Pharmacology & Pharmacy最新文献

{"title":"Physiology, pharmacology and prospects for dipeptidilpeptidase-4 inhibitors use","authors":"D. Kurkin, D. A. Bakulin, E. Morkovin, A. Strygin, Y. Gorbunova, E. Volotova, I. E. Makarenko, V. Saparova, R. Drai, V. Petrov","doi":"10.19163/2307-9266-2023-11-1-19-47","DOIUrl":"https://doi.org/10.19163/2307-9266-2023-11-1-19-47","url":null,"abstract":"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.","PeriodicalId":20031,"journal":{"name":"Pharmacology & Pharmacy","volume":"200 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85482639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioequivalence study of generic nirmatrelvir in healthy volunteers","authors":"R. Oseshnyuk, A. Nikiforova, A. Boroduleva, P. Sobolev, S. A. Lesnichuk, B. B. Garyaev, A. A. Abramova, V. G. Mozgovaya, O. Filon, A. Zinkovskaya, A. Dolgorukova, E. K. Khanonina, V. G. Ignatiev, M. Samsonov","doi":"10.19163/2307-9266-2023-11-1-62-71","DOIUrl":"https://doi.org/10.19163/2307-9266-2023-11-1-62-71","url":null,"abstract":"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 Cmax 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.","PeriodicalId":20031,"journal":{"name":"Pharmacology & Pharmacy","volume":"55 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80976689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DF-5 COMPOUND DELAYS DEVELOPMENT OF DIABETIC NEPHROPATHY IN RATS","authors":"A. Spasov, O. Zhukovskaya, A. I. Rashchenko, A. A. Brigadirova, R. Litvinov, N. A. Gurova, A. Smirnov, N. G. Pan’shin, H. S. Abbas, A. S. Morkovnik","doi":"10.19163/2307-9266-2022-10-6-549-561","DOIUrl":"https://doi.org/10.19163/2307-9266-2022-10-6-549-561","url":null,"abstract":"Advanced glycation end-products play an important role in the development of diabetic complications, so slowing down of glycated proteins’ cross-links formation have been suggested as a potential therapeutic option for the treatment of vascular diabetic complications and preventing their progression.The aim of the work was to assess the influence of novel anticrosslinking agent DF-5 on the renal advanced glycation end-products and collagen contents, body weight, blood glucose and glycated hemoglobin levels and the development of early renal disease in streptozotocin-induced diabetic rats.Materials and methods. 40 male Sprague-Dawley rats were used in the study. Two months after inducing diabetes, the study substance was administered intragastrically once a day for 28 days (12.5 mg/kg). Measurements included the assessment of blood glucose and HbA1c levels, the evaluation of the renal function, and the results of histology and immunohistochemical staining of kidneys.Results. A repeated intragastric administration of DF-5 for 30 days significantly reduced the level of HbA1c in the blood, but did not affect the level of fasting blood glucose. DF-5 compound significantly reduced proteinuria and prevented kidney damage in experimental animals by limiting damage of the glomeruli and tubules. It was found that DF-5 inhibits the progression of an early renal dysfunction in rats with streptozotocin-induced diabetic nephropathy. This was associated with a decreased accumulation of advanced glycation end-products in the kidney, accompanied by the improvement of both renal morphology and function.Conclusion. The results obtained provide investigators with additional therapeutic options for the treatment of diabetic nephropathy and possibly other complications of diabetes.","PeriodicalId":20031,"journal":{"name":"Pharmacology & Pharmacy","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75249688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EFFICACY AND SAFETY OF ORIGINAL DRUG BASED ON HEXAPEPTIDE SUCCINATE IN COMPLEX COVID-19 THERAPY IN ADULTS HOSPITALIZED PATIENTS","authors":"L. Balykova, O. Radaeva, K. Zaslavskaya, P. A. Bely, V. Pavelkina, N. Pyataev, A. Ivanova, G. Rodoman, N. Kostina, V. B. Filimonov, E. Simakina, D. Bystritsky, A. S. Agafyina, K. N. Koryanova, D. Pushkar","doi":"10.19163/2307-9266-2022-10-6-573-588","DOIUrl":"https://doi.org/10.19163/2307-9266-2022-10-6-573-588","url":null,"abstract":"Currently, there are data that that make it possible to speak about a high clinical efficacy of the use of succinic salt of tyrosyl-D-alanyl-glycyl-phenylalanyl-leucyl-arginine (hexapeptide succinate) for the COVID-19 treatment. This article is devoted to the results of clinical trials of the original Russian drug based on it.The aim of the study was to evaluate a clinical efficacy, safety and tolerability of intramuscular and inhalation use of hexapeptide succinate in complex therapy in comparison with standard therapy in patients with moderate COVID-19.Materials and methods. The research was conducted from February 28, 2022 to November 22, 2022 based on 10 research centers in the Russian Federation. The study included hospitalized patients (n=312) over 18 years of age with moderate COVID-19 who had undergone a screening procedure and were randomized into 3 groups: group 1 received standard therapy in accordance with the Interim Guidelines in force at the time of the study, within 10 days; group 2 received hexapeptide succinate (Ambervin® Pulmo) intramuscularly at the dose of 1 mg once a day for 10 days; group 3 received hexapeptide succinate (Ambervin® Pulmo) 10 mg once a day by inhalation for 10 days.Results. According to the results of the study, therapy with the drug hexapeptide succinate, both intramuscular and inhaled, provided an acceleration of recovery up to the complete absence of the disease signs in more than 80% of hospitalized COVID-19 patients. By the end of the therapy course with the drug, more than 60% of patients had met the criteria for discharge from hospital and could continue the treatment on an outpatient basis. About 70% of patients in the inhalation group and 80% in the intramuscular hexapeptide succinate injection group had concomitant diseases (hypertension – 28%, obesity – 14%), which indicates the effectiveness of this drug use in comorbid patients. The use of the drug contributed to the restoration of damaged lung tissues, normalization of oxygenation, the disappearance of shortness of breath and a decrease in the duration of the disease symptoms compared with standard therapy. As a result of a comparative analysis of adverse events in terms of their presence, severity, causal relationship with the therapy and outcome, there were no statistically significant differences between the treatment groups.Conclusion. Thus, the results of the clinical study of the succinate hexapeptide efficacy and safety showed the feasibility of using the drug in pathogenetic therapy COVID-19 regimens.","PeriodicalId":20031,"journal":{"name":"Pharmacology & Pharmacy","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78167286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EXPERIMENTAL PARTICIPATION OF PHARMACOLOGICAL SUBSTANCES IN MECHANISMS OF LEAD ACETATE TOXICITY","authors":"S. Dzugkoev, F. Dzugkoeva, O. I. Margieva, A. E. Khubulova, I. V. Mozhaeva","doi":"10.19163/2307-9266-2022-10-6-589-600","DOIUrl":"https://doi.org/10.19163/2307-9266-2022-10-6-589-600","url":null,"abstract":"The aim of the work is to study pharmacological substances that play a role of eNOS expression regulators in the modification of lead intoxication effects in the experiment.Materials and methods. In the experiment, linear male rats of the same age were used: intact and with lead intoxication (120 heads). The study design was the following: group 1 – control; group 2 – intoxication with a lead acetate solution; group 3 – intact + L-nitroarginine methyl ester; group 4 – lead acetate + L-nitroarginine methyl ester; group 5 – intact + L-arginine; group 6 – lead acetate + L-arginine. The research carried out the study state of the redox reactions, the content of nitric oxide (NOx) stable metabolites, a lipid profile, the level of NO-synthase (eNOS) expression in the vascular endothelium, the main processes of urination and the activity of Na+/K+-ATPase in the renal tissue layers, as well as in the liver. The results were subjected to statistical processing.Results. Saturnism caused the oxidative stress development, a decrease in the NOx content in blood plasma, a violation of the L-arginine for eNOS bioavailability, and an endothelial dysfunction. Indicators of the impaired renal function were a decrease in the glomerular filtration rate (GFR), the tubular reabsorption of water, sodium, and the Na+/K+-ATPase activity. The damage to hepatocytes was evidenced by changes in the activity of organ-specific enzymes in the blood and Na+/K+-ATPase. L-arginine exhibited antioxidant properties, increased the NOx content and the level of eNOS expression. The eNOS L-nitroarginine methyl ester inhibitor showed the effects opposite to L-arginine.Conclusion. Biochemical markers of damage to kidney and liver cells during saturnism are indicators of the oxidative stress, NOx deficiency and hemodynamic disturbances in them. These mechanisms involved the following pharmacological substances: an eNOS inhibitor, L-nitroarginine methyl ester, which caused a decrease in the expression level of the enzyme, and an eNOS inducer, L-arginine, which increased this indicator severity. The lead toxicity mechanisms have been implicated in the impaired cholesterol metabolism, contributing to the L-arginine reduced availability for eNOS and the NOx production. Therefore, the use of L-arginine can be recommended as a regulator of the oxidative