Research Results in Pharmacology

Regulation of 11β-hydroxysteroid dehydrogenase isoforms: pharmacophore search and molecular design of prospective 11β-HSD1 inhibitors

2025-09-26T12:02:52+03:00

Introduction: Osteoporosis is an important medical and social public health problem in an aging or elderly society, the issue of pharmacological correction of which remains unresolved to this day.

Materials and Methods: A design of prospective 11β-HSD1 inhibitors was performed on the basis of the literature data. A virtual screening of the designed compounds was performed using pharmacophore searching (DataWarrior, Flexophore), pharmacophore alignment (PhESA), and molecular docking (Jamda). 2D protein-ligand interaction maps were generated using PoseEdit, and 3D visualizations were produced in VMD. The cytotoxicity of the compounds was assessed in HEK-293 cells across a concentration range of 8–1024 μM, with IC₅₀ values calculated in RStudio.

Results and Discussion: A comprehensive virtual screening of prospective 11β-HSD1 inhibitors was performed, incorporating pharmacophore searching, PhESA alignment, and molecular docking against the 11β-HSD1 complex (PDB: 4YYZ). Several compounds (TS-897, TS-883, TS-945, and others) demonstrated Jamda Score values comparable to or exceeding that of the native ligand, indicating strong predicted binding affinity. Additional candidates were identified based on high pharmacophore similarity (>0.95). Among the 14 proposed compounds, four (IV-81, IV-91, IV-158) exhibited no cytotoxicity in HEK-293 cells (IC₅₀ > 1024 µM). These findings support the potential of the synthesized azoloazine derivatives as novel 11β-HSD1 inhibitors for further in vitro and in vivo studies in osteoporosis therapy.

Conclusion: As a result of this work, original azoloazine derivatives have been developed for further biological testing aimed at regulating the activity of 11β-hydroxysteroid dehydrogenase isoforms (11β-HSDs) for pharmacological correction of bone remodeling and osteoreparation disorders.

First discovered effect of L-norvaline on tissue saturation and the activity of respiratory chain enzymes in ischemic and reperfusion injury of the small intestine

2025-09-26T12:02:21+03:00

Introduction: Prevention and treatment of ischemic and reperfusion injury plays an important role in correcting the pathological manifestations of acute mesenteric thrombosis. The development of effective therapy and the study of the mechanisms of pharmacological agents’ action are an important problem faced by researchers.

Materials and Methods: All studies were performed on 12 female Wistar rats weighing 250±25 g. Isolated mesenteric ischemia and reperfusion were reproduced by ligation and subsequent removal of ligatures from three segmental arteries in the ileum. The saturation and activity of respiratory enzymes were studied by hyperspectral imaging and biofluorescence.

Results and Discussion: For the first time, we investigated the effect of L-norvaline at a dose of 15 mg/kg on tissue saturation and the activity of respiratory chain enzymes in ischemic and reperfusion injury of the small intestine. The study revealed an increase in the level of tissue saturation and NADH activity against the background of L-norvaline administration during ischemia, in the absence of a significant effect on saturation during reperfusion during the restoration of NADH activity.

Conclusion: The arginase inhibitor L-norvaline has a protective effect in ischemic and reperfusion injuries of the small intestine.

Regulation of 11β-hydroxysteroid dehydrogenase isoforms – novel drug targets for osteoporosis therapy

2025-09-26T12:01:55+03:00

Introduction: Osteoporosis is an significant medical and social public health problem in an aging or elderly society, the issue of pharmacological correction of which remains unresolved to this day.

Materials and Methods: The rationale for this idea stems from our previous findings on the role of 11B-HSD type 2 in bone remodeling and osteoreparation, combined with a content analysis and literature review of scientific publications from PubMed, Scopus, Cyberleninka, Google Scholar, and ResearchGate.

Results and Discussion: Current understanding of the molecular mechanisms of bone homeostasis allows for a significant shift and expansion in the paradigms for treating and preventing osteoporosis. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a key metabolic enzyme that catalyzes the intracellular conversion of inactive glucocorticoids into physiologically active ones. Research conducted over the past decade has shown that abnormal 11β-HSD1 activity contributes to the pathogenesis of obesity, type 2 diabetes, metabolic syndrome, and osteoporosis. The scientific challenge of regulating the activity of 11β-hydroxysteroid dehydrogenase (11β-HSD) isoforms and restoring homeostasis in the 11β-HSD1/11β-HSD2 enzymatic system is proposed to be addressed through the design and application of novel azole-based heterocyclic compounds as 11β-HSD1 inhibitors.

Conclusion: The development of azole-based heterocyclic 11β-HSD1 inhibitors is expected to yield promising drug candidates for pharmacologically correcting impaired bone remodeling and repair.

