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Research Results in Pharmacology
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ISSN (Online) 2658-381X
Published by Pensoft Homepage  [58 journals]
  • Classical analgesic drugs modulate nociceptive-like escape behavior in
           Drosophila melanogaster larvae

    • Abstract: Research Results in Pharmacology 8(4): 185-196
      DOI : 10.3897/rrpharmacology.8.91390
      Authors : Thamyris Santos-Silva, Caio Fábio Baeta Lopes, Jennifer Diniz Soares Guimarães, Felipe Berti Valer, Gustavo Campos Silva e Kuhn, Thiago Roberto Lima Romero, Lígia Araújo Naves, Igor Dimitri Gama Duarte : Introduction: Nociceptive stimulus triggers escape responses in Drosophila melanogaster larvae, characterized by 360° rolling behavior along its own body axis. Therefore, it is possible to study analgesic drugs based on this stereotypical nociceptive-like escape behavior. Here, we aimed to develop an analgesic predictive validity test of thermal nociception through D. melanogaster larvae. Materials and methods: We evaluated the effect of classical analgesics (morphine, dipyrone, acetylsalicylic acid (ASA) and dexamethasone (DXM)) in the rolling behavior latency of D. melanogaster larvae exposed to thermal-acute noxious stimulus and nociceptive sensitization paradigm. Drugs were injected into hemocoel (100 nL) before nociceptive measurement. Results and discussion: Rolling behavior latency was increased by morphine (2, 4, 8 and 16 ng) in dose-dependent manner. Naloxone (4 ng) fully reversed maximum effect of morphine. Dipyrone (32, 64 and 128 ng) and DXM (8 and 16 ng) elicited dose-dependent antinociceptive effects. Exposure of larvae to 97% of maximal infrared intensity induced nociceptive sensitization, i.e., latency changed from 12 to 7.5 seconds. ASA (25, 50 and 100 ng) and DXM (4, 8 and 16 ng) were administered 150 min after nociceptive sensitization and displayed reverse sensitization in rapid onset (30 min after injection). DXM (16 ng), injected prior to nociceptive sensitization, displayed a delay in the onset of action (150 min after injection). Locomotor behaviors were not affected by analgesic substances. Conclusion: Our findings open perspectives for evaluation and discovery of antinociceptive drugs using D. melanogaster larvae model. Graphical abstract HTML XML PDF
      PubDate: Thu, 22 Dec 2022 12:10:22 +020
  • The mechanism of antidepressant action of a new 3-substituted
           thiethane-1,1-dioxide derivative in tests of neuropharmacological

    • Abstract: Research Results in Pharmacology 8(4): 175-183
      DOI : 10.3897/rrpharmacology.8.86560
      Authors : Irina L. Nikitina, Gulnara G. Gaisina, Aleksandr V. Samorodov : Introduction: The present study is aimed at investigation of the mechanism of action of a new 3-substituted thietane-1,1-dioxide derivative (N-199/1) exhibiting antidepressant properties, in several tests of neuropharmacological interaction. Materials and methods: To study the mechanism of action of N-199/1, its effect on 5-hydroxytryptophan (5-HTP)-induced head-twitch response (50 mg/kg and 300 mg/kg), haloperidol-induced catalepsy (1 mg/kg), arecoline-induced tremor (6 mg/kg), picrotoxin-induced seizures (6 mg/kg) and hypothermia, induced by apomorphine (10 mg/kg) or L-3,4-dihydroxyphenylalanine (L-DOPA, 140 mg/kg), was assessed when administered singly to white outbred male mice at a dose of 2 mg/kg. Results and discussion: N-199/1 reduced the number of head twitches, induced by 5-HTP (300 mg/kg), by 83% 45 min after 5-HTP injection; decreased the duration of haloperidol catalepsy by 1–32 s 15–45 min after haloperidol injection; attenuated L-DOPA-induced hypothermia by 0.7 °С and apomorphine-induced hypothermia by 0.6 °С at the timepoint of 30 min; reduced the duration and severity of arecoline tremor and did not affect the convulsive effect of picrotoxin. Conclusion: N-199/1 acts on serotonergic, noradrenergic, dopaminergic and cholinergic neurotransmission and does not affect neuronal reuptake of monoamines or monoamine oxidase. The mechanism of action of N-199/1 is probably due to stimulation of serotonergic 5HT1A-receptors and/or blockade of 5HT2A/2C-receptors and/or α2-adrenergic receptors; dopaminergic and cholinergic receptors may also be involved. Graphical abstract HTML XML PDF
      PubDate: Thu, 22 Dec 2022 12:10:11 +020
  • Recent advances in the pharmacotherapy of osteoarthritis

    • Abstract: Research Results in Pharmacology 8(4): 167-174
      DOI : 10.3897/rrpharmacology.8.84951
      Authors : Muthu Meera : Introduction: Osteoarthritis (OA) is a common debilitating disease affecting the geriatric population. Management of osteoarthritis is a challenge for orthopedicians because till date there has been no such drug that can completely cure the disease or at least retard/arrest the disease progression. In addition to the currently available treatment options for OA like NSAIDs, opioids, nutraceuticals (glucosamine sulphate and chondroitin sulphate), many new drugs are being discovered or repurposed for use in osteoarthritis. Most of these recent drugs aim at retarding the disease progression rather than providing just a symptomatic relief. Materials and methods: All relevant articles regarding approved new drugs and pipeline drugs for osteoarthritis published between 2012–2021 were analysed. Those included animal studies as well as clinical trials. Some older articles were also referred to, provided they highlighted any significant data. The obtained data were analysed and compiled. Results and discussion: Broadly the recent drugs for OA can be classified based upon their site of action as (i) drugs targeting articular cartilage, (ii) drugs targeting inflammation, (iii) drugs targeting the subchondral bone, and (iv) drugs for relieving pain. Ranging from in vitro studies to clinical trials, these drugs are in various phases of drug discovery. Early diagnosis of OA and its management with a drug that retards disease progression rather than prescribing just a symptom reliever is very much necessary in the current situation. Conclusion: Need for new drugs for OA is increasing day by day. More number of clinical trials with larger sample sizes alone can satisfy the need of disease modifying drugs for OA. This review provides a deep insight into all the recent advances in the pharmacotherapy of osteoarthritis. Graphical abstract: HTML XML PDF
      PubDate: Thu, 22 Dec 2022 12:10:00 +020
  • Characteristics of the state of bone tissue in genetically modified
           mice with impaired enzymatic regulation of steroid hormone metabolism

    • Abstract: Research Results in Pharmacology 8(4): 157-166
      DOI : 10.3897/rrpharmacology.8.98779
      Authors : Mikhail V. Korokin, Oleg S. Gudyrev, Petr R. Lebedev, Elena V. Kuzubova, Alexandra I. Radchenko, Ivan S. Koklin, Eduard I. Taran, Alim A. Kochkarov : Introduction: The aim was to evaluate the structural and functional changes of bone tissue in mice with null expression of 11β-HSD2 or both 11β-HSD2 and Apolipoprotein E. Materials and methods: The experimental study was performed in 60 male mice, weighting 24–30 g. The animals were kept in accordance with the rules of laboratory practice for preclinical studies on the territory of the Russian Federation. Mice lacking 11β-HSD2 (Hsd2-/-) and male mice lacking 11β-HSD2 and Apolipoprotein E (Hsd2-/-/Apoe-/-) were used in the study. We studied and characterized the state of bone tissue, indicators of bone density, microcirculation in bone tissue, endothelial dysfunction coefficient, width of bone trabeculae, as well as serum concentrations of bone alkaline phosphatase, hydroxyproline, deoxyprinoline and expression levels of p53, Bcl2, Bax, eNOS genes. Results and discussion: We showed that mice with the Hsd2-/- genotype with no expression of 11ß-HSD2 by the 6th month of life showed a statistically significant decrease in bone density, which progresses to the 7th and 8th months of life. At the 8th month of animal life, a decrease in bone density is accompanied by a statistically significant decrease in the level of microcirculation in the bone and an increase in the coefficient of endothelial dysfunction. Taking into account the relationship of endothelial dysfunction, atherogenesis and disorders in the processes of bone remodeling, in the framework of this study, we also assessed the state of bone tissue in double transgenes with the genotype Hsd2-/-/Apoe-/-, which lack the expression of both 11ß-HSD2 and Apolipoprotein E. In this study, we also saw increased activation of processes leading to disruption of bone remodeling processes. In the group of the animals with the genotype Hsd2-/-/Apoe-/-, we found statistically significant differences from the mice with no expression of 11ß-HSD2 in bone density and microcirculation, and the width of bone trabeculae. Also, a statistically significant increase in hydroxyproline and deoxyprinoline was found in the group of double transgenes, in the absence of significant changes in the concentration of bone alkaline phosphatase. This fact indicates a pronounced activation of bone resorption processes in the absence of activation of osteosynthesis processes, which leads to the detected violation of bone remodeling processes. Conclusion: Thus, we have shown that a violation of the metabolic regulation of steroid hormone metabolism in animals with null expression of the 11ß-HSD2 (Hsd2-/- genotype) leads to the development of signs of osteoporosis – bone density decreases, which is accompanied by a decrease in the width of bone trabeculae, the level of microcirculation in bone tissue decreases simultaneously with an increase in the coefficient of endothelial dysfunction. The additional null expression of ApoE gene in double transgenes with the genotype Hsd2-/-/Apoe-/- leads to an increase in the severity of changes associated with a violation of bone remodeling processes and, in addition to a more pronounced change in bone tissue density, bone trabecular width, microcirculation and the coefficient of endothelial dysfunction leads to an increase in the concentration of biochemical markers of bone resorption. These changes indicate the important role of the enzyme 11ß-hydroxysteroid dehydrogenase type 2 in the processes of bone remodeling disorders. Graphical abstract HTML XML PDF
      PubDate: Thu, 22 Dec 2022 12:09:49 +020
  • The effect of the composition of Soderm®-Forte gel and the new
           injectable form of Rexod® on pathology findings in gingival tissue in
           experimental periodontitis in rats

    • Abstract: Research Results in Pharmacology 8(4): 141-156
      DOI : 10.3897/rrpharmacology.8.98809
      Authors : Pavel A. Galenko-Yaroshevsky, Valeriy K. Leontev, Aleksandr A. Slavinskiy, Kristina V. Tseluiko, Mark A. Zadorozhniy, Sergey S. Todorov, Viktor L. Popkov, Svetlana A. Lebedeva, Anait V. Zelenskaya, Andrey V. Zadorozhniy, Aleksandr A. Verevkin : Introduction: Periodontitis is the most important problem of modern dentistry. The development of new medicines and treatment regimens for patients with periodontal complex lesions is a strategic direction of modern pharmacology and dentistry. In this view, pride of place goes to morphological research, which allows not only to study the effect of drugs on pathomorphological changes in periodontal tissues, but also to estimate their therapeutic effectiveness. Aim of the study: to determine the nature of the effect of the composition of Soderm®-Forte gel and the new injectable form of Rexod® on the pathology findings in gingival tissue of rats with experimental periodontitis. Materials and methods: Experimental periodontitis (EP) was induced in rats by ligature method. The study was performed according to the following algorithm: animals with intact periodontium; animals with untreated EP; animals with EP treated with traditional drug therapy (TDT); animals with EP treated with combinations of TDT with Soderm®-Forte gel and TDT with Soderm®-Forte gel and the new injectable form (NIF) of Rexod®. For pathomorphological examination, biopsy specimen was taken from the gingival margin of the lower incisors. The ImageJ software was used for computer morphometry. Results and discussion: Examination of the gum samples revealed moderate therapeutic effects of the TDT. The combinations of TDT with Soderm®-Forte gel and, to a greater extent, TDT with Soderm®-Forte gel and the NIF of Rexod® showed high pharmacotherapeutic efficacy, manifested in rapid regeneration of the gingival tissues. Conclusion: The combination of TDT, Soderm®-Forte gel and the NIF of Rexod® shows the most beneficial effect on the pathological processes in the gum. The pharmacotherapeutic effect of the studied combination promotes the earliest regeneration of damaged gum tissues and reduces the risk of persistent pathology changes in them. HTML XML PDF
      PubDate: Thu, 22 Dec 2022 12:09:39 +020
  • Endothelial dysfunction: developmental mechanisms and therapeutic