stress and an NO-producing endothelial function in other pathologies.","PeriodicalId":20031,"journal":{"name":"Pharmacology & Pharmacy","volume":"116 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87749562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BIOEQUIVALENCE STUDY OF GENERIC MOLNUPIRAVIR IN HEALTHY VOLUNTEERS","authors":"V. Vasilyuk, A. Boroduleva, P. Sobolev, A. Nikiforova, V. G. Mozgovaya, O. Filon, A. Zinkovskaya, V. G. Ignatiev, M. Samsonov, I. S. Kozlova, E. K. Khanonina","doi":"10.19163/2307-9266-2022-10-6-562-572","DOIUrl":"https://doi.org/10.19163/2307-9266-2022-10-6-562-572","url":null,"abstract":"Molnupiravir is one of the drugs for the etiotropic therapy of a new coronavirus infection COVID-19. It has confirmed its clinical efficacy in the treatment of patients with mild and moderate COVID-19, including those who are at high risk of progressing to severe disease.The aim of the study was to evaluate bioequivalence of the generic drug molnupiravir ALARIO-TL and the original drug Lagevrio with a single oral administration in healthy volunteers.Materials and methods. This bioequivalence study was an open, randomized, two-period crossover study. In each of the two periods, volunteers received a single dose of the test drug, or reference drug molnupiravir, in the form of capsules at the dose of 200 mg. The washout period between the doses was 3 days. To determine pharmacokinetic (PK) parameters and bioequivalence, the concentration the concentration of N-hydrozycytidine (NHC), the main molnupiravir metabolit in the blood plasma of volunteers was evaluated. The blood plasma sampling was carried out in the range from 0 to 16 hours in each of the study periods. Bioequivalence was assessed by comparing 90% confidence intervals (CIs) for the ratio of geometric means of AUC(0–16) and Cmax of the test drug and reference drugs with the established equivalence limits of 80.00 – 125.00%.Results. A total of 28 healthy male volunteers were included in the study. According to the results of the statistical analysis, after the administration of the test and reference drugs, the 90% CIs for the ratio of the geometric means of AUC (0–16) and Cmax were 96.31% – 113.64% and 91.37% – 114.8%, respectively. These intervals fit within the established limits of 80.00–125.00%, which confirms the bioequivalence of the drugs. When comparing the frequency of the individual adverse events registration, no significant differences were found out after the administration of the test and reference drugs.Conclusion. Based on the results of this study, it can be concluded that the test and reference drugs of molnupiravir are bioequivalent. In addition, the data obtained indicate that the drugs have similar safety profiles.","PeriodicalId":20031,"journal":{"name":"Pharmacology & Pharmacy","volume":"70 3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87692922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HYPOGLYCEMIC EFFECT OF SITAGLIPTIN AND AMINOGUANIDINE COMBINATION IN EXPERIMENTAL DIABETES MELLITUS","authors":"D. Kurkin, D. A. Bakulin, E. Morkovin, Y. Gorbunova, A. Strygin, T. M. Andriashvili, A. Sokolova, N. S. Bolokhov, V. E. Pustynnikov, E. A. Fomichev","doi":"10.19163/2307-9266-2022-10-6-536-548","DOIUrl":"https://doi.org/10.19163/2307-9266-2022-10-6-536-548","url":null,"abstract":"The aim of the work was to determine the antidiabetic effect of a sitagliptin and aminoguanidine combination in rats with experimental diabetes mellitus.Materials and methods. The study was carried out on male Wistar rats and C57BL/KsJ-db/db mice. According to the models used, it was divided into 4 series, in which alloxan, steroid-induced (dexamethasone) and streptozotocin-nicotinamide-induced diabetes mellitus (DM) were formed, respectively, in rats, and in the 4 series, obese C57BL/KsJ-db/db mice were used. In the 1 and 2 series, the treatment was started prophylactically – 3 h after the alloxan administration and simultaneously with the dexamethasone administration, in the 3rd and 4th series, the treatment was carried out after the pathology had developed – 7 days after the streptozotocin with nicotinamide administration, and in the obese mice – immediately after their distribution according to the groups. The treatment was carried out with sitagliptin (10 mg/kg), aminoguanidine (25 mg/kg), or a combination thereof. The treatment was continued till the end of the experiment, which was completed with an oral glucose tolerance test (OGTT) after 4 h of fasting. The obtained data were subjected to statistical processing.Results. In the course of the experiments, it was found out that the prophylactic administration of a sitagliptin and aminoguanidine combination, unlike each of the components, prevented