CDs). At the 3-month follow-up, clinical efficacy of ACS was significant in all groups, versus PRP. PRP had significant versus baseline efficacy in subclinical, but not in moderate, synovitis cases. ACS was more effective than PRP regarding all analytical parameters. It induced endogenous IL-1Ra expression, downregulated IL-1b, and improved SF viscosity. ACS reduced-significantly stronger than PRP-the concentration of CDs-interpreted as reactive oxygen species footprints-and NO3-interpreted as nitric oxide footprint-in SF. ACS displayed significant efficacy in all groups, which was clinically and biochemically superior to PRP. ACS appears to improve i.a. homeostasis. Strength of this open clinical study is the combination of clinical and biochemical data.

The number of women and the elderly has now increased among marathon runners. This cohort has a high risk of osteoarthritis development. The hypothesis, based on little scientific evidence, is that the additional stress on knee joints that occurs during long running can potentially lead to damage to joint structures and osteoarthritis development. The review presents modern generalized data on magnetic resonance imaging (MRI) of knee joints in long-distance runners. Special attention is paid to the syndrome of fluid increase in subchondral bone, which is determined by increasing the signal intensity in T2-weighted images (decrease in T1-weighted images), called bone marrow oedema (BMO). Classification and pathogenetic variants of BMO development (theory of intrusion and contusion) are presented. Particular cases of BMO development in marathon runners are considered. The dynamics of BMO in different time intervals after the races in beginners and professional marathon runners is described. Changes in MRI images of knee cartilage after running on the treadmill in healthy women and in women suffering from osteoarthritis are shown. A comparison of the frequency of osteoarthritis of knee joints in runners compared to footballers and weightlifters was made. The conclusion was made on the preventive effect of long walking and running (at least 12.5 km/week), including marathon distances, on the development and progression of osteoarthritis of knee joints.

The number of women and the elderly has now increased among marathon runners. This cohort has a high risk of osteoarthritis development. The hypothesis, based on little scientific evidence, is that the additional stress on knee joints that occurs during long running can potentially lead to damage to joint structures and osteoarthritis development. The review presents modern generalized data on magnetic resonance imaging (MRI) of knee joints in long-distance runners. Special attention is paid to the syndrome of fluid increase in subchondral bone, which is determined by increasing the signal intensity in T2-weighted images (decrease in T1-weighted images), called bone marrow oedema (BMO). Classification and pathogenetic variants of BMO development (theory of intrusion and contusion) are presented. Particular cases of BMO development in marathon runners are considered. The dynamics of BMO in different time intervals after the races in beginners and professional marathon runners is described. Changes in MRI images of knee cartilage after running on the treadmill in healthy women and in women suffering from osteoarthritis are shown. A comparison of the frequency of osteoarthritis of knee joints in runners compared to footballers and weightlifters was made. The conclusion was made on the preventive effect of long walking and running (at least 12.5 km/week), including marathon distances, on the development and progression of osteoarthritis of knee joints.