    • Abstract: Research Results in Pharmacology 8(4): 115-139
      DOI : 10.3897/rrpharmacology.8.80376
      Authors : Dmitry V. Shcheblykin, Anton A. Bolgov, Mikhail V. Pokrovskii, Julia V. Stepenko, Julia M. Tsuverkalova, Olesya V. Shcheblykina, Polina A. Golubinskaya, Liliya V. Korokina : Introduction: Every year the importance of the normal functioning of the endothelial layer of the vascular wall in maintaining the health of the body becomes more and more obvious. The physiological role of the endothelium: The endothelium is a metabolically active organ actively involved in the regulation of hemostasis, modulation of inflammation, maintenance of hemovascular homeostasis, regulation of angiogenesis, vascular tone, and permeability. Risk factors for the development of endothelial dysfunction: Currently, insufficient bioavailability of nitric oxide is considered the most significant risk factor for endothelial dysfunction. Mechanisms of development of endothelial dysfunction: The genesis of endothelial dysfunction is a multifactorial process. Among various complex mechanisms, this review examines oxidative stress, inflammation, hyperglycemia, vitamin D deficiency, dyslipidemia, excess visceral fat, hyperhomocysteinemia, hyperuricemia, as well as primary genetic defect of endotheliocytes, as the most common causes in the population underlying the development of endothelial dysfunction. Markers of endothelial dysfunction in various diseases: This article discusses the main biomarkers of endothelial dysfunction currently used, as well as promising biomarkers in the future for laboratory diagnosis of this pathology. Therapeutic strategies: Therapeutic approaches to the endothelium in order to prevent or reduce a degree of damage to the vascular wall are briefly described. Conclusion: Endothelial dysfunction is a typical pathological process involved in the pathogenesis of many diseases. Thus, pharmacological agents with endothelioprotective properties can provide more therapeutic benefits than a drug without such an effect. HTML XML PDF
      PubDate: Thu, 22 Dec 2022 12:09:27 +020
  • Effect of recombinant Sox9 protein on the expression of
           cartilage-specific genes in human dermal fibroblasts cell culture

    • Abstract: Research Results in Pharmacology 8(4): 109-114
      DOI : 10.3897/rrpharmacology.8.90447
      Authors : Mikhail S. Bozhokin, Svetlana A. Bozhkova, Julia V. Sopova, Elena R. Mikhailova, Daria V. Marchenko, Mikhail G. Khotin : Introduction: Damage to the hyaline layer of large joints resulting from injuries or age-related changes restricts their mobility. The repair of these disorders is an actual issue in medicine. One of the promising therapies is the usage of cell engineering constructs based on a biodegradable scaffold and a modified cell culture. A frequently used method to modify the proliferation of cell culture for tissue engineering of hyaline cartilage, which makes it possible to introduce an experimental technique into clinical practice, is the application of recombinant proteins that affect chondrogenesis and lead to increase synthesis of extracellular matrix proteins. The goal of this work was to elucidate the effect of the key transcription factor in the chondrogenesis process – Sox9 protein – on the expression of genes responsible for chondrogenesis (Tgfβ3, Sox9, Acan, Comp, Col2a1). Materials and methods: Human dermal fibroblasts were used as a cell culture; recombinant Sox9 was added at each change of medium; the modification was carried out for 21 days, and difference in gene expression was determined by real-time PCR and -ΔΔCt method. Results and discussion: To assess the effectiveness of fibroblast modification, we analyzed the changing of expression of genes responsible for chondrogenesis (Tgfß3, Sox9, Col2a1, Acan, Comp). We studied the direct effect of different concentrations of the recombinant Sox9 protein on the proliferation of dermal fibroblasts in the chondrogenic direction. We showed that the addition of the recombinant Sox9 protein in various concentration did not significantly change the expression of both the genes encoding proteins of the extracellular matrix of hyaline cartilage (Acan, Col2a1, Comp) and the genes encoding chondrogenesis inducers (Tgfß3, Sox9). Conclusion: As a result of the experiments, it was shown that the recombinant Sox9 protein has practically no effect on chondrogenic differentiation and does not significantly change the expression of chondrogenesis genes. HTML XML PDF
      PubDate: Thu, 15 Dec 2022 17:34:14 +020
  • Future directions in cancer immunotherapy with monoclonal

    • Abstract: Research Results in Pharmacology 8(4): 101-107
      DOI : 10.3897/rrpharmacology.8.85918
      Authors : Lucía Cabello-Alemán : Introduction: Cancer immunotherapy with monoclonal antibodies (mAbs) has become a therapy with great potential nowadays. It is based on the affinity of antibodies to bind to specific molecules, thus inhibiting the growth and spread of cancer. There is a wide variety of mAbs with differentiated mechanisms and enormous clinical benefits. However, different immunotherapeutic alternatives have emerged due to their limitations, such as the long duration of organ toxicity and the inability to penetrate intracellularly. This mini-review will discuss the emerging alternatives of cancer immunotherapies based on mAbs. Bispecific antibodies (BsAbs): Antibodies designed to bind to two epitopes of an antigen. Antibody fragments: Fragments of the Fab region generated from the variable region of IgG and IgM and a scFv. Antibody-drug conjugates (ADCs): Administration of mAbs and a toxin of high specificity for a tumour target. Nanobodies (or nanocomponents): Small fragments of antibody heavy chain. Intrabodies (or intracellular antibodies): Antibodies that are expressed intracellularly and synthesised inside cells by retroviral delivery systems. Stereospecific and catalytic mAbs: Antibodies that recognise the 3D configurations of target molecules. Combination immunotherapies: Therapies that combine cytokines with tumour-targeted mAbs. Small molecule immunotherapeutics: Small molecule drugs that can stimulate intracellular pathways primarily involved in immune cell checkpoints and bind to mAb-like targets. Conclusion: These new varieties of immunotherapy present significant advantages, but future research should continue to improve their efficacy and safety and identify new biomarkers. Graphical abstract: HTML XML PDF
      PubDate: Thu, 15 Dec 2022 17:34:02 +020
  • In-silico identification of novel inhibitors for human Aurora kinase B
           form the ZINC database using molecular docking-based virtual screening

    • Abstract: Research Results in Pharmacology 8(4): 89-99
      DOI : 10.3897/rrpharmacology.8.82977
      Authors : Ashraf Ahmed Ali Abdusalam : Introduction: Aurora kinase enzymes play critical functions in mammals. Aurora kinases are mitotic regulators that are involved in a variety of processes during cell division. The overexpression of these enzymes is associated with tumour formation and is symptomatic of clinical circumstances in cancer patients who have been diagnosed. Materials and methods: The current study reports an in-silico virtual screening (VS) and molecular docking analysis of 2500 compounds retrieved from the ZINC database and five current clinical trial compounds against Aurora Kinase B using AutoDock Vina to identify potential inhibitors. Results and discussion: The top six compounds that resulted from the screening were ZINC00190959, ZINC07889110, ZINC0088285, ZINC01404326, ZINC00882846 and ZINC08813187, which showed lower free energy of binding (FEB) against the target protein binding pocket. The FEB were as follows: -11.92, -11.85, -11.46, -11.33, -11.21 and -11.1 kcal/mol, using AutoDock, and -11.7, -11.5, -11.2, -11.0, -10.8 and -10.6 kcal/mol for AutoDock Vina, respectively. These findings were superior to those obtained with the co-crystallized ligand VX-680, with a -7.5 kcal/mol and the current clinical trial drug. Finally, using a VS and molecular docking approach, novel Aurora kinase B inhibitors were effectively identified from the ZINC database fulfilling the Lipinski rule of five with low FEB and functional molecular interactions with the target protein. Conclusion: The findings suggest that the six compounds could be used as a potential agent for cancer treatments. Graphical abstract HTML XML PDF
      PubDate: Thu, 15 Dec 2022 17:32:50 +020
  • Study of neuroprotective activity of new acetylcholinesterase
           inhibitors TVA and TVS in experimental model of Alzheimer’s disease

    • Abstract: Research Results in Pharmacology 8(4): 77-88
      DOI : 10.3897/rrpharmacology.8.87431
      Authors : Hrachik V. Gasparyan, Sona A. Buloyan, Hayk A. Harutyunyan, Anahit E. Pogosyan, Lilit M. Arshakyan, Lusine S. Harutyunyan, Zubeida A. Avetisyan, Syuzanna R. Tosunyan, Armen A. Hovhannisyan, Vigen O. Topuzyan : Introduction: Alzheimer’s disease (AD) is a severe neurodegenerative disease characterized by loss of synaptic connection between neurons of the cortex and subcortical regions. The cholinergic deficit is a consistent and early finding in AD, hence acetylcholinesterase inhibitors (AChEIs) are used for symptomatic improvement of AD. Most of these therapeutic agents are hepatotoxic, leading to liver failure and other complications. Therefore, the study of new AChEIs with less toxic impact and better effectivity is a topical challenge. In view of this, we synthesized novel chemical compounds: TVA and TVS that possess AChEI activity and studied their neuroprotective effect in an experimental AD model. Materials and methods: Studies were performed on white rats. Acute toxicity studies were performed by Karber’s method. AD was induced via bilateral intracerebroventricular administration of Aβ 25–35. Histopathological examinations were performed in the hippocampus and the entorhinal cortex. Liver tissue was additionally examined to monitor the hepatotoxicity of these compounds. Results: Studies of the hippocampus showed that compared to control and TVA-treated groups, under the influence of TVS there were few morphological alterations. Experimental groups showed an increase in the glial cell count, compared to the intact animals. In comparison to the AD group, the increase in microglia was not that prominent under the action of the novel compounds. Under the influence of TVA and TVS, the entorhinal cortex was more susceptible to neuronal injury, although TVS protected pyramidal neurons. Also, the group treated with TVA had signs of acute liver damage, while under the influence of TVS there were no signs of liver changes. Discussion: Histopathological examination showed that the neurodegenerative processes in the hippocampus, as well as in the entorhinal cortex, were significantly reduced under the influence of TVS, compared with the control group. At the same time, TVA had no significant effect on the protection of neuronal cells. Also, TVS was less toxic, and there was no sign of hepatotoxicity during the experiments. Conclusion: These studies demonstrated that TVS possesses neuroprotective activity and reduces neuronal damage induced by Aβ. Graphical abstract: HTML XML PDF
      PubDate: Tue, 29 Nov 2022 10:34:20 +020
  • Physicians’ knowledge and preferences in tactics of management and
           rational pharmacotherapy of arterial hypertension in pregnant women
           (PHYGEST study)

    • Abstract: Research Results in Pharmacology 8(4): 57-64
      DOI : 10.3897/rrpharmacology.8.80759
      Authors : Roman A. Bontsevich, Tatiana I. Balamutova, Natalia A. Chukhareva, Oksana V. Tsygankova, Galina A. Batisheva, Alena Paleskava, Olga G. Kompaniets, Galina G. Ketova, Valeriya O. Barysheva, Vera A. Nevzorova, Irina M. Martynenko, Sergey P. Pakhomov : Introduction: The issues of rational antihypertensive therapy in pregnant women are always extremely relevant, since high blood pressure in a pregnant woman is associated with serious risks for a mother and a fetus. The aim of the study: To determine the knowledge and preferences of physicians in the management of pregnant women with arterial hypertension. Materials and methods: A multicenter study was conducted in 2018–2021 using an anonymous questionnaire among 411 doctors from 8 regions of Russia. Results and discussion: The levels of knowledge and preferences of specialists in the issues of diagnosing and formulating a diagnosis of arterial hypertension and preeclampsia in pregnant women, prescribing basic and additional drugs for the treatment and prevention of hypertension were revealed, and the degree of compliance with the current clinical guidelines was assessed. Conclusion: Due to the insufficient level of knowledge of specialists, it is required to pay increased and special attention to this problem, strengthen control over compliance with clinical guidelines, and introduce it into postgraduate recommendations and continuing education programs. HTML XML PDF
      PubDate: Thu, 17 Nov 2022 13:30:03 +020
  • Bisacodyl overcomes morphine-induced constipation by decreasing colonic
           Aquaporin-3 and Aquaporin-4 expression