the development of alloxan DM. More effectively than the administration of sitagliptin alone, it reduced the severity of steroid-induced DM, which was expressed in a significantly lower level of fasting glycemia (after 4 h of fasting) and postprandial glycemia (during OGTT). Under the conditions of streptozotocin-nicotinamide-induced DM, the studied combination slowed down the progression of the pathology, and in the obese mice, the course therapeutic administration of sitagliptin and its combination reduced the severity of carbohydrate metabolism disorders (fasting glycemia) and increased the rate of glucose utilization.Conclusion. As an iNOS blocker, aminoguanidine enhances the antidiabetic effect of sitagliptin, preventing the development of alloxan diabetes and reducing the severity of steroid-induced DM when administered prophylactically. When administered therapeutically, it reduces the severity of streptozotocin-nicotinamide-induced DM in rats and type 2 DM in mice with a predisposition to obesity. ","PeriodicalId":20031,"journal":{"name":"Pharmacology & Pharmacy","volume":"58 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80974643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FEATURES OF QUALITY CONTROL STRATEGY FOR DRUGS BASED ON VIABLE SKIN CELLS","authors":"O. Rachinskaya, E. Melnikova, V. Merkulov","doi":"10.19163/2307-9266-2022-10-6-515-524","DOIUrl":"https://doi.org/10.19163/2307-9266-2022-10-6-515-524","url":null,"abstract":"The aim of the study was to research the international experience in quality assurance of the products based on skin cells in order to identify the features of the quality control strategy in the development, production, as well as during an expert quality assessment as a part of the state registration procedure in the Russian Federation.Materials and methods. The article provides an analysis of the materials presented in the assessment reports of the USA and Japanese regulatory authorities, as well as on the official websites of manufacturers, in review and scientific papers on the study of the structure and properties of tissue-engineered skin analogs.Results. The manufacture of products containing human skin cells is associated with such risks as the possibility of contamination of the preparation with infective agents transmitted by materials of the animal origin, feeder cells, donor cells, or during the manufacturing process; a small amount of biopsy materials; a complexity of a three-dimensional product structure when combining cells with a scaffold; continuity of the manufacture process and a short product expiry date. The raw materials and reagents control, the creation of cell banks, using animal feeder cells only from qualified cell banks, an in-process control and release testing in accordance with the requirements of the finished product specification, make it possible to obtain a preparation with a reproducible quality. The specification should contain information about the identity, safety and potency of the product. For each preparation, the choice of approaches for assessing the quality is individual and depends on its composition and mode of action.Conclusion. The features of the quality control strategy for the drugs based on human skin cells, consist in the implementation of control measures in order to obtain a proper quality of cellular (viability, sterility, identity, potency, et al) and non-cellular (physico-chemical scaffold properties) components or the whole graft (bioburden, barrier properties). The approaches and methods for determining the potency should be selected individually for each product and reflect the number, viability and identity of cells, a proliferative activity and secretable ability of the cellular component.","PeriodicalId":20031,"journal":{"name":"Pharmacology & Pharmacy","volume":"50 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81284850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MOLECULAR MECHANISMS UNDERLYING THERAPEUTIC ACTION OF VITAMIN B6","authors":"O. A. Zagubnaya, Y. Nartsissov","doi":"10.19163/2307-9266-2022-10-6-500-514","DOIUrl":"https://doi.org/10.19163/2307-9266-2022-10-6-500-514","url":null,"abstract":"The aim of the study was to analyze the molecular mechanisms that determine the possibility of using vitamin B6 in clinical practice for the correction of various pathological conditions.Materials and methods. Information retrieval (Scopus, PubMed) and library (eLibrary) databases were used as research tools. In some cases, the ResearchGate application was used for a semantic search. The analysis and generalization of the scientific literature on the topic of research, covering the period from 1989 to the present, has been carried out in the work.Results. It has been shown