Studying dose-dependent endothelio- and cardioprotective activity of selective arginase II inhibitor in hyperhomocysteineinduced endothelial dysfunction

This paper deals with the study of endothelio- and cardioprotective activity ofarginase II selective inhibitor, the substance under the code ZB49-0010C in the model of hyperhomocysteine-induced endothelial dysfunctio

Search and evaluation of pharmacodynamic and pharