The development of new drugs to combat neuroinflammation is highly relevant as it opens up possibilities for the treatment of a wide range of diseases, including Alzheimer’s disease, Parkinson’s disease, epilepsy, schizophrenia, depression, and others. Kappa-opioid agonists represent a promising class of compounds with а high potential to be used in the treatment of neurological conditions accompanied by neuroinflammation.

The aim of the study was to provide a summary of the current strategies employed to evaluate the neurotropic anti-inflammatory effects of kappa-opioid ligands in laboratory animals with induced neuroinflammation.

Materials and methods. The databases, such as Google Scholar, PubMed, ScienceDirect, Scopus, e-Library were used as search tools. The search comprised the following keywords and phrases in Russian and English: kappa opioids + neuroinflammation; kappa opioid receptors + neuroinflammation; neuroinflammation models; neuroinflammation models in rats, neuroinflammation models in mice. 148 relevant articles were found, 122 were included in this review.

Results. Various experimental models of neuroinflammation, including chemically-induced and bacterial endotoxin-induced neuroinflammation, as well as traumatic and genetic models in mice and rats were evaluated. In addition, the strengths and limitations of each model were critically assessed to identify the most appropriate and reliable approach for investigating the relationship between neuroinflammation and signaling pathways associated with kappa-opioid receptors.

Conclusion. The neurotropic anti-inflammatory activity of kappa-opioid ligands have been comprehensively described. The review discusses both experimental models where the effects of kappa-opioid agonists have been investigated, as well as the models where the anti-inflammatory properties of kappa-opioid agonists have not been studied yet.

Modern requirements for the treatment of type 2 diabetes mellitus (DM2) include not only achieving a glycemic control, but also reducing the risk of developing cardiovascular complications. Dipeptidyl peptidase 4 (DPP-4) inhibitors are inferior in the effectiveness to some other actively developing groups of hypoglycemic drugs (SGLT2 inhibitors and GLP-1 receptor agonists); however, they seem relevant at the present time.

The aim of the study is to analyze the literature data on the therapeutic potential and results of the of DPP-4 inhibitors research.

Materials and methods. When searching for the review article materials, the abstracting databases of PubMed, Google Scholar and e-Library were used. The search was carried out on the publications for the period from 2006 to 2022, using the following keywords: DPP-4 inhibitors; glucagonlike peptide-1 (GLP-1); glucose-dependent insulinotropic peptide (GIP); sitagliptin, and other drugs.

Results. DPP-4 belongs to the serine proteases family and is involved in the degradation of various chemokines and peptide hormones, including incretins secreted by intestinal L- and K-cells – GLP-1 and GIP. They regulate a postprandial insulin secretion and a β-cell function, modulate a fasting and postprandial glucagon secretion, regulate the eating behavior and have many pleiotropic (immunomodulatory, anti-inflammatory, antifibrotic, etc.) effects. DPP-4 inhibitors reduce an enzyme activity by 70–90%, increasing plasma incretin levels by 2–4 times and have been used to treat DM2 since 2006. Now there are 13 DPP-4 inhibitors on the market in different countries, differing primarily in pharmacokinetic parameters. They are actively used in the combination therapy for type 2 diabetes, increasing the glycemic control effectiveness without increasing the risk of hypoglycemia. The evidence is emerging about the therapeutic potential of DPP-4 inhibitors in COVID-19.

Conclusion. A peroral form, an ability to create effective combinations with other hypoglycemic drugs without increasing the risk of hypoglycemia, the pleiotropic effects of DPP-4 inhibitors, make this group relevant at the present time.

From the point of view of the mechanisms for the implementation of pathogenetic links in the development of steroid-induced osteoporosis considered in the paper, the increased risk of the oxidative stress in osteoblasts, as well as the development of the vessels endothelial dysfunction of the microcirculatory bloodstream in the bone tissue, are of particular interest. They lead to the impaired bone tissue trophism and progression of osteoporosis.

