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Pharmacy & Pharmacology

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Vol 13, No 2 (2025)
View or download the full issue PDF (Russian)
https://doi.org/10.19163/2307-9266-2025-13-2

RESEARCH ARTICLE

70-83 30
Abstract

The aim. To investigate the metabolic profile of zebrafish embryos when exposed to drugs with known risks of cardiotoxicity, such as acetaminophen, carbamazepine, salbutamol, ketorolac, bisoprolol, and metoprolol. The analysis is aimed at detecting changes in the level of amino acids (including branched chain BCAAs), products of carnitine metabolism (acylcarnitines) and related metabolic indices reflecting mitochondrial dysfunction, oxidative stress and disorders of the nitric oxide signaling pathway.

Materials and methods. Zebrafish embryos were incubated with the test substances in a concentration gradient (0.5–10×NOEC). A quantitative targeted metabolomics analysis was performed using high-performance liquid chromatography with tandem mass spectrometry (HPLC–MS/MS) with a panel of 98 metabolites (amino acids, nitric oxide metabolism products, vitamins, nucleosides and acylcarnitines). The obtained concentrations of metabolites were compared with the control (0.1% DMSO). Statistically significant deviations were expressed as the ratio of concentration to control on a base 2 logarithmic scale (log2FC).

Results. Changes in concentrations of metabolites under the influence of cardiotoxic drugs were revealed. There was an accumulation of BCAAs (the sum of leucine, isoleucine, valine; log2FC≈0.5–2.2; p <0.05) compared with the control, as well as an increase in the level of acylcarnitines, indicating mitochondrial dysfunction: for example, metoprolol and bisoprolol caused an increase in the ratio of the sum of acylcarnitines to free carnitine by more than 4–6 times (log2FC=+3.8 for bisoprolol and -1.27 for metoprolol; p <0.01), as well as accumulation of long-chain acylcarnitines. Pronounced changes in indicators related to oxidative stress were noted: in the samples after exposure to beta-1 blockers (bisoprolol, metoprolol) and ketorolac, the concentration of methionine sulfoxide (by 80–130%, p < 0.01), the product of methionine oxidation, and the ratio of methionine sulfoxide/methionine increased, whereas when exposed to salbutamol, on the contrary, the level of methionine sulfoxide decreased (-120%, p <0.01), indicating a multidirectional effect on the oxidative status. Violations of the nitric oxide signaling pathway were reflected in an increase in the level of asymmetric dimethylarginine.

Conclusion. Each of the analyzed compounds produced a specific metabolic “imprint” in Zebrafish samples, reflecting the mechanisms of their cardiotoxicity. An increase in BCAA levels and related indicators indicates a violation of myocardial energy metabolism, the accumulation of long-chain acylcarnitines indicates incomplete beta-oxidation of fatty acids. An increase in the concentration of ADMA is associated with endothelial dysfunction, and an increase in methionine sulfoxide is associated with increased oxidative stress.

84-97 29
Abstract

A significant part of patients with diabetes purchase sugar-lowering drugs (SLDs) on their own in retail pharmacy chains, and the market trends they generate represent an urgent area for this study.

The aim. To study the turnover of hypoglycemic drugs, including insulins, in the commercial sector of the pharmaceutical market of the Russian Federation (RF) for 2020–2024.

Materials and methods. The data presented in this article is based on a periodic retail audit conducted by the biotech company IQVIA. The period of 5 years (2020–2024) was covered. Data collection covered 33,613 commercial pharmacies in all regions of the RF (about 43% of pharmacies).

Results. In the period from 2020 to 2023, a relatively stable increase in the volume of SLDs purchases was revealed, with small fluctuations, while in 2024 a significant leap in consumption was recorded, both in quantitative (packages) and in value (rubles) terms. During the entire monitoring period, the total volume of SLDs and insulin purchases in the retail market segment increased by more than 1.2 times, from 41.98 million packages in 2020 to 51.70 million in 2024. At the same time, the total procurement budget (at wholesale prices) increased by more than 2 times — from 19.40 to 41.57 billion rubles. The average price per package has also increased significantly, from 462 rubles in 2020 to 923 rubles in 2024, an increase of 1.7 times, reflecting significant inflation in the commercial pharmaceutical sector. In general, the Russian pharmaceutical market offers all variants of modern innovative hypoglycemic drugs (dipeptidyl peptidase-4 inhibitors [iDPP4], sodium-glucose cotransporter 2 inhibitors [iSGLT2], glucagon-like peptide-1 receptor agonists [arGPP-1]), which, according to general trends, demonstrate a steady increase in turnover. Older and less effective sulfonylureas and their combinations with metformin still occupy a significant market share. arGPP-1 group showed the greatest growth in quantity (11 times) and value (5 times), mainly due to the entry of Russian semaglutide analogues into the market. Government measures and investments in import substitution have led to a significant increase in the share of Russian drugs in purchases. Despite the positive dynamics of Russian production, import substitution in the SLDs segment has not achieved complete success and accounts for less than half of the turnover of hypoglycemic drugs.

Conclusion. The growth of SLDs consumption in the retail segment of the RF in 2020–2024 has been revealed, especially due to the innovative drugs arGPP-1 and iNGLT2. Despite maintaining the leading position of metformin, the consumption structure is shifting towards more expensive schemes. The increase in the total procurement budget and the average package price highlights the need to expand preferential security programs. Import substitution has increased significantly over the indicated period, however, the share of domestic drugs is still less than half of the turnover.

98-110 31
Abstract

Kappa opioid receptors play a pivotal role in regulating both physiological and cognitive processes. RU-1205, a benzimidazole derivative acting as a specific kappa opioid receptor agonist, has demonstrated the capacity to modulate neuronal activity. However, the nuanced effects of RU-1205 on neuronal activity remain incompletely understood.