that all chemical forms of vitamin B6 are able to penetrate the membranes of most cells by free diffusion, while forming phosphorylated forms inside. Pyridoxal phosphate is a biologically important metabolite that is directly involved as a cofactor in a variety of intracellular reactions. Requirements for this cofactor depend on the age, sex and condition of the patient. Pregnancy and lactation play a special role in the consumption of vitamin B6. In most cases, a balanced diet will provide an acceptable level of this vitamin. At the same time, its deficiency leads to the development of a number of pathological conditions, including neurodegenerative diseases, inflammations and diabetes. Negative manifestations from the central nervous system are also possible with an excessive consumption of B6.Conclusion. Replenishment of the vitamin B6 level in case of its identified deficiency is a necessary condition for the successful treatment of the central nervous system diseases, diabetes and correction of patients’ immune status. At the same time, it is necessary to observe a balanced intake of this cofactor in order to avoid negative effects on metabolism in case of its excess.","PeriodicalId":20031,"journal":{"name":"Pharmacology & Pharmacy","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78577439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DEVELOPMENT OF MURINE STEM CELLS WITH CONDITIONAL KNOCKOUT OF HUMANIZED SNCA GENE","authors":"E. A. Patrakhanov, V. M. Pokrovsky, A. Karagodina, A. Krayushkina, N. S. Zhunusov, A. Deykin, M. V. Korokin, M. Pokrovsky, O. Altukhova","doi":"10.19163/2307-9266-2022-10-6-525-535","DOIUrl":"https://doi.org/10.19163/2307-9266-2022-10-6-525-535","url":null,"abstract":"α-synuclein is one of the key molecular links in the pathogenesis of Parkinson’s disease. The accumulated data indicate that pathogenic mutations in the Snca gene are associated with the development of neurodegenerative brain damage, indicating the relevance of studying the synuclein neurobiological role.The aim of the study was to create a genetically modified clone of mouse stem cells with a conditional knockout of humanized α-synuclein, which can be used for the reinjection into mouse blastocysts, as well as for basic and applied in vitro research in the field of pathophysiology and neuropharmacology.Materials and methods. To create mouse stem cells with a conditional knockout of the humanized Snca gene, a previously obtained clone with the first Snca exon flanked by LoxP sites, was used. The CRISPR/Cas9-mediated homologous recombination system with donor DNA oligonucleotides of the human sites of the corresponding gene sites was used to humanize the fourth and fifth exons. Cas9 nuclease, single guide RNA, and donor DNA were transfected into mouse cells.Results. An approach to obtaining clones of mouse genetically modified stem cells expressing pathological humanized α-synuclein, has been proposed and implemented. The resulting clones were plated on Petri dishes for propagation and a further genetic analysis. Clone 126-2F4 was found out carrying the necessary genetic modifications. The results obtained are fundamentally important not only for understanding the development of the pathological process in α-synucleinopathies, but which is more important, for the development of new therapeutic approaches that will stop the extension of the human α-synuclein aggregation pathology throughout the nervous system, and the validation of these approaches in preclinical trials.Conclusion. As a result of the study, a strategy for CRISPR/Cas9-assisted homologous recombination in the genome of mouse embryonic stem cells has been developed to create a fully humanized Snca gene encoding α-synuclein, and the clone genome of mouse embryonic stem cells has been edited using a CRISPR technology. The RNA and DNA oligonucleotides necessary for the creation of RNP complexes that carry out a directed homologous recombination in the Snca locus of the mouse genome have been synthesized. The developed cell clone can serve to create a line of genetically modified mice that serve as a test system for pathophysiological and neuropharmacological studies associated with synucleinopathies. Herewith, before the induction of the Cre-dependent recombination, this line is a representative model for studying a biological role of mutant Snca. At the same time, after a Cre-dependent knockout activation, it is possible to imitate the pharmacological inhibition of α-synuclein, which is of particular interest for applied research in neuropharmacology.","PeriodicalId":20031,"journal":{"name":"Pharmacology & Pharmacy","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73007753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}