The aim of the study was research of the osteoprotective effects of a 3-hydroxypyridine derivatives composition on the model of steroid-induced osteoporosis.

Materials and methods. To model osteoporosis pathology, the animals (male Wistar rats) were injected with methylprednisolone (MP) at the dose of 5 mg/kg (intraperitoneally) every 5^th day for 5 weeks. Аs a non-selective blocker of NO synthase, L-NAME was used at the dose of 25 mg/kg (intraperitoneally). Derivatives of 3-hydroxypyridine (hereinafter referred to as composition No. 1) were administrated at the dose of 50 mg/kg (per os) In all experimental groups, the level of microcirculation and the bone mineral density, as well as the analysis of histomorphological and biochemical samples, were assessed.

Results. The study results showed that composition No. 1 (50 mg/kg) has an osteoprotective activity, effectively prevents a decrease in the level of the regional bone tissue microcirculation and in the development of an endothelial dysfunction. That makes it possible to increase the bone mineral density and to slow down the thinning of bone trabeculae. In addition, composition No. 1 (50 mg/kg) reduces the production of reactive oxygen species and increases the NO bioavailability.

Conclusion. The data obtained indicate that the studied composition of 3-hydroxypyridine derivatives is considered a promising compound for the prevention and treatment of steroid-induced osteoporosis.

Nirmatrelvir is an antiviral drug that, in combination with ritonavir, is an effective agent for the etiotropic therapy of patients with mild to moderate COVID-19.

The aim of the study was to evaluate bioequivalence of the generic drug nirmatrelvir Аrpaxel in combination with ritonavir and the original drug Paxlovid, which is a combination of nirmatrelvir/ritonavir, in a single dose administration to healthy volunteers.

Materials and methods. This research was an open-label, randomized, two-period crossover bioequivalence study. It included 2 periods, in each of which the volunteers received either a test drug (nirmatrelvir at the dose of 300 mg) in combination with ritonavir (100 mg), or a reference drug (a combination of nirmatrelvir 300 mg and ritonavir 100 mg), given as a single dose. A wash-out period between each of the administrations was 7 days. The blood sampling to determine the concentration of nirmatrelvir was carried out in the range from 0 to 36 h in each of the study periods. A nirmatrelvir concentration was determined by a validated HPLC-MS/MS method with a lower quantitation limit of 10 ng/mL. Bioequivalence was assessed by comparing 90% confidence intervals (CIs) for the ratio of geometric means of AUC_(0–16) and C_max of the test drug and reference drugs with the established equivalence limits of 80.00–125.00%.

Results. In the study were included 68 healthy volunteers, 67 participants of which were included in the bioequivalence population. The pharmacokinetic parameters of the drugs were comparable to each other. The 90% confidence interval for the ratio of the geometric mean of the maximum drug concentration in the blood plasma and the area under the pharmacokinetic curve «concentration-time» from zero to the last blood draw within 36 hours of nirmatrelvir was 87.26–100.83 and 93.27–103.74%, which meets the criteria for assessing bioequivalence. The test drugs were well tolerated by the volunteers. The incidence of adverse events was similar for the test and reference drugs. No serious adverse events were recorded during the entire study.

Conclusion. As a result of this study, bioequivalence of the test and reference drugs has been established.

The aim of the study was to evaluate the efficacy and safety of an RNA double-stranded sodium salt drug, a lyophilisate for a solution preparation for an intramuscular and subcutaneous administration, as a means of post-exposure COVID-19 prophylaxis in comparison with placebo.

Material and methods. A double-blind, placebo-controlled, multicenter, randomized phase III clinical trial was conducted to evaluate the efficacy and safety of a double-stranded sodium salt RNA drug (RADAMIN^®VIRO), a lyophilisate for preparing a solution for intramuscular and subcutaneous administration as a means of post-exposure prophylaxis of COVID-19. The study was conducted in 10 research centers in the Russian Federation from May 31, 2022 to January 17, 2023. The study included men and women aged ≥18 years who cohabitate with a person with a documented COVID-19 diagnosis and do not have symptoms characteristic of COVID-19. At the randomization stage, the subjects were assigned to one of two groups: group 1 (n=400) received a study drug RADAMIN^®VIRO 5 mg (1 vial) intramuscularly once a day; group 2 (n=400) received placebo 1 vial intramuscularly once a day. The total duration of the study for each subject was no more than 30 days.