The aim of the study was to identify and elucidate the effects of the kappa opioid agonist RU-1205 on local field potentials and behavior in the discriminative stimulus paradigm.

Materials and methods. The experiments were conducted in male rats weighing 260–280 g. The animals were surgically implanted with cortical electrodes (F — frontal, O — occipital, P — parietal) as well as deep electrodes in specific brain regions, including the medial prefrontal cortex (mPFC), hippocampus (Hipp), nucleus accumbens (NAc), ventral tegmental area (VTA) and amygdala (Amy). LFP signals were obtained and analyzed after the administration of the compound RU-1205 (350 μg/5 μl intracerebroventricular injections) using spectral and coherence analysis methods. Drug discrimination paradigm was employed to evaluate the similarity of the compound RU-1205 to the selective kappa opioid receptor agonist U-50488 and the p38 MAPK inhibitor SB203580 (including in combination with the opioid receptor blocker naloxone).

Results. Electrophysiological changes observed include an increase in power of theta frequencies (4–8 Hz) in F, P and mPFC leads, along with a reduced power of delta frequencies (0.5–4 Hz) in O and Hipp leads, and a suppression of gamma activity (30–50 Hz) in F and mPFC leads, all with statistical significance (p <0.05). Post-administration of RU-1205 resulted in a decreased coherence between pairs of electrodes: P–O, P–F, F–O, and mPFC–Hipp (all p <0.05). It was found that the compound RU-1205 is similar to U-50488 and does not exhibit p38 inhibitory activity in the discriminative stimulus paradigm.

Conclusion. Compared to the selective kappa-opioid agonist U-50488, the compound RU-1205 induces less significant changes in LFP activity without electrophysiological and behavioral signs of beta-arrestin pathway activation. The overall data suggest that RU-1205 is a functionally selective agonist of kappa-opioid receptors.

REVIEW

111-127 23
Abstract

The aim. The review presents the analysis of publications on modern approaches to oncolytic viral immunotherapy of malignant diseases which is predominantly based on usage of enteroviruses.

Materials and methods. Electronic data bases — PubMed, Scopus, Web of Science, Google Scholar, eLibrary, and other accessible datasets were used for gathering and analyzing appropriate publications for the following keywords: oncolytic virotherapy, oncolytic viruses, enteroviruses, poliovirus, coxsackievirus, echovirus, preclinical and clinical trials. The research included the time interval from 1990 till 2024.

Results. The data present the properties of wild type and gen modified viruses — the supposed basis for development of the drugs, as well as their action mechanisms. The described mechanisms include direct cytolysis caused by the intracellular reproduction of the virus, activation of antitumor immunity of the host body (viral recipient) due to presentation of the tumor-associated antigens from the damaged cells to dendritic cells for their further maturation, presentation of these antigens to T-lymphocytes and activation of cytotoxic lymphocytes, modulation of tumor microenvironment due to immunostimulation,  and transition of “cold” tumor and its environment into “hot” state. It has been noticed that the most pronounced therapeutic efficacy is observed in immunosensitive tumors. This observation correlates with the action mechanism of the oncolytic viruses.  Clinical trials of viral drugs still have not led to superior results in therapeutic efficacy but they have demonstrated the synergistic efficacy with other methods of conservative therapy. According to the results of preclinical and clinical trials, enteroviruses demonstrate a favorable toxic profile. Factors which reduce the efficacy of virotherapy were evaluated. They include non-targeted and non-specific absorption of viruses by tumor cells, weak endocytosis and reproduction followed by distribution in the body, preexisting immunity against the concrete viruses and induction of antiviral antibody expression during viral therapy, and lack of sensitivity of the tumor and its microenvironment to the virus.

Conclusion. Enterovirus-based oncolytic therapy is a promising therapeutic option but its efficacy needs to be enhanced using mechanisms of its therapeutic impact.

128-138 35
Abstract

To date, pharmaceutical activities in the manufacture of medicines in a pharmacy, intra-pharmacy packaging of registered medicines in Russia and the countries of the Eurasian Economic Union (EAEU), is one of the priorities of regulatory authorities in order to improve drug supply.

The aim. To study the current state of legal regulation of the circulation of medicines “in bulk” and the possibility of their packaging in a pharmacy.

Materials and methods. To solve the tasks set, the methodology of system analysis in the field of drug provision, content analysis of documents regulating the sphere of circulation of drugs was used. The regulatory framework of the study was the legislative and by-laws regulating the sphere of circulation of medicines of the Russian Federation and the common market of the EAEU. The search for regulatory legal acts was carried out in the Directory of the legal system “ConsultantPlus”. In the course of the research, a set of scientific methods was used such a systematic, logical, structural and comparative.

Results. The article consider the issues of legal regulation of the circulation of medicines “in bulk” in the pharmaceutical market. The current state of the legislative and regulatory framework has been studied and the problems of legal regulation of packaging of medicicnes “in bulk” in pharmacies have been identified. The article also focuses on the general problem of compliance with modern packaging requirements for medicines compounded in pharmacy. The possibility of introducing a new concept of “Pharmacy packaging” into Federal Law No. 61-FZ dated April 12, 2010 “On the circulation of medicines” is considered. The approaches developed in world practice to the regulation of issues related to the packaging of drugs “in bulk” in pharmacy are considered. Based on the results of the study, the possibilities have been identified and ways to improve the mechanisms of state regulation have been proposed.

Conclusion. Packaging of medicines “in bulk” will increase the effectiveness of individual drug therapy, optimize and reduce the cost of circulation of budget funds, pharmacies and citizens.



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ISSN 2307-9266 (Print)
ISSN 2413-2241 (Online)