    • Abstract: Research Results in Pharmacology 8(4): 65-75
      DOI : 10.3897/rrpharmacology.8.82242
      Authors : Mahardian Rahmadi, Chrismawan Ardianto, Ahmad D. Nurhan, Rafiqa A. Chasanah, Dewi I. Krismonika, Arina D. Puspitasari, Budi Suprapti, Santhra Segaran, Chia-Wei Phan, Junaidi Khotib : Introduction: Morphine is an opioid prescribed to treat aches and pains. However, morphine often causes opioid-induced constipation (OIC). Aquaporin (AQP) transporters, especially AQP3 and AQP4, play an essential role in mediating constipation. Bisacodyl is a common laxative used to treat constipation. To date, the effects of bisacodyl on AQP3 and AQP4 expression and the role this interaction plays in constipation are unclear. This study aimed to determine the effects of bisacodyl on AQP3 and AQP4 expression in mice after induction of constipation with morphine. Materials and methods: The laxative effects of bisacodyl on both acute and chronic morphine-induced constipation were determined. Fecal water content, colonic bead expulsion, and colonic mRNA levels for AQP3 and AQP4 mRNA were measured. Results and discussion: The administration of morphine to mice resulted in decreased fecal water content, longer bead expulsion times, and increased AQP3 and AQP4 mRNA levels in the colon. Meanwhile, bisacodyl administration prevented the morphine-induced changes in fecal water content, bead expulsion time, and AQP3 and AQP4 mRNA levels in the colons of mice. Conclusion: This study suggests that bisacodyl may prevent morphine-induced constipation by preventing morphine-induced increases in AQP3 and AQP4 expression in the colon. Graphical abstract: HTML XML PDF
      PubDate: Thu, 17 Nov 2022 13:29:48 +020
  • Evaluation of gastroprotective activity of a chitosan-based gel
           containing dexpanthenol

    • Abstract: Research Results in Pharmacology 8(4): 43-55
      DOI : 10.3897/rrpharmacology.8.84777
      Authors : Anna V. Buzlama, Solaiman Doba : Introduction: Development of new gastroprotectants for treatment of acid-related digestive disorders remains an urgent task of gastroenterology and pharmacology, due to the wide prevalence of this category of diseases, as well as the problem of insufficient efficacy and safety of the existing regimens. The aim of this study is to develop a chitosan-based gel containing dexpanthenol, and experimentally evaluate its gastroprotective activity in preclinical studies. Materials and methods: Preclinical studies were carried out on 4 different models of ulcer formation: NSAID gastropathy, 2 schemes (preventive or curative), ethanol-induced ulcerogenesis, and stress-induced ulcerogenesis. The gel under study containing chitosan and dexpanthenol was used in 3 doses (0.08, 0.16 and 0.24 ml/100 g of body weight). Results and discussion: The chitosan-based gel containing dexpanthenol in models of NSAID gastropathy and stress-induced ulcerogenesis (preventive scheme) has a pronounced gastroprotective effect, exceeding the effect of sucralfate. In NSAID-gastropathy model (curative scheme), chitosan-based gel containing dexpanthenol has a gastroprotective effect exceeding that of omeprazole, and also reduces the manifestations of organotropic toxicity of diclofenac sodium, exhibiting, in addition to the gastroprotective effect, anti-inflammatory, hepatoprotective and hemostatic properties according to laboratory and histological studies. Conclusion: The chitosan-based gel containing dexpanthenol is low toxic and has a pronounced gastroprotective effect in models of NSAID gastropathy (preventive and curative schemes) and stress-induced ulcerogenesis, which makes it promising for the prevention and treatment of ulcer formation in NSAID gastropathy and stress ulcers, in order to reduce the number and area of ulcerative defects, and to reduce the manifestations of organotropic toxicity of NSAIDs. Graphical abstract: HTML XML PDF
      PubDate: Thu, 17 Nov 2022 13:29:34 +020
  • Zinc metabolism in healthy men and in patients with chronic
           bacterial prostatitis

    • Abstract: Research Results in Pharmacology 8(4): 35-41
      DOI : 10.3897/rrpharmacology.8.94845
      Authors : Oleg I. Bratchikov, Pavel A. Dubonos, Igor A. Tyuzikov, Yuliya A. Zhilyaeva : Introduction: Zinc is a vital trace element, which regulates metabolism of a prostate gland. It has been established that a low plasma zinc level in men increases the risk of chronic prostatitis and vice versa, chronic prostatitis is often accompanied by zinc deficiency in the prostate gland. The purpose of this study is to research the features and possible correlations of zinc metabolism disorders at systemic (in blood) and local (in prostatic fluid) levels in healthy men and patients with chronic bacterial prostatitis (CBP). Materials and methods: Ninety patients with CBP (main group) and thirty healthy men (control group) were randomized by age (mean age 38.5±2.9 years) and examined. In addition to standard examinations, the zinc levels in blood serum and prostatic fluid were determined, and the oxidative status of the prostate gland was assessed (the level of reactive oxygen species (ROS), conjugated dienes, malondialdehyde, superoxide dismutase (SOD) activity in the prostatic fluid) according to standard methods. Results and discussion: In patients with CBP, the absolute deficiency of plasma and prostatic zinc was detected 2.89 and 2.5 times more often, respectively, than in healthy men (p < 0.05). At the same time, both the patients with CBP and healthy men had significant correlations between plasma zinc and zinc in prostatic fluid (r = 0.345; n = 37; p = 0.001 and r = 0.156; n = 30; p = 0.001; respectively). A significant positive correlation between the zinc level and the activity of SOD in prostatic fluid was revealed only in the patients with CBP (r = 0.389; n = 90; p = 0.001). Conclusion: Zinc concentration in blood plasma does not objectively reflect zinc metabolism disorders in the prostate gland, and therefore the determination of zinc in prostatic fluid is the most reliable and sensitive method for assessing zink disorders in patients with CBP. HTML XML PDF
      PubDate: Thu, 17 Nov 2022 13:29:18 +020
  • Molecular mechanisms of myocardial damage in the hypertensive rats and
           hypertensive rats with metabolic disorders (diabetes mellitus,

    • Abstract: Research Results in Pharmacology 8(4): 25-33
      DOI : 10.3897/rrpharmacology.8.78534
      Authors : Igor F. Belenichev, Andrii V. Abramov, Andrii Puzyrenko, Nina V. Bukhtiyarova, Nadiia O. Gorchakova, Pavlo G. Bak : Introduction: Despite the success which was achieved in the treatment of arterial hypertension, for optimization of the treatment, it is necessary to study the pathogenesis of primary arterial hypertension and target organ damage on the molecular level. Materials and methods: Our team studied the molecular mechanisms of myocardial damage during arterial hypertension and metabolic disorders. We used the spontaneously hypertensive rats (SHR) as an experimental model, and, additionally, we modeled diabetes mellitus and atherosclerosis in these rats. Results and discussion: Our study obtained evidence of a much higher level of the energy imbalance in the cardiomyocytes and more intensive production of reactive oxygen species in the SHRs with diabetes mellitus and atherosclerosis compared with the healthy animals and the animals with only hypertension. The indicated defections create an environment for further cellular damage – mitochondrial dysfunction, depletion in the thiol-disulfide system, and formation of highly reactive NO products. At the same time, we have noticed a higher activity of the Hsp70 in the hypertensive groups compared with the normotensive animals. The source of these deviations is in the formation of mitochondrial dysfunction of cardiocytes, the cause of which is oxidative modification of the protein structures of mitochondria under conditions of activation of oxidative stress reactions, insufficiency of mPT pores, and impaired mitochondrial chaperone function. The presented data give reason to believe that mitochondrial dysfunction, which develops against the background of deficient HSP70, is an integral aspect of arterial hypertension, contributes to its aggravation, and triggers a cascade of molecular and biochemical mechanisms of myocardial damage. These mechanisms include disturbances in the L-arginine-NO-synthase-NO system, production of mitochondrial iNOS oxygen radicals, neutralization of the vasorelaxant effect of NO and its transformation into an active participant in nitrous stress due to reduced intermediates of the thiol-disulfide system. The question of cause-and-effect relationships of oxidative stress remains open for discussion. Conclusion: We envisage that studies in this direction may lead to a better insight into a pathogenetic therapy of essential hypertension, diabetes mellitus, and atherosclerosis. Graphical abstract: HTML XML PDF
      PubDate: Wed, 5 Oct 2022 18:22:37 +0300
  • Ribosome biogenesis and ribosome therapy in cancer cells

    • Abstract: Research Results in Pharmacology 8(4): 15-24
      DOI : 10.3897/rrpharmacology.8.81706
      Authors : Gazmend Temaj, Rifat Hadziselimovic, Hilada Nefic, Nexhibe Nuhii : Introduction: The process of protein synthesis is a vital process for all kingdoms of life. The ribosome is a ribonucleoprotein complex that reads the genetic code, from messenger RNA (mRNA) to produce proteins and to tightly regulate and ensure cells growth. The fact that numerous diseases are caused by defect during the ribosome biogenesis is important to understand this pathway. Materials and methods: We have analyzed the literature for ribosome biogenesis and its links with different diseases which have been found. Results and discussion: We have discussed the key aspect of human ribosome biogenesis and its links to diseases. We have also proposed the potential of applying this knowledge to the development of a ribosomal stress-based cancer therapy. Conclusion: Major challenges in the future will be to determine factors which play a pivotal role during ribosome biogenesis. Therefore, more anti-cancer drugs and gene therapy for genetic diseases will be developed against ribosomal biogenesis in the coming years. Graphical abstract: HTML XML PDF
      PubDate: Wed, 5 Oct 2022 18:22:22 +0300
  • Pharmacological correction of the sequelae of acute alcohol-induced
           myocardial damage with new derivatives of neuroactive amino acids coupled
           with the blockade of the neuronal NO synthase isoform

    • Abstract: Research Results in Pharmacology 8(4): 1-13
      DOI : 10.3897/rrpharmacology.8.90241
      Authors : Margarita V. Kustova, Valentina N. Perfilova, Igor I. Prokofiev, Elena A. Musyko, Aida S. Kucheryavenko, Elena E. Kusnetsova, Diana E. Tsetsera, Ivan N. Tyurenkov : Introduction: Acute alcohol intoxication (AAI) induces a number of myocardial disorders, which result in mitochondrial dysfunction in cardiomyocytes, oxidative stress, and decreased cardiac contractility. Nitric oxide produced by the nNOS is one of the major modulators of cardiac activity. New derivatives of GABA (RSPU-260 compound) and glutamate (glufimet) can be potentially regarded as such agents as the interaction between the NO system and the GABA and glutamatergic systems has been proved. Materials and methods: All the studies were performed on female white Wistar rats, aged 10 months, whose weight was 280–320g AAI intoxication was modeled of 32% ethanol (gavage, 4g/kg). Results and discussion: Glufimet and the RSPU-260 compound caused a significant improvement in myocardial contractility, increased oxygen consumption in the V3 state according to Chance, raised the respiratory control ratio and decreased the intensity of LPO intensity. Their effectiveness exceeded that of mildronate, their comparator. nNOS inhibition resulted in a pronounced aggravation of oxidative stress implicated in MDA accumulation in cardiac mitochondria and decreased activity of SOD; myocardial contractility and mitochondrial function indicators did not show a significant difference from the control group. The compounds under study coupled with nNOS inhibition had a cardioprotective effect. Conclusion: Glufimet and the RSPU-260 compound, derivatives of neuroactive amino acids, have a pronounced cardioprotective effect, restrict LPO processes, enhance SOD activity, improve the mitochondrial respiratory function after acute alcohol intoxication when coupled with neuronal NO-synthase inhibition, the expression of which persists after AAI. Graphical abstract: HTML XML PDF
      PubDate: Wed, 5 Oct 2022 18:21:47 +0300
  • CRISPR/Cas-edited pigs for personalized medicine: more than
           preclinical test-system