Efficacy and safety profiles of monoclonal antibodies used in the therapy of Alzheimer’s disease

2025-10-10T13:41:46+03:00

Introduction: Advances in molecular biology and biotechnology in recent decades have led to creation of new therapeutic strategies for Alzheimer’s disease (AD) patients. Among the emerging therapeutic approaches, monoclonal antibodies are attracting particular attention due to their ability to modulate the accumulation of amyloid plaques and tau protein in the brain, thus proposing promising pathogenetic approach. Aim: to summarize efficacy, side effects and mortality rates of monoclonal antibodies based on the results of clinical trials in comparison with conventional therapy.

Methods: All registered clinical studies related to AD treatment using monoclonal antibodies were found in ClinicalTrials.gov database. The information on adverse effects was obtained from the articles related to the third phase clinical studies, with total 21 articles included in the analysis. Data on conventional therapy were retrieved from clinical guidelines related to AD treatment.

Results: We found that the number of significant side effects and mortality varies significantly for different monoclonal antibodies. For the most part, side effects are not specific to the drugs used, and therefore it is not possible to assess the direct effect of the drug on the development of certain adverse events, as well as to adequately compare the safety of different drugs, due to different mechanisms of action and recommended doses. Magnetic resonance imaging with estimation of amyloid-related imaging abnormalities changes is the most promising method for antibodies comparison, but this approach still lacks correlation with clinical course. Also, it is recommended to separately consider the side effects associated with infusion.

Conclusion: The use of pathogenetic antibody therapy will improve the quality of AD treatment in the future. However, up to date, there are no unified protocols for estimation of drug effectiveness and its comparison. Evaluation of side effects and determination of antibody-specific side effects is necessary to improve the safety of treatment of patients with AD.

Anti-anxiety properties of new 5H-2,3-benzodiazepine and 5H-[1,2,5]triazepine derivatives

2025-07-21T13:33:47+03:00

Introduction: Previous studies have examined the anxiolytic properties of compounds containing mutually annulated systems of 5H-2,3-benzodiazepine and [1,2,4]triazole, namely 7H-[1,2,4]triazolo[3,4-a][2,3]benzodiazepine derivatives. In the present work, another group of 5H-2,3-benzodiazepine and 5H-[1,2,5]triazepine derivatives was examined for psychotropic activity.

Materials and Methods: For in silico assay the PASS online test system and ADMET analysis were used. Compounds under study were also tested in vivo in Elevated Plus Maze, Open Field and Rotarod tests.

Results and Discussion: Of note is that the presence of a 3,4-dimethoxyphenyl substituent at position 4 of the diazepine ring (RD-1, RD-7) leads to a decrease in anxiolytic activity compared to 4-methoxyphenyl derivatives (RD-6, RD-9). Among the derivatives of condensed 5H-[1,2,5]triazepines, a more pronounced anti-anxiety effect was exerted by compound RD-8 with an annelated benzimidazole bicycle compared to its analog RD-15 with a pyrrole cycle. The high anxiolytic activity of the compounds is facilitated by the presence of slightly branched (RD-6, RD-9) or unbranched (RD-8) substituents in position 4 of the diazepine or triazepine cycle. In the Rotarod test, it was noted that 4-(3,4-dimethoxyphenyl)-1-hydrazino-5H-2,3-benzodiazepine (RD-1) and 4-hydrazino-7,8,9-trimethyl-1-phenyl-5H-pyrrolo[2,1-d][1,2,5]triazepine (RD-15) have a negative effect on muscle tone in mice due to the presence of a hydrazino group in their composition. According to ADMET analysis, compounds RD-6, RD-8 and RD-9 are low toxic; however, a specific toxicity study among these derivatives is recommended.

Conclusion: The most active and safe compound for further studies among the studied derivatives with a single administration is 1,4-diphenyl-5H-[1,2,5]triazepino[5,4-a]benzimidazole (RD-8) at a dose of 1.3 mg/kg.

Semaglutide reduces hypothalamic glial cell damage in a streptozocin-induced model of Alzheimer's disease

2025-07-16T18:32:11+03:00

Introduction: Reactive changes in glial cells, as well as their dysfunction, particularly cerebrospinal fluid dynamics disturbances, are associated with multiple neurodegenerative diseases and Alzheimer’s disease (AD). Intraventricular administration of streptozotocin (STZ) is considered a model of sporadic AD, though data on hypothalamic glial cell changes, ependymal glia, and tanycytes in this model remain limited. Of particular interest is the potential for glucagon-like peptide-1 (GLP-1) receptor agonists to address STZ-induced changes following intraventricular administration.