Results. By day 10-11, in the double-stranded sodium salt RNA preparation group, the proportion of the subjects with confirmed COVID-19 and at least 1 symptom characteristic of COVID-19 was 5.76% (23/399), and in the placebo group – 11. 03% (44/399). The difference in proportions between the study drug and placebo groups was 0.0526 (5.26%), the 95% confidence interval (CI) for the difference in proportions between the groups was -95% CI [0.0123;0.0937]). More than 94% of single-dose subjects did not become infected with COVID-19 with any symptoms during the 11 days of the follow-up. As a result of a comparative analysis, it was shown that the infection frequency in the study drug group was statistically significantly (almost twice) less than in the comparison group, which indicates a high efficiency and expediency of using the double-stranded sodium salt RNA preparation as a means of the post-exposure COVID-19 prophylaxis.

Conclusion. Thus, regardless of the vaccination availability, the effectiveness and feasibility of using the study double-stranded sodium salt RNA preparation as a means of the post-exposure COVID-19 prophylaxis was demonstrated not only in medical institutions (outpatient clinics and hospitals), but also in caregivers and/or the persons in contact with COVID-19 patients. The situation was the same in the organizations and enterprises in case of evolution of a mass infection threat and the availability of appropriate medical personnels.

Quinazolin-4(3Н)-one derivatives are characterized by a wide range of pharmacological properties, among which the most significant one is a pronounced effect on the central nervous system. In this regard, a molecular design of biologically active compounds that have an analgesic activity due to the formation of ligand-receptor complexes with nociceptive and dopamine receptors, has been performed.

The aim of the study was a molecular design and a subsequent targeted synthesis of 2-phenyl- and 2-benzyl derivatives of 4(3H)-quinazolinone with an analgesic activity, as well as the creation of a mathematical model in order to identify significant molecular descriptors.

Materials and methods. A molecular design was carried out by a logical-structural approach using the PASS program with the identification of the biological activity of the predicted structures, as well as the energy calculation of the ligand-receptor interaction. The synthesis of 2-phenyl derivatives of 4(3H)-quinazolinone was carried out by the reaction of 2-aminobenzamide with aromatic aldehydes in polyphosphoric acid when heated, while the 2-benzyl derivatives were synthesized by fusing amides of anthranilic and homoveratric acids followed by sulfonation with sulfuric acid. The analgesic activity of the synthesized compounds was studied in the models of nociceptive reactions induced by chemical stimuli (a formalin test and “acetic acid writhings”).

Results. A molecular design made it possible to identify promising structures in the series of 4(3H)-quinazolinone derivatives that affect nociceptive and dopamine receptors and have an analgesic activity. A modification was made to the synthesis of 2-phenyl- and 2-benzyl derivatives of 4(3H)-quinazolinone in order to increase the yield of the target products by a simpler and more cost-effective method. The predicted compounds were synthesized by cyclocondensation of anthranilic acid amide with aromatic aldehydes or with homoveraic acid amide. It follows from the primary pharmacological studies results that the synthesized substances are promising from the point of view of creating painkillers based on them. A structure-activity relationship between the molecular descriptors, which are largely responsible for the analgesic activity, and the results of biological tests, has been revealed.

Conclusion. The use of computer modelling made it possible to identify the amino acid residues involved in the formation of the ligand-receptor complex with the nociceptive receptor, and to construct a mathematical model to explain the analgesic activity of 2-phenyl- and 2-benzyl derivatives of 4(3H)-quinazolinone. Modified procedures for the synthesis of target compounds have been proposed. The obtained coefficients of the approximation between the theoretical values and the data of the pharmacological experiment make it possible to state a sufficient reliability of the carried out studies.