    • Abstract: Research Results in Pharmacology 8(3): 87-98
      DOI : 10.3897/rrpharmacology.8.83872
      Authors : Elena I. Leonova, Vasily V. Reshetnikov, Julia V. Sopova : Novel CRISPR-Cas-based genome editing tools made it feasible to introduce a variety of precise genomic modifications in the pig genome, including introducing multiple edits simultaneously, inserting long DNA sequences into specifically targeted loci, and performing nucleotide transitions and transversions. Pigs serve as a vital agricultural resource and animal model in biomedical studies, given their advantages over the other models. Pigs share high similarities to humans regarding body/organ size, anatomy, physiology, and a metabolic profile. The pig genome can be modified to carry the same genetic mutations found in humans to replicate inherited diseases to provide preclinical trials of drugs. Moreover, CRISPR-based modification of pigs antigen profile makes it possible to offer porcine organs for xenotransplantation with minimal transplant rejection responses. This review summarizes recent advances in endonuclease-mediated genome editing tools and research progress of genome-edited pigs as personalized test-systems for preclinical trials and as donors of organs with human-fit antigen profile. Graphical abstract: HTML XML PDF
      PubDate: Tue, 13 Sep 2022 17:41:38 +030
  • Antitumor activity of the novel pyridine derivative

    • Abstract: Research Results in Pharmacology 8(3): 81-86
      DOI : 10.3897/rrpharmacology.8.89997
      Authors : Ekaterina V. Blinova, Anna V. Epishkina, Oksana M. Tumutolova, Olga N. Deryabina, Sofia Ya. Skachilova, Mihail Yu. Kudriavtsev, Evgenia V. Shikh, Olga S. Vavilova, Yulia S. Gilevskaya, Gordey V. Brykin, Anna A. Makhrova, Dmitry S. Blinov : Introduction: The study aim was to explore a toxicological property and antitumor action of the novel pyridine derivative LHT-17-19 in cell culture and on experimental models of lung cancer in mice. Materials and methods: The study was performed on male and female ICR(CD-1), male BALB/c, male BALB/c nu/nu mice. Pyridine derivative (LHT-17-19) was studied as water-soluble pharmaceutical substance. Acute toxicity was evaluated in groups of 5 animals, and the results were analyzed by Finney. Antitumor and antimetastatic activity was studied in syngeneic and xenograft models of lung cancer in mice. Results and discussion: LHT-17-19 belongs to class 3 of the toxicity classification of chemicals in accordance with GOST 12.1.007–76. The substance demonstrated an antitumor and antimetastatic property in mice with syngeneic tumor Lewis lung carcinoma as well as on the heterotopic tumor model of non-small cell lung cancer in humanized animals. Conclusion: LHT-17-19 belongs to class 3 of the toxicity classification of chemicals in accordance with WHO recommendation. LHT-17-19 exerts antitumor and antimetastatic property on both syngeneic and patient-derived lung cancer xenograft murine models. Graphical abstract HTML XML PDF
      PubDate: Tue, 13 Sep 2022 17:41:00 +030
  • Acute poisoning in children: Etiology, structure, treatment
           tactics and outcomes

    • Abstract: Research Results in Pharmacology 8(3): 71-79
      DOI : 10.3897/rrpharmacology.8.85058
      Authors : Ekaterina S. Karpushkina, Olga A. Zhdanova, Galina A. Batishcheva : Introduction: Acute poisoning is often observed in children and can have serious consequences since it is characterized by rapid development of symptoms and obvious disfunction of vital organs. Materials and methods: Retrospective analysis of the case histories of the children with acute poisoning admitted to Voronezh Regional Children’s Clinical Hospital No. 1 in 2016–2019 was carried out. Anamnesis, clinical and laboratory studies and effective treatment criteria were entered into electronic spreadsheets and served as the basis for a database on children’s poisoning. Results and discussion: Analysis of 183 case histories of children with intoxication aged 4 months to 17 years old was performed. Distribution per age showed bimodal peaks at 1–2 years and 13–14 years. Poisoning was accidental in 96.2% of the cases, and 3.8% of the adolescents reported suicide cases. In the group of young children, acute drug poisoning is more frequent in girls (P < 0.05). In the older groups, there is no gender difference in frequency of poisoning cases. Early call for medical help is typical for the adolescent age group. Correlation between time of help-seeking and children’s age is statistically significant (correlation coefficient r = 0.38, P < 0.05). Conclusion: Study of poisoning issue in children will allow to carry out targeted preventive measures to reduce the number of poisoning cases, prevent their consequences and to determine the most rational modus operandi for medical personnel for effective and safe pharmacotherapy. Graphical abstract In pediatric practice, intoxication by poisons and drugs is among the most common reasons for seeking medical help and hospitalization in intensive care units. It is important to study and record dynamics, structure and frequency of acute poisoning with subsequent development of prevention and treatment methods. HTML XML PDF
      PubDate: Tue, 13 Sep 2022 17:40:23 +030
  • Efficiency evaluation of Amlodipine combined with N-acetylcysteine on
           Indomethacin-induced gastritis in rats

    • Abstract: Research Results in Pharmacology 8(3): 63-69
      DOI : 10.3897/rrpharmacology.8.81003
      Authors : Yara Annouf, Shaza Al laham, Eyad Chatty : Introduction: It is a well-known phenomenon that nonsteroidal anti-inflammatory drugs cause gastric mucosal damage. Amlodipine is a third generation dihydropyridine-type calcium channel blocker; it can inhibit inflammatory cytokines and enhance antioxidant defenses. N-acetylcysteine can act both as a precursor of reduced glutathione and as a direct ROS scavenger. Moreover, N-acetylcysteine has been purported to have anti-inflammatory properties. Materials and methods: 34 albino Wistar rats were used. The model of gastritis was induced by subcutaneous Indomethacin prepared in 5% sodium bicarbonate administered at a dose rate of 9 mg/kg for two days at 24h intervals. N-acetylcysteine (500 mg/kg), Amlodipine (10 mg/kg) and N-acetylcysteine (500 mg/kg) combined with Amlodipine (5 mg/kg) were administrated for seven consecutive days beginning 24 h after the first Indomethacin injection. Rats were sacrificed under ether anesthesia on the 8th day. The stomach injury was assessed by macroscopic damage and histological study. Results and discussion: The results showed that macroscopic stomach damage scores caused by administration of Indomethacin did not significantly decrease by administration of N-acetylcysteine alone (p>0.05), but it decreased significantly by administration of Amlodipine alone or by its combination with N-acetylcysteine (p0.05), but they decreased significantly by administering the combination of Amlodipine with N-acetylcysteine (p
      PubDate: Thu, 25 Aug 2022 11:39:50 +030
  • Harmine and 7,8-dihydroxyflavone synergistically suitable for
           amyotrophic lateral sclerosis management: An in silico study

    • Abstract: Research Results in Pharmacology 8(3): 49-61
      DOI : 10.3897/rrpharmacology.8.83332
      Authors : Toluwase Fatoki, Stanley Chukwuejim, Omodele Ibraheem, Christiana Oke, Blessing Ejimadu, Isaiah Olaoye, Oluwabukola Oyegbenro, Taiwo Salami, Romilola Basorun, Oluwafisayomi Oluwadare, Yetunde Salawudeen : Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease characterized by progressive degeneration of both upper and lower motor neurons, resulting in paralysis and eventually leads to death from respiratory failure typically within 3 to 5 years of symptom onset. The aim of this work was to predict the pharmacokinetics and identify unique protein targets that are associated with potential anti-ALS phytochemicals and FDA-approved drugs, by in silico approaches. Materials and methods: Standard computational tools (webserver and software) were used, and the methods used are clustering analysis, pharmacokinetics and molecular target predictions, and molecular docking simulation. Results and discussion: The results show that riluzole, β-asarone, cryptotanshinone, harmine and 7,8-dihydroxyflavone have similar pharmacokinetics properties. Riluzole and harmine show 95% probability of target on norepinephrine transporter. Huperzine-A and cryptotanshinone show 100% probability of target on acetylcholinesterase. 7,8-dihydroxyflavone shows 35% probability of target on several carbonic anhydrases, 40% probability of target on CYP19A1, and 100% probability of target on inhibitor of nuclear factor kappa B kinase beta subunit and neurotrophic tyrosine kinase receptor type 2, respectively. Harmine also shows 95% probability of target on dual specificity tyrosine-phosphorylation-regulated kinases, threonine-protein kinases (haspin and PIM3), adrenergic receptors, cyclin-dependent kinases (CDK5 and CDK9), monoamine oxidase A, casein kinase I delta, serotonin receptors, dual specificity protein kinases (CLK1, CLK2, and CLK4), and nischarin, respectively. Also, the results of gene expression network show possible involvement of CDK1, CDK2, CDK4, ERK1, ERK2 and MAPK14 signaling pathways. This study shows that riluzole and harmine have closely similar physicochemical and pharmacokinetics properties as well as molecular targets, such as norepinephrine transporter (SLC6A2). Harmine, huperzine-A and cryptotanshinone could modulate acetylcholinesterase (AChE), which is involved in ALS-pathogenesis. The impact of 7,8-dihydroxyflavone on several carbonic anhydrases (CA) I, II, VII, IX, XII, and XIV, as well as CYP19A1, could help in remediating the respiratory failure associated with ALS. Conclusion: Overall, harmine is found to be superior to riluzole, and the combination of harmine with 7,8-dihydroxyflavone can provide more effective treatment for ALS than the current regime. Further work is needed to validate the predicted therapeutic targets of harmine identified in this study on ALS model or clinical trials, using in silico, in vitro and in vivo techniques. Graphical abstract: HTML XML PDF
      PubDate: Thu, 25 Aug 2022 11:39:18 +030
  • Search for compounds with antioxidant and antiradical activity among
           N9-substituted 2-(biphenyl-4-yl)imidazo[1,2-a]benzimidazoles

    • Abstract: Research Results in Pharmacology 8(3): 41-48
      DOI : 10.3897/rrpharmacology.8.85498
      Authors : Alexander A. Spasov, Anastasia A. Brigadirova, Olga N. Zhukovskaya, Anatoly S. Morkovnik, Yuliya V. Lifanova : Introduction: Biphenyl and imidazobenzimidazole derivatives attract ongoing attention as a combination of these two privileged substructures with promising pharmacological activities. The aim of this study was to synthesize and investigate in vitro antioxidant activity of promising novel compounds: 2-(biphenyl-4-yl)imidazo[1,2-a]benzimidazoles. Materials and methods: The newly synthesized compounds were characterized by IR, 1H NMR and CHBr(Cl)NO analyses. All newly synthesized compounds were screened for their in vitro antioxidant activity: inhibition of lipid peroxidation (LPO), 2,2’-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS•+) radical cation decolorization and inhibition of hemoglobin (Hb)-H2O2-induced luminol chemiluminescence. Results and discussion: 2-Amino-3-[(2-biphenyl-4-yl)-2-oxo-ethyl)]-1-R-1Н-benzimidazolium bromides were synthesized, and their cyclization into functionalized imidazo[1,2-a]benzimidazole derivatives was studied. The resulting compounds showed LPO inhibitory activity comparable to that of dibunol. Compounds 1a and 1d (see graphical abstract), containing a methyl or dimethylaminoethyl substituent in the N9 position also proved to be equally highly active in the Hb-H2O2-induced luminol chemiluminescence model, while compound 1a was somewhat more active than 1d in the ABTS• radical scavenging assay. Conclusion: The study showed that compounds 1a and 1d have the highest antioxidant activity. Thus, this new class of 2-(biphenyl-4-yl)imidazo[1,2-a]benzimidazole derivatives represents a valuable leading series with great potential for use as antioxidants and as promising candidates for further efficacy evaluation. Graphical abstract: HTML XML PDF
      PubDate: Thu, 18 Aug 2022 09:41:38 +030
  • Effects of fumarate on renal vascular reactivity and the modulation of
           blood pressure in normotensive rats: Possible contribution of the nitric
           oxide synthase-nitric oxide system