Material and Methods: Using immunomorphological methods, this study assessed changes in staining density and distribution of glial proteins (GFAP, aquaporine-4, connexin 43, vimentin) and neuronal alterations in hypothalamic structures following intraventricular STZ administration (3 mg/kg) and course treatment with intraperitoneal semaglutide (0.1 mg/kg, 16 injections).

Results: STZ caused neuronal damage in the ventromedial hypothalamic nucleus, disrupted the ependymal lining and tanycytes of the third ventricle, induced reactive astrogliosis, and altered the distribution of aquaporin-4 and connexin-43. Semaglutide administration reduced astroglial activation, normalized aquaporin and connexin distribution, decreased neuronal death, and suppressed caspase-3 activation in the ventromedial hypothalamic nucleus.

Conclusion: Intraventricular single-dose STZ administration causes long-term impairment of glial functions related to cerebrospinal fluid exchange. The course treatment GLP-1R agonist semaglutide (started 5 days after streptozocin administration, 16 injections every other day) demonstrated normalizing effects on both glial and neuronal parameters in the STZ-induced AD model.

Anxiolytic, antidepressant and analgesic activities of novel derivatives of 1-(3-phenylpyrrol-2-yl)-1,3-dihydro-2H-benzimidazol-2-one

2025-07-14T14:19:46+03:00

Introduction: Benzimidazole (1,3-benzodiazole) derivatives hold an important place in the field of medicinal chemistry, since they have a wide spectrum of pharmacological activity, as well as high variability of the mechanisms of action: GABA-, serotonin-, dopamine-, adrenaline-, angiotensin-, adenosine-, and glutamatergic. In view of the diversity of the ways of influence of benzimidazole derivatives on neurotransmitter systems, as well as the pharmacological effects of these compounds, the synthesis of highly effective neurotropic drugs with an improved safety profile on their basis is ofinterest for study. The aim of this study was to investigate the neuropsychotropic potential of new derivatives of 1-(3-phenylpyrrol-2-yl)-1,3-dihydro-2H-benzimidazole-2-one in vivo.

Materials and Methods: The study was conducted on 258 white outbred male mice weighing 25-30 g. The work was carried out in several stages. At the first stage, the safety of the compounds was studied by in silico methods using the PASS-online program with a preliminary calculation of LD₅₀. At the second stage, animals were tested under the influence of the compounds in the Open Field and Light-Dark Box tests. Etifoxine (50 mg/kg) and phenazepam (0.1 mg/kg) were chosen as comparison drugs. At the third stage, the behavior of rodents was studied in Porsolt test, with amitriptyline (10 mg/kg) and fluoxetine (10 mg/kg) used as reference drugs. At the fourth stage, the analgesic properties of the compounds were assessed in the Tail-flick and Hot Plate tests in comparison with morphine (5 mg/kg).

Results and Discussion: Based on the obtained results, it can be noted that the phenyl-containing compound CHS-Bi-46 has anxiolytic activity with an antidepressant component. Compounds containing pyridin-3-yl (CHS-Bi-48) and 2-bromophenyl (CHS-Bi-52) are characterized by antidepressant properties, and CHS-Bi-52 also showed a weak analgesic effect in the Hot plate test. For the substance with a pyridin-4-yl fragment CHS-Bi-47, no significant effects were registered according to the results of the tests, but this substance may have other pharmacological activities. 4-Chlorophenyl substance coded CHS-Bi-50 exhibits antinociceptive activity at the spinal level, which is equal to the reference drug morphine at a dose of 5 mg/kg. The 4-bromophenyl-containing compound CHS-Bi-51 is characterized by a moderate combined spinal and supraspinal analgesic property. It can be noted that the most suitable structure for the manifestation of anxiolytic and antidepressant properties of compounds is the presence of a phenyl substituent in the 5 position of the pyrrole ring, and the severity of the analgesic effects of substances is affected by the presence of Cl atoms in the phenyl radical in position 4 for spinal effects and Br – in positions 2 and 4 for supraspinal effects.

Conclusion: The obtained data indicate the prospects of further study of 1-(3-phenylpyrrol-2-yl)-1,3-dihydro-2H-benzimidazole-2-one derivatives in order to search for substances with neuropsychotropic activity.

Adherence to dual antiplatelet therapy among outpatients after acute myocardial infarction in primary care

2025-08-08T07:07:07+03:00

Introduction: The efficacy outcomes of dual antiplatelet therapy (DAPT) observed in randomized controlled trials are often not replicated in real-world post-myocardial infarction (MI) patients due to suboptimal adherence to prescribed pharmacotherapy. This study aimed to assess DAPT adherence in outpatients after MI and evaluate its association with risk of major adverse cardiovascular events (MACE).

Material and methods: This retrospective pharmacoepidemiologic study included 276 patients who experienced AMI between January 1, 2021, and December 31, 2023, based on electronic medical data. Adherence was measured using proportion of days covered (PDC) metric. Kaplan-Meier curves were constructed to evaluate the impact of DAPT adherence on the incidence of MACE over a 12-month period.

Results: Patients primarily received ASA 100 mg (91.3%) in combination with P2Y12 inhibitor ticagrelor (68.5%). The proportion of patients fully adherent to DAPT (PDC≥80% for both components) over 12 months was only 46.4%, with a significant decline from 60.9% to 42.0% between first and second half-year periods (p<0.001). Adherence to P2Y12 inhibitors was significantly higher compared to ASA (87.8±18.9% vs. 73.6±27.5%; p<0.001), largely due to high adherence to ticagrelor (PDC=92.5±12.8%). Post-MI patients fully adherent to DAPT had a lower probability of MACE compared to non-adherent (p=0.047). The protective effect of optimal adherence, adjusted for patient comorbidity, was also assessed using Cox regression, which demonstrated a 2% reduction in MACE risk for every 1% increase in PDC (p<0.05).

Conclusion: Higher adherence to DAPT following MI was associated with lower risk of MACE. However, adherence declined over time, underscoring the necessity of enhancing medication adherence in post-MI outpatients.

Orthogonal approach and critical quality attributes for gene and cell therapy products

2025-05-26T16:24:23+03:00

Introduction: Gene and cell therapy (GCT) products are revolutionizing medicine because they are made up of unique biological components like genetic material, viral vectors, and viable cells. However, their complexity necessitates rigorous quality control strategies to ensure efficacy, safety, and batch consistency. This manuscript explores the application of an orthogonal approach – employing multiple independent methods – to assess critical quality attributes, such as identity, potency, and purity of GCT products.

Materials and Methods: To achieve the aim of our work, we analyzed 15 GCT products for 11 different types of diseases and reports of multiple regulatory agencies.

Results: For cell-based therapies, identity is confirmed through genotypic, phenotypic, and morphological analyses, while potency is evaluated using functional assays tailored to the product’s mechanism of action, such as cell viability, differentiation status, or cytokine secretion. Viral vector-based therapies require characterization of structural integrity, transgene expression, and the ratio of full to empty capsids, employing techniques like dynamic light scattering (DLS), PCR, and ELISA.

Conclusion: The paper highlights regulatory recommendations from the FDA, EMA, and WHO, emphasizing the need for validated assays during product release and stability testing. Case studies, including CAR-T cells and AAV-based therapies, illustrate the practical implementation of orthogonal methods. Challenges such as assay variability and the need for clinical correlation are discussed, underscoring the importance of assay development early in the product lifecycle. By integrating diverse analytical techniques, the orthogonal approach ensures comprehensive product characterization facilitating the translation of GCTs from research to clinical application.

Glucose effects on the brain in the healthy and unhealthy individuals: metabolic and cognitive aspects

2025-08-11T16:24:17+03:00

Introduction: Glucose serves as the brain’s primary energy substrate and plays a critical role in maintaining cognitive function. Even slight fluctuations in glucose levels can influence attention, learning, and emotional regulation.

Materials and Methods: The authors organised a screening of PubMed and Google Scholar reference databases on relevant articles from 1995 till 2025 to perform a systematic review.

Results:

Glucose metabolism and its regulation in the brain: The brain consumes a significant portion of the body’s glucose, especially in cortical and subcortical regions involved in cognitive processing. Glucose regulation is mediated by neuroglia, particularly astrocytes, which are essential for energy transfer and utilization. Neurobehavioral and neuroimaging markers: Neuroimaging studies using fMRI and PET reveal distinct patterns of activation in the brain

’

s reward system when comparing glucose and fructose consumption. Glucose more strongly activates the hypothalamus and regions related to satiety and appetite regulation, whereas fructose is associated with a reduced sense of fullness. Effects of sweet substances on cognitive function: Comparisons between glucose and non-caloric sweeteners (e.g., sucralose) highlight differences in the engagement of dopaminergic pathways and reward anticipation mechanisms. Glucose demonstrates a more stable effect on short-term memory and attention. Role of incretins and calorie awareness: Gut hormones such as GLP-1 are involved in satiety signaling and influence activity in limbic structures. Additionally, cognitive awareness of caloric content and food composition can modulate neural responses, underscoring the importance of cognitive factors in regulating eating behavior.

Conclusion: Understanding the differences in perception and processing of glucose, fructose, and non-caloric sweeteners is crucial for developing dietary strategies and interventions for metabolic and neuropsychiatric disorders. Further research into neuroenergetics and individual variability in nutrient responses may support more precise and personalized approaches in medicine.