    • Abstract: Research Results in Pharmacology 8(3): 31-40
      DOI : 10.3897/rrpharmacology.8.79765
      Authors : Osaze Edosuyi, Myung Choi, Ighodaro Igbe, Adebayo Oyekan : Introduction: Fumarate, the tricarboxylic acid (TCA) cycle intermediary, has been linked to nitric oxide (NO) production. NO plays a prominent role in the physiological regulation of blood pressure and renal hemodynamics. This study is aimed to investigate any contribution of fumarate to blood pressure and renal hemodynamics in normotensive rats with a possible link to the nitrergic system. Materials and methods: Fumarate (1, 3 and 10 µmol) was injected into isolated perfused kidneys, pre-constricted with epinephrine (30 µM). The fumarase inhibitor, pyromellitic acid (PMA) (1, 3 and 10 µM), was used to perfuse the isolated kidney and perfusate was collected for nitric oxide and fumarate assays. An acute blood pressure study involved the injection of bolus doses of fumarate (0.1, 0.3 and 1 µg/kg, iv) or PMA (1, 3 and 10 µg/kg, iv) to normotensive rats in the presence of N(ω)-nitro-L-arginine methyl ester (L-NAME) (10 mg/kg, iv) or PMA (1, 3 and 10 µg/kg). Results and discussion: Fumarate reduced perfusion pressure and elicited a peak reduction at the highest dose. Perfusing the kidney with PMA caused a paradoxical increase in perfusion pressure (70%, p
      PubDate: Thu, 18 Aug 2022 09:41:18 +030
  • Transient receptor potential Ankyrin 1: structure, function and

    • Abstract: Research Results in Pharmacology 8(3): 19-29
      DOI : 10.3897/rrpharmacology.8.90214
      Authors : Natalia V. Pyatigorskaya, Olga V. Filippova, Natalia S. Nikolenko, Aleksey D. Kravchenko : Introduction: Transient receptor potential ankyrin 1 (TRPA1) is a protein expressed in many living organisms. During the study of TRPA1, its unique biological role as a universal and polymodal sensor of various altering agents was found. The aim of this study is to search and generalize information about structural features and molecular determinants, mechanisms of activation, action and modulation of TRPA1 as a universal pain and inflammation sensor, as well as the nature of activators and antagonists of this target and their therapeutic potential. Materials and methods: This article presents an overview of the results of scientific research of TRPA1, its modulators, as well as an overview of their pharmacological potential over the period from the discovery of these channels to the present, with an emphasis on the last decade. Results and discussion: The main collected data on expression, structural features and molecular determinants, mechanisms of activation and action of TRPA1 indicate its role as a universal and labile element of the primary response of the body to adverse exogenous and endogenous factors. Regardless of the nature of the stimulus, hyperstimulation of TRPA1 channels can lead to such phenomena as pain, inflammation, itching, edema and other manifestations of alteration, and therefore TRPA1 blockade can be used in the treatment of various diseases accompanied by these pathological conditions. Currently, TRPA1 antagonists are being actively searched for and studied, as evidenced by a high patent activity over the past 14 years; however, the molecular mechanisms of action and pharmacological properties of TRPA1 blockers remain understudied. Conclusion: Acquire of new information about TRPA1 will help in the development of its modulators, which can become promising analgesics, anti-inflammatory drugs, bronchodilators, and agents for the treatment of cardiovascular diseases of new generations. HTML XML PDF
      PubDate: Wed, 20 Jul 2022 13:55:17 +030
  • Clinical and histopathological effects of ointment prepared from
           kombucha floating cellulose layer on wound healing and the activity of
           matrix metalloproteinase 1 in diabetic rats

    • Abstract: Research Results in Pharmacology 8(3): 9-18
      DOI : 10.3897/rrpharmacology.8.81288
      Authors : Soheila Rajaei, Monir Doudi, Mahbubeh Setorki, Ali Mohammad Ahadi : Introduction: High blood glucose results in high levels of matrix metalloproteinases. Clinical and histopathological effects of the kombucha ointment on the healing of diabetic wounds were evaluated. Materials and methods: This study was conducted at research Lab, Department of Micobiology, Falavarjan of Branch Islamic Azad University, Isfahan, Iran from October 2019 to September 2020. A 6 mm diameter ulcer was aseptically created on the back of forty-eight rats with streptozotocin-induced diabetes. The animals were randomly divided into 4 groups: the group that was treated with base ointment, the group that was treated with 10% kombucha ointment, the group that was treated with 20% kombucha ointment, and the group that received no ointment treatment. Then the rats in each group were divided to 4 sampling groups that were sampled on the second, fifth, tenth, and fourteenth days. Microscopic features, inflammation and vasculature and fibroblast infiltration, as well as the matrix metalloproteinase 1(MMP1) were evaluated on days 2, 5, 10, 14 after wound healing. Results: 20% kombucha ointment let to inflammation and an angiogenesis decrease compared to those in the basic group and 10%-kombucha-ointment group. Also 20% kombucha ointment led to an increase in vascular remodeling and penetration of fibroblasts. MMP1 levels increased on the second (p < 0.001) and fifth days after wounding when treatrd with 10% and 20% kombucha ointment (p > 0.05). The expression of MMP1 decreased on the ten and fourteenth days when using 20% kombucha ointment compared to the control, placebo, and 10% kombucha ointment groups (p > 0.05). Discussion: The histopatological finding indicated that both quantity and time duration of the treatment had significant effects on a degree of inflammation and angiogenesis. Сonclusion: Ointment prepared from 20% scoby improved the healing of diabetic ulcers within 14 days. HTML XML PDF
      PubDate: Tue, 12 Jul 2022 23:25:45 +030
  • Study of the effect of acetylsalicylic acid and a selective arginase II
           inhibitor KUD 975 on the correction of hemostatic disorders in
           experimental preeclampsia

    • Abstract: Research Results in Pharmacology 8(3): 1-8
      DOI : 10.3897/rrpharmacology.8.87539
      Authors : Anastasia V. Gureeva, Olga V. Severinova, Vladimir V. Gureev, Indira S. Kochkarova, Elena V. Avdeyeva : Introduction: The disruption of the functional state of the vascular endothelium is among the main causes of preeclampsia, which is one of the most common causes of maternal and perinatal mortality. It can be enhanced by the humoral factors secreted by the activated platelets. The use of acetylsalicylic acid is an effective way to prevent preeclampsia. However, its ability to activate eNOS is a prerequisite for researching its ability to correct the disorders in developing preeclampsia, including by reducing the platelet activity. In this case its effect can be enhanced through increasing the bioavailability of L-arginine by using a selective arginase II inhibitor KUD 975. These facts were the prerequisite for conducting this study. Materials and methods: The study was conducted on 180 female Wistar rats weighing 250–300 g. Acetylsalicylic acid was used at a dose of 7 mg/kg/day and 10 mg/kg/day, KUD 975 – at a dose of 1 mg/kg/day and 3 mg/kg/day. Adenosine diphosphate (ADP, 6.5 microns), arachidonic acid (ASPI, 0.5 mM), and collagen (3.2 mcg/ml) were used as aggregation inducers. Results and discussion: ADMA-like preeclampsia simulation led to an increase in platelet aggregation ability when using all aggregation inducers. This is evidenced by an increase in a degree, rate of aggregation, and a shortened time of thrombus formation. The use of acetylsalicylic acid and a selective arginase II inhibitor KUD 975 led to a decrease in the aggregation ability of platelets and an increase in thrombosis time, while the combined administration of the studied agents showed a more pronounced effect. Conclusion: The data obtained while performing a series of experiments strongly indicate a promising outlook for using acetylsalicylic acid and a selective arginase II inhibitor KUD 975 in order to correct emerging disorders in preeclampsia. HTML XML PDF
      PubDate: Tue, 12 Jul 2022 13:27:54 +030
  • Involvement of monoaminergic system in the antidepressant effect of
           3-substituted thietane-1,1-dioxide derivative

    • Abstract: Research Results in Pharmacology 8(2): 87-94
      DOI : 10.3897/rrpharmacology.8.81007
      Authors : Irina L. Nikitina, Gulnara G. Gaisina : Introduction: The aim of the study was to assess the involvement of the monoaminergic system in the antidepressant effect of a new 3-substituted thietane-1,1-dioxide derivative (N-199/1) using tests with several pharmacological antagonists and agonists. Materials and methods: We conducted 3 sets of experiments in white outbred male mice. In Experiment 1, we assessed the antidepressant effect of N-199/1 in the forced swimming test (FST) and tail suspension test (TST) when administered repeatedly for 2 weeks intraperitoneally (i.p.). In Experiment 2, we evaluated the antidepressant effect of N-199/1 in FST and TST when co-administered with 5HT1A- (WAY100635, 0.1 mg/kg), 5HT2A/2C- (ketanserin, 5 mg/kg), 5HT3- (ondansetron, 1 mg/kg) serotonergic and α2-adrenergic (yohimbine, 1 mg/kg) receptors antagonists. In Experiment 3, we assessed the effect of N-199/1 on the hypothermia induced by i.p. injection of α2-adrenergic receptors agonist clonidine (0.3 mg/kg). Results and discussion: N-199/1 reduced immobility time (IT) and index of depression (ID) in FST, and did not affect IT in TST, either when administered repeatedly in Experiment 1, or acutely in Experiment 2. In Experiment 2, ketanserin enhanced the effect of N-199/1, decreasing ID by 36%, while WAY100635 and yohimbine antagonized it, increasing ID by 27% and IT by 115%, respectively, in comparison with N-199/1. N-199/1 attenuated the effect of ondansetron, increasing IT by 36%. In Experiment, 3 N-199/1 reduced clonidine-induced hypothermia 1 h after the injection of clonidine. N-199/1 exhibited pronounced antidepressant properties in FST, an agonism to 5HT1A-receptors and an antagonism to 5HT2A/2C- and α2-receptors in tests of neuropharmacological interaction, which indicates an atypical mechanism of its antidepressant action. Conclusion: The antidepressant effect of N-199/1 is due to the stimulation of 5HT1A-receptors and blockade of 5HT2A/2C- and α2-receptors. Graphical abstract: HTML XML PDF
      PubDate: Thu, 30 Jun 2022 23:34:07 +030
  • Combined anti-mediator therapy for severe destructive forms of acute
           necrotizing pancreatitis in rats

    • Abstract: Research Results in Pharmacology 8(2): 95-110
      DOI : 10.3897/rrpharmacology.8.79939
      Authors : Tatiana I. Firsova, Sergey A. Alekhin, Dmitry P. Nazarenko, Lyudmila M. Danilenko, Antonina G. Chub, Elena S. Malyutina, Tatyana Yu. Lazareva, Leontiy V. Druzhikin : Introduction: Inflammatory mediators play a major role in pathogenesis of acute pancreatitis with TNF (tumor necrosis factor) as the most important one. Development of effective combined therapy could help to decrease tissue damage, improve results and, finally, diminish the mortality rate in this severe pathology. Materials and methods: All the studies were performed on 120 female white Wistar rats, weighing 250±25g. Acute pancreatitis reproduced by an intracanalicular injection of bile salts compound. Results and discussion: The data obtained in the course of the study on the pronounced pancreatoprotective effect of infliximab are explained by its key role in the onset of the systemic inflammatory response, and, therefore, with the blockade of tumor necrosis factor alpha in the early stages, there is no pronounced secondary damage to the pancreas, which is reflected in a significant decrease in edema from 4.87±0.03 in the model up to 2.75±0.04, and as a consequence, an improvement in the blood supply of the acinar tissue from 182.38±15.92 PU up to 287.92±14.64 PU, which is expressed in a decrease in the zones of necrosis and in a decrease in mortality and, finally, efficiency coefficient from 13480.000 to 4283.348. A selective blocker of cysteinyl leukotrienes has a less pronounced protective reaction against damage to pancreatocytes, but to a much greater extent than octreotide. That is expressed by changes in the efficiency coefficient to the level of 8621.18 in montelukast group and 12767.30 in octreotide group, respectively. On the other hand, the effect of the use of infliximab does not surpass that of montelukast, and their combined use has a pronounced additive effect, which is proved by the efficiency coefficient at the level of 2390.33. This reaction is explained by the fact that TNF alpha-mediated pathway of activation of leukotriene biosynthesis is the main, but not the only one. Conclusion: The combined anti-mediator therapy provides a great opportunity to improve the standard therapy of acute pancreatitis. HTML XML PDF
      PubDate: Thu, 30 Jun 2022 14:02:56 +030
  • Current view on the problem of treating fibrocystic breast disease in
           terms of herbal medicine

    • Abstract: Research Results in Pharmacology 8(2): 77-85
      DOI : 10.3897/rrpharmacology.8.79286
      Authors : Olena P. Sokolik, Galina O. Prozorova : Introduction: Fibrocystic breast disease, commonly called fibrocystic breasts or fibrocystic change, is a benign (noncancerous) condition, which is the most common pathology in women of reproductive age. Treatment of fibrocystic breast disease and concomitant pathologies can involve using herbs. Materials and Methods: To make an analysis of literary sources on the development of fibrocystic breast disease in the pathogenesis of diseases of the female reproductive system (clinical human (75%) and animal studies (25%)) were published in the period of 2017–2021. Results and discussion: The diversity of plants in the world is a promising ground for therapeutic improvisation, allowing for an individual approach to each patient, but, most importantly, creates possibilities for maneuvering in the event of ineffectiveness of any means. In some situations, herbal medicine is not only possible or permissible, but strictly mandatory, and is essentially the only effective therapeutic method, which is relatively safe provided the correct selection of combinations and control by a doctor who applies a certain method of phytotherapy, especially given a duration of treatment. The need for a deeper study is long overdue for the pharmacological capabilities of various plant raw materials in the treatment of not only this pathology, but others as well. Conclusion: The development of phytotherapy should be based primarily on scientific developments, but this area can not be considered the prerogative of only phytotherapists, as herbal medicines should be in the arsenal of doctors of all specialties. HTML XML PDF
      PubDate: Wed, 22 Jun 2022 16:57:11 +030
  • Searching for novel antagonists of adenosine A1 receptors among
           azolo[1,5-a]pyrimidine nitro derivatives

    • Abstract: Research Results in Pharmacology 8(2): 69-75
      DOI : 10.3897/rrpharmacology.8.77854
      Authors : Dmitry S. Yakovlev, Pavel M. Vassiliev, Yana V. Agatsarskaya, Anastasia A. Brigadirova, Kira T. Sultanova, Maria O. Skripka, Alexander A. Spasov, Konstantin V. Savateev, Vladimir L. Rusinov, Dmitriy V. Maltsev : Introduction: Ligands of adenosine A1Rs are potential candidates for the development of drugs for the treatment of paroxysmal supraventricular tachycardia, angina pectoris, hypertriglyceridemia, type 2 diabetes mellitus, neuropathic pain, and heart failure. At the same time, there is a deficiency of drugs that can regulate the functions of A1 receptors. A number of A1-antagonists are at the various stages of clinical trials; other drugs are not very selective or are characterized by an insufficient breadth of their therapeutic action. Therefore, the search for new medicinal compounds for the prevention and treatment of A1-depended diseases among nitro derivatives of tetrazolo[1,5-a]pyrimidine and 1,2,4-triazolo[1,5-a]pyrimidine is of scientific interest. Materials and methods: The search for active compounds was carried out by in silico and in vitro methods. At the first stage, a computer forecast of A1-antagonistic activity was carried out using the Microcosm BioS software. At the second stage, the prediction results were verified in vitro in a model of isolated mouse atria. Results and discussion: Based on the results of the prediction by the method of maximum similarity to standards, the most active compounds III, VIII, and XVII were selected. After testing the prediction results by the isolated atria method, the compound VIII was characterized by A1-blocking effect in vitro at a concentration of 10 μmol/L. Conclusion: The most promising compound with A1-blocking effect in vitro was identified; it is a derivative of tetrazolo[1,5-a]pyrimidine under the code of VIII. It is of interest for us for further in-depth study of its pharmacological properties. HTML XML PDF
      PubDate: Wed, 15 Jun 2022 12:56:28 +030
  • Neuroprotective effects of a 40% ethanol extract of the black
           walnut bark (Juglans nigra L.)

    • Abstract: Research Results in Pharmacology 8(2): 59-68
      DOI : 10.3897/rrpharmacology.8.77172
      Authors : Dmitry I. Pozdnyakov, Zhanna V. Dayronas, Denis S. Zolotych, Anastasya D. Geraschenko, Natalya B. Shabanova : Introduction: Neuroprotection is a promising area of adjuvant therapy of ischemic brain lesions. At the same time, among potentially effective neuroprotectors, herbal remedies are distinguished due to their high efficiency and safety of use. In this work, some aspects of the neuroprotective effect of 40% ethanol extract of black walnut bark were investigated in comparison with its major component juglone. Materials and methods: The work was performed on male Wistar rats, which were simulated with cerebral ischemia by irreversible occlusion of the middle cerebral artery. The acute toxicity of the extract was preliminarily evaluated. During the work, the following parameters were determined: changes in the behavior of animals in the Morris water maze, cerebral blood flow, brain necrosis zone area, the activity of mitochondrial complexes, citrate synthase activity, lactic, pyruvic, and ATP concentrations. The activity of the studied extract was compared with juglone in a concentration of 1 mg/kg (per os). Discussion: The study showed that the use of black walnut bark extract in conditions of cerebral ischemia contributed to an increase in the activity of mitochondrial complexes I-V, citrate synthase, which in turn led to the normalization of aerobic-anaerobic metabolism reactions. The increase in the activity of respiratory complexes is probably mediated by the antioxidant properties of juglone, which is a major component of the test extract of black walnut bark. Conclusion: Thus, the test extract can be a potentially effective neuroprotective agent and requires further study. HTML XML PDF
      PubDate: Tue, 14 Jun 2022 17:49:27 +030
  • Antiproliferative activity of a new derivative from the class of
           N-glycoside of indolo[2,3-a]pyrrolo[3,4-c]carbazoles

    • Abstract: Research Results in Pharmacology 8(2): 49-57
      DOI : 10.3897/rrpharmacology.8.79424
      Authors : Marina P. Kiseleva, Larisa M. Borisova, Galina B. Smirnova, Yulia A. Borisova, Anna V. Lantsova, Ekaterina V. Sanarova, Lyudmila L. Nikolaeva, Lydia V. Ektova, Marina V. Komarova : Introduction: The creation of highly effective original anticancer drugs remains an urgent direction of scientific research in tumor therapy. One of the promising groups in this regard is indolocarbazoles and their derivatives, which are capable of initiating various pathways of tumor cell death. The aim of the study was to evaluate an antiproliferative activity of a new, Russian derivative of N-glycoside substituted indolocarbazole 6-amino-12-(α-L-arabinopyranosyl)indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione (LCS-1208) on models of transplantable tumors of mice and on human tumors in Balb/c nude mice. Materials and methods: Indolocarbazole sensitivity to LCS-1208 was assessed on transplantable tumors of mice – lymphatic leukemia L-1210, cervical carcinoma (CC-5), and colon adenocarcinoma (CAC) by five-fold intraperitoneal administration (ip) of the LCS-1208 substance in single doses of 50, 75, 100 mg/kg. Investigation into the effectiveness of the LCS-1208 lyo dosage form was performed on subcutaneous xenografts of human colon cancer SW620 by an intravenous administration (iv). The antitumor effect was evaluated by the tumor growth inhibition (TGI) and an increase in life span (ILS) of the treated animals as compared with the control ones. Evaluation of specific antitumor activity on xenografts was performed according to the tumor/control (T/C%) criterion (maximum criterion T/C≤42%). Results and discussion: According to the results of the study, the most sensitive to the action of the LCS-1208 substance in the case of an ip administration of a total dose of 375 mg/kg were CAC with TGI=97–62%, p≤0.001 up to 16 days after the treatment, and ILS=36% (criteria for TGI≥70% and ILS≥25%). On xenografts of a human colon cancer SW620, the effectiveness of the LCS-1208 lyo drug dosage form within the range of total doses from 50 to 150 mg/kg in case of iv to Balb/c nude mice was set at T/C = 35–2% (criterion T/C
      PubDate: Tue, 14 Jun 2022 17:49:11 +030
  • Evaluation of methods of modeling and formation of experimental
           allergic encephalomyelitis

    • Abstract: Research Results in Pharmacology 8(2): 37-48
      DOI : 10.3897/rrpharmacology.8.77361
      Authors : Oleksandr O. Nefodov, Igor F. Belenichev, Mykola P. Fedchenko, Olena O. Popazova, Victor P. Ryzhenko, Oksana V. Morozova : Introduction: Experimental autoimmune (allergic) encephalomyelitis (EAE) induced by intradermal injection of homogenate of the brain, spinal cord and peripheral nerve with Freund’s stimulator, refers to a true autoimmune disease of the nervous system. Materials and methods: Experimental studies were conducted on white nonlinear rats. To induce experimental allergic encephalomyelitis (EAE), homologous brain homogenates was used, which leads among other drugs (homologous, heterogeneous brain and spinal cord homogenates) by encephalitogenity. The connective tissue of the animal’s tail base was injected with a mixture of encephalitogenic suspension of 0.1 ml per 100 g of the body weight. Results and discussion: According to the results, in the rats, there was weight loss, and the abnormal neurological symptoms were found on an average of 10–12th days. Our experimental studies on the formation of EAE were confirmed morphologically by electron microscopy. Conclusion: Thus, the use of this technique allowed us to obtain a simulated pathologic condition of multiple sclerosis in the form of experimental allergic encephalomyelitis and can be used in future studies to identify appropriate laws, the extent and nature of changes in the immune and nervous systems of the body when inducing experimental pathological conditions. HTML XML PDF
      PubDate: Tue, 14 Jun 2022 17:48:59 +030
  • Remote ischemic preconditioning combined with atorvastatin improves
           memory after global cerebral ischemia-reperfusion in male rats

    • Abstract: Research Results in Pharmacology 8(2): 27-35
      DOI : 10.3897/rrpharmacology.8.75753
      Authors : Azim Hedayatpour, Maryam Shiasi, Peyman Modarresi, Alieh Bashghareh : Introduction: Damage to hippocampus can occur through ischemia. Memory problems are among the most significant disabilities after stroke. Therefore, improving memory is of great interest in helping post-stroke patients. This study demonstrated that intraperitoneally injection of atorvastatin with a short cycle of ischemia-reperfusion in the left femoral artery improved hippocampal CA1 neurons injury and memory problems after global cerebral ischemia. Materials and methods: In this article survey, we used 64 animals. Rats were divided into 8 groups, (n=8). Group 1: control; group 2: sham; group 3: global cerebral ischemia (GCI) only; group 4: remote ischemic preconditioning (RIP) + GCI; group 5: GCI + atorvastatin (ATO); group 6: GCI + vehicle; group 7: RIP + GCI + ATO; group 8: RIP + GCI + vehicle. We created global cerebral ischemia (GCI) with 20 min occlusion of the Common carotid artery. Results and discussion: Remote ischemic preconditioning could improve rats performance in water maze tests along with a decrease in neuronal death. Also, atorvastatin combined with remote ischemic preconditioning was more effective for memory improvement and reduction of neuronal death. Inconsistent with our result, the function of the animals in the ischemia group was impaired. CA1 hippocampal neurons have an important role in memory and learning, and they can be damaged after cerebral ischemia. Therefore, ischemia can create memory problems. Remote ischemic preconditioning and atorvastatin had a neuroprotective effect and could improve rat performance in water maze test. Conclusion: This study showed that remote ischemic preconditioning with atorvastatin could improve CA1 neuronal injury and memory. Graphical abstract: HTML XML PDF
      PubDate: Tue, 14 Jun 2022 17:48:27 +030
  • Genetically modified animal models of hereditary diseases for testing
           of gene-directed therapy

    • Abstract: Research Results in Pharmacology 8(2): 11-26
      DOI : 10.3897/rrpharmacology.8.82618
      Authors : Anna V. Polikarpova, Tatiana V. Egorova, Maryana V. Bardina : Disease-causing genes have been identified for many severe muscular and neurological genetic disorders. Advances in the gene therapy field offer promising solutions for drug development to treat these life-threatening conditions. Depending on how the mutation affects the function of the gene product, different gene therapy approaches may be beneficial. Gene replacement therapy is appropriate for diseases caused by mutations that result in the deficiency of the functional protein. Gene suppression strategy is suggested for disorders caused by the toxic product of the mutant gene. Splicing modulators, genome editing, and base editing techniques can be applied to disorders with different types of underlying mutations. Testing potential drugs in animal models of human diseases is an indispensable step of development. Given the specific gene therapy approach, appropriate animal models can be generated using a variety of technologies ranging from transgenesis to precise genome editing. In this review, we discuss technologies used to generate small and large animal models of the most common muscular and neurological genetic disorders. We specifically focus on animal models that were used to test gene therapies based on adeno-associated vectors and antisense nucleotides. HTML XML PDF
      PubDate: Tue, 14 Jun 2022 17:48:15 +030
  • Atherosclerosis is a side effect of cellular senescence

    • Abstract: Research Results in Pharmacology 8(2): 1-9
      DOI : 10.3897/rrpharmacology.8.81358
      Authors : Elena I. Leonova, Angelina V. Chirinskaite, Julia V. Sopova : Atherosclerosis is a systemic autoimmune disease of the arterial wall characterized by chronic inflammation, high blood pressure, oxidative stress, and progressive loss of cell and organ function with aging. An imbalance of macrophage polarization is associated with many aging diseases, including atherosclerosis. The polarization toward the pro-inflammatory M1 macrophage is a major promoter of the atheroma formation. It is known that efferocytosis, or ingestion of apoptotic cells, is stimulated by M2 macrophage polarization. A failure of efferocytosis leads to the prolongation of chronic pathology in tissue. In addition, fat-laden macrophages contribute to the plague progression by transforming into foam cells in response to excess lipid deposition in arteries. In spite of the generally accepted theory that macrophages capture oxidized low-density lipoprotein by phagocytosis and become foam cells, we postulate that the main source of lipid accumulation in foam cells are senescent erythrocytes. Senescent erythrocytes lose their plasticity, which affects the rheological blood properties. It is known that their membrane contains high levels of cholesterol. There is evidence that senescent erythrocytes play a pathogenic role in the atheroma formation after breaking down during flowing through an artery bifurcation. Here we review the current knowledge on the impact of age-associated immune cells and red blood cells modifications on atherogenesis. Graphical abstract: HTML XML PDF
      PubDate: Fri, 10 Jun 2022 10:54:01 +030
  • Validation of structural-based virtual screening protocols with the PDB
           Code 3G0B and prediction of the activity of Tinospora crispa compounds as
           inhibitors of dipeptidyl-peptidase-IV

    • Abstract: Research Results in Pharmacology 8(1): 95-102
      DOI : 10.3897/rrpharmacology.8.76237
      Authors : Andri Prasetiyo, Shirly Kumala, Esti Mumpuni, Raymond R. Tjandrawinata : Introduction: Brotowali (Tinospora crispa) has been traditionally used as an antidiabetic drug. DPP-IV inhibitor as an antidiabetic will increase insulin secretion. It indirectly escalates incretin hormones, such as Glucagon-Like peptide-1 (GLP-1) which depends on glucose. This study predicts potential compounds from the Brotowali plants, such as DPP-IV inhibitors, using the Molegro Virtual Docker (MVD). Materials and methods: Before the molecular docking simulation, internal validation and external validation are necessary. Internal validation was carried out by re-docking the native ligands in the DPP-IV enzyme crystal structure (PDB codes 3G0B, 3W2T, and 3BJM). The external validation was carried out by simultaneous docking of 59 active compounds and 1918 inactive compounds (decoys) from the A Directory of Useful Decoys (DUD) database with PDB code 3G0B on 16 combinations, four search algorithms, and four functions scoring. Results and discussion: The molecular docking simulation was carried out on 50 compounds from the Brotowali plant and alogliptin as standard compounds with PDB code 3G0B. The best results of the docking method validation yielded the RMSD values of 0.43 and EF1% of 20.34 and EF20% of 3.1 (the combination of search algorithm Moldock optimizer and scoring function Moldock score). The re-rank score of 5 compounds from the Brotowali plant (Rumphioside C, Borapetoside E, Borapetoside F, Rumphioside I, and 6’-O-Lactoyl Borapetoside B) were -107.7 kcal/mol; -105.4 kcal/mol; -104.2 kcal/mol, and -102.8 kcal/mol. Alogliptin (standard ligands) had a re-rank score of -101.6 kcal/mol. The combination of search algorithms MolDock optimizer and scoring function MolDock score is a valid protocol with a good result. The similarity of the binding sites of Borapetoside E and 6’-O-Lactoyl Borapetoside B is 75% when compared to the alogliptin binding sites (Glu 205, Glu 206, Tyr 547). Conclusion: Based on the re-rank score and binding sites similarity, Borapetoside E and 6’-O-Lactoyl Borapetoside B have potential as an antidiabetic drug with a mechanism of action of DPP-IV inhibitors. HTML XML PDF
      PubDate: Thu, 31 Mar 2022 18:06:06 +030
  • Evaluation of the pharmacological activity of hybrid organotin
           compounds in a B16 melanoma model in the classical and metronomic
           administration modes

    • Abstract: Research Results in Pharmacology 8(1): 85-93
      DOI : 10.3897/rrpharmacology.8.76363
      Authors : Margarita A. Dodokhova, Andrey V. Safronenko, Inga M. Kotieva, Margarita S. Alkhuseyn-Kulyaginova, Dmitry B. Shpakovsky, Elena R. Milaeva : Introduction: In modern medical chemistry, much attention is paid to the search for new antimetastatic agents based on metal compounds. Organotin compounds promise to be good candidates as the treatment of malignant neoplasms. In order to reduce a possible nonspecific toxic effect of tin compounds and to expand the intended therapeutic use, the paper presents hybrid tin (IV) complexes with Sn-S bond containing a fragment of 2,6-di-tert-butylphenol. The aim of the study was to evaluate the antitumor and antimetastatic effects of bis (3,5-di-tert-butyl-4-hydroxyphenylthiolate) dimethylolol (Me3) and (3,5-di-tert-butyl-4-hydroxyphenylthiolate) triphenylolol (Me5) in a model of transplanted melanoma tumor in B16 mice in classical and metronomic administration mode. Materials and methods: The efficacy of organotin compounds was studied in a model of a transplanted tumor with spontaneous metastasis of C57Bl/6 (female) melanoma B16 mice using the following indicators: average life expectancy, inhibition of tumor growth by weight, tumor mass, and metastasis inhibition index. Results and discussion: The most pronounced antimetastatic effect (54% and 36%) is achieved with a five-fold intraperitoneal injection of Me3 and Me5 at the total doses of 375 mg/kg and 250 mg/kg. The comparable results of the efficacy were obtained in the classical and metronomic modes of the injection of hybrid organotin compounds. With an increase in the injected dose, there is an effect of activating the tumor process with the generalized metastasis. Conclusion: Bis dimethylolol (Me3) and triphenylolol (Me5) compounds demonstrate both a pronounced antimetastatic activity and a multidirectional effect on the growth of the primary focus and the metastasis in lungs, depending on an injected dose. HTML XML PDF
      PubDate: Thu, 31 Mar 2022 18:05:51 +030
  • Experimental study of new derivatives of 3-hydroxypyridine as
           pharmacological agents for the correction of ischemic brain injury after
           intracerebral hemorrhage

    • Abstract: Research Results in Pharmacology 8(1): 71-83
      DOI : 10.3897/rrpharmacology.8.80378
      Authors : Olesya V. Shcheblykina, Dmitry V. Shcheblykin, Konstantin S. Trunov, Anton P. Danilenko, Vladimir S. Lipatov : Introduction: Limiting the action of secondary injury factors can improve the prognosis in acute cerebral accidents. The aim of the investigation is to study the neuroprotective effects of 3-hydroxypyridine derivatives. Materials and methods: The study was performed in Wistar rats. An intracerebral hemorrhage (ICH) model was used. The animals were once administered intraperitoneally with the test drugs 1 hour before the surgery and on the 1st, 2nd and 3rd days. The registration of behaviors and condition of the animals on days 1, 3, 7 and 14 and the morphological examination of the brain were performed. Results and discussion: The use of the substances LKhT 4-97 and LKhT 11-02 in the treatment of experimental ICH had a positive effect on the survival rate of the animals and on the resolution rate of pathological signs (p
      PubDate: Thu, 31 Mar 2022 18:05:36 +030
  • The effectiveness of Soderm® – forte gel and a new injectable dosage
           form of Rexod® in the complex treatment of experimental periodontitis in

    • Abstract: Research Results in Pharmacology 8(1): 51-58
      DOI : 10.3897/rrpharmacology.8.79641
      Authors : Pavel A. Galenko-Yaroshevsky, Kristina V. Tseluiko, Valeriy K. Leontev, Mark A. Zadorozhniy, Viktor L. Popkov, Anait V. Zelenskaya, Sergey A. Babichev, Andrey V. Zadorozhniy, Sonya V. Meladze : Introduction: Insufficient effectiveness of traditional drug therapy in a treatment of patients with chronic generalized periodontitis, as well as high social significance of this problem, determines the need to search for new drugs and their compositions aimed at solving it. Aim of the study: To increase the efficacy of complex treatment of periodontitis with the administration of Soderm®-Forte gel and a new injectable form of Rexod®. Materials and methods: Experiments were performed in 50 male Wistar rats. Experimental periodontitis (EP) was simulated by ligation of the necks of lower incisors. We studied the animals with intact periodontium, untreated EP, and when traditional drug therapy (TDT), as well as the combinations of TDT with Soderm®-Forte gel and additionally with the new injectable dosage form (NIF) of Rexod® were administered. The general condition, behavior, nutrition and body weight of the animals were evaluated. The Schiller-Pisarev test and the Muhlemann-Cowell bleeding index were used, and the amount of crevicular fluid (CF) was measured. The contamination of the marginal gum with microorganisms was determined. Results and discussion: The TDT in EP has a moderate therapeutic effect, which does not lead to a sufficiently high pharmacotherapeutic effect, whereas the combinations of TDT with Soderm®-Forte and, to a greater extent, TDT with Soderm®-Forte and NIF of Rexod® have high therapeutic efficacy, which is statistically confirmed by a sharp decrease in the amount of CF, the Schiller-Pisarev test and the Muhlemann-Cowell bleeding index, as well as absolute suppression of pathogenic microorganisms. Conclusion: The combinations of TDT with Soderm®-Forte gel and NIF of Rexod® in EP in rats can significantly increase the effectiveness of the treatment. The data obtained indicate the expediency of the administration of Soderm®-Forte gel, as well as its combination with NIF of Rexod® in dental practice in the complex therapy of patients with periodontitis. HTML XML PDF
      PubDate: Thu, 31 Mar 2022 18:05:23 +030
  • Nortriptyline overcomes corticosteroid resistance in NK and NKT-like
           cells from peripheral blood of patients with chronic obstructive pulmonary

    • Abstract: Research Results in Pharmacology 8(1): 59-70
      DOI : 10.3897/rrpharmacology.8.75467
      Authors : Aliaksei G. Kadushkin, Anatoli D. Tahanovich, Lyudmila V. Movchan, Volha V. Dziadzichkina, Olga V. Levandovskaya, Tatsiana V. Shman : Introduction: An antidepressant nortriptyline potentiates glucocorticoid (GC) action with synergistic suppression of inflammatory mediator release, but the precise molecular mechanism is unknown. Materials and methods: Peripheral blood cells from patients with chronic obstructive pulmonary disease (COPD) (n = 21) were incubated with nortriptyline (1 µM or 10 µM), budesonide (10 nM), or their combinations, followed by stimulation with phorbol myristate acetate (PMA) and ionomycin. Cytokine production, glucocorticoid receptor β (GRβ), histone deacetylase 2 (HDAC2) and histone H4 acetylation of K8 (HAT) expression, p65 NF-kB and p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation in NK (CD3-CD56+) and NKT-like (CD3+CD56+) cells were analyzed by flow cytometry. Results: We observed that nortriptyline (10 µM) significantly attenuated the effects of PMA/ionomycin on the synthesis of interferon γ (IFNγ), interleukin 4 (IL-4), and IL-8, expression of GRβ and HAT, as well as p65 NF-kB and p38 MAPK phosphorylation in NK and NKT-like cells, whereas nortriptyline (1 µM) only inhibited IL-4 production by NK and NKT-like cells. Discussion: The combination of nortriptyline (10 µM) and budesonide decreased IFNγ, tumor necrosis factor α, IL-4, IL-8, and GRβ expression, as well as phosphorylated p38 MAPK and p65 NF-κB levels by NK and NKT-like cells above that of budesonide alone. Furthermore, the same association of drugs enhanced HDAC2 expression in NK and NKT-like cells. Conclusion: Collectively, our results show that nortriptyline might enhance GC function through modulation of HAT, HDAC2, GRβ, phospho-p38 MAPK expression. These data provide a strong rationale for combining nortriptyline with budesonide to treat COPD. HTML XML PDF
      PubDate: Thu, 31 Mar 2022 18:05:09 +030
  • Cytotoxic activities of ethanolic crude extracts from fruiting bodies
           of bamboo mushrooms (Dictyophora spp.) against cholangiocarcinoma cells

    • Abstract: Research Results in Pharmacology 8(1): 33-41
      DOI : 10.3897/rrpharmacology.8.72098
      Authors : Pathanin Chantree, Sirilak Chumkiew, Mantana Jamklang, Pongsakorn Martviset : Introduction: Cholangiocarcinoma (CCA) is a highly progressive tumor. The standard chemotherapy varies in its effectiveness, with generally low efficacy. So, the discovery of novel chemotherapy is still required. The objective of this preliminary study was to determine the cytotoxic effects induced by three kinds of bamboo mushrooms (Dictyophora indusiata or Chinese bamboo mushroom; Ch-DTP, Short skirt bamboo mushroom (Thai isolate); Th-DTP, and orange skirt bamboo mushroom; Or-DTP) on CCA cells. Materials and methods: CCA cell lines, including CL-6, HuCCT1, HuH28, and OUMS normal fibroblast cells, were treated with various concentrations of DTP extracts. The MTT assay was used to determine cytotoxicity, and cell morphology was observed by using phase-contrast microscopy. Results and discussion: The results suggested that Ch-DTP effectively killed all three CCA cell lines in both low (0.3 mg/mL) and high (0.6 mg/mL) doses, but Th-DTP and Or-DTP had significantly reduced cell viability only at high doses (p
      PubDate: Wed, 16 Mar 2022 23:53:21 +020
  • Study of dose-dependent actoprotective effect of ATACL on physical

    • Abstract: Research Results in Pharmacology 8(1): 13-22
      DOI : 10.3897/rrpharmacology.8.75981
      Authors : Anastasia D. Gerashchenko, Dmitry I. Pozdnyakov, Andrey V. Voronkov : Introduction: The aim of the study was to investigate the dose-dependent actoprotective effect of ATACL on physical performance and psychoemotional status of animals under conditions of exhausting exercise. Materials and methods: Outbred male mice (23–25 g) were used in the experiment. The test compound in various dosages, as well as the reference drug, were administered intragastrically 60 minutes before the forced swimming test for 10 days of the experiment. At the end of the physical activity, the psychoemotional status of the animals was assessed in the Open Field (OF) and Elevated plus maze (EPM) tests. Results and discussion: In the course of the experiment, it was found that under conditions of exhausting physical execise, a smooth increase in performance was observed in the group that had received the test compound 4-hydroxy-3,5-di-tert butyl cinnamic acid (ATACL) at a dosage of 100 mg/kg for 10 days. The peak of performance was recorded on the 8th day, which was 47.3% (p
      PubDate: Wed, 16 Mar 2022 16:29:45 +020
  • Development of novel effective agents from 1H-indolylammonium
           trifluoroacetates effective against conditionally pathogenic

    • Abstract: Research Results in Pharmacology 8(1): 43-50
      DOI : 10.3897/rrpharmacology.8.73329
      Authors : Irina S. Stepanenko, Semen A. Yamashkin, Tatyana N. Platkova, Anastasia I. Kiryutina, Ilya N. Sorokvasha : Introduction: The problem of antibiotic resistance of microorganisms is becoming more urgent in the twenty-first century. More and more pathogenic microbes are becoming resistant to two or more antibiotics. This problem has become worse into the COVID-19 pandemic. The search for new compounds with antimicrobial activity is one of the principles for overcoming the antibiotic resistance of microorganisms. Materials and methods: Methods for the preparation, isolation, and identification of salts of 2,3,5-trimethyl-, 1,2,3,5-tetramethyl-, 2,3-dimethyl-5-methoxy-, 5-methoxy-1,2,3-trimethyl-1H-indole-6-amines and trifluoroacetic acid were developed and laboratory microbiological studies of them for antimicrobial activity were carried out. Sensitivity of the test-strains of microorganisms to the new compounds was studied. A method of serial dilutions to determine the minimal inhibitory concentration (MIC) of the compounds under study was used in the study. Results and discussion: The compounds 5–8 showed a pronounced antibacterial activity against the test strains of microorganisms in vitro with MIC from 0.98 µg/mL to 125.0 µg/mL. The prospects for targeted synthesis of biologically active compounds which are derivatives of 1H-indolylamines with a trifluoromethyl group in the molecule were determined, and after additional studies, the compounds 5–8 may find application as water-soluble synthetic antimicrobial agents. Conclusion: The laboratory microbiological screening of showed that they have an antimicrobial effect that exceeds the activity of the reference drug, dioxidine. The presence of molecular mechanisms predicted in silico in the spectrum of biological activity of the studied compounds, such as Pseudolysin inhibitor, Omptin inhibitor, Undecaprenyldiphospho-muramoylpentapeptide beta-N-acetylglucosaminyltransferase inhibitor, UDP-epimerase inhibitor, Bacterial efflux pump inhibitor, suggests the presence of antimicrobial activity against gram-positive and gram-negative microorganisms. Trifluoroacetates 2,3,5-trimethyl-1H-indole-6-ammonium (5), 1,2,3,5-tetramethyl-1H-indole-6-ammonium (6), 2,3-dimethyl-5-methoxy-1H-indole-6-ammonium (7), 1,2,3-trimethyl-5-methoxy-1H-indole-6-ammonium (8), after additional studies, may find application as water-soluble synthetic antimicrobial agents. HTML XML PDF
      PubDate: Wed, 16 Mar 2022 11:45:06 +020
  • Study of pharmacokinetic of new peptide drug
           1-deamino-arginine-vasotocin for hypernatremia correction

    • Abstract: Research Results in Pharmacology 8(1): 23-31
      DOI : 10.3897/rrpharmacology.8.71802
      Authors : Vera M. Kosman, Natalya M. Faustova, Marina V. Karlina, Valery G. Makarov, Marina N. Makarova : Introduction: The pharmacokinetics studies are some of the necessary parts of the drugs preclinical investigations. Pharmacokinetic properties of new peptide drug 1-deamino-arginine-vasotocin (dAVT) in the form of an injection solution for intravenous and intramuscular administration for hypernatremia correction were investigated. Materials and methods: The study was carried out on male rats and rabbits with a single intravenous administration of the drug in three doses, a single intramuscular administration in one dose and multiple administration to rats in one dose. To determine natriiuretic peptide concentration in blood plasma, tissues, and excretes, assays based on a sodium level change measurement using a biochemical analyzer have been developed and validated. Pharmacokinetic parameters were calculated by the model-independent method of statistical moments. Results and discussion: The pharmacokinetics of the drug was found to be linear after a single administration of dAVT drug in the dose range 3–10 μg/kg for rats and rabbits. The relative bioavailability of dAVT after intramuscular and intravenous administrations was more than 30%. After a biomarker content change, the active substance was intensively distributed into highly vascularized organs (spleen), the organs that provide metabolism and subsequent excretion (liver and kidneys), whereas it hardly reached moderately and weakly vascularized tissues (muscles, omentum). Less than 10% dAVT was excreted with urine; no dAVT was determined in feces; and repeated administration did not lead to its cumulation. Conclusion: Pharmacokinetics parameters of new nonapeptide drug 1-deamino-arginine-vasotocin were evaluated after original analytical biomarker approach. The study included all main areas necessary to characterize the original drug pharmacokinetic. HTML XML PDF
      PubDate: Wed, 16 Mar 2022 11:09:04 +020
  • Synthesis, molecular docking, ADMET study and in vitro pharmacological
           research of
           as a promising non-opioid analgesic drug

    • Abstract: Research Results in Pharmacology 8(1): 1-11
      DOI : 10.3897/rrpharmacology.8.80504
      Authors : Aleksey D. Kravchenko, Natalia V. Pyatigorskaya, Galina E. Brkich, Larysa V. Yevsieieva, Alexander V. Kyrychenko, Sergiy M. Kovalenko : Introduction: The discovery of novel drugs that can block the transmission of pain signals for treating the pain of various etiologies is an urgent topic in pharmaceutics. The aim of this paper is to synthesize and to investigate in vitro and in silico characteristics of a promising novel compound: 7-(2-chlorophenyl)-4-(4-methylthiazol-5-yl)-4,6,7,8-tetrahydroquinoline-2,5(1H,3H)-dione (HSV-DKH-0450). Materials and methods: The specific activity and the inhibitory mechanism of HSV-DKH-0450 were studied using the HEK293 culture cells expressing the IPTG-induced TRPA1 ion channels. Cardiotoxicity was determined by estimating the binding of HSV-DKH-0450 to the hERG channel. Inhibition of human liver cytochromes was determined by the effect on the activity of cytochromes 1A2, 2C9, 2D6, 2C8, and 3A4. Cellular toxicity was assessed by the effect on the viability of human hepatocytes. ADMET properties were evaluated using admetSAR and SwissADME web-based tools. Molecular docking was carried out using AutoDock Vina tools to predict the binding affinity of all HSV-DKH-0450 stereoisomers toward the TRPA1 and TRPV1 receptors. Results and discussion: In silico predictions of ADMET properties of HSV-DKH-0450 showed that it has optimal pharmaceutical profiles. A series of in vitro pharmacological studies revealed that HSV-DKH-0450 is a promising antagonist of the TRPA1 ion channel with the IC50 of 91.3 nM. The molecular docking of HSV-DKH-0450 stereoisomers against the TRPA1 and TRPV1 receptors demonstrates that they all are characterized by an approximately similar high binding affinity. Conclusion: The obtained data for substance HSV-DKH-0450 look promising for its further development as a potential therapeutic agent for pain relief. Graphical abstract: HTML XML PDF
      PubDate: Wed, 16 Feb 2022 11:36:20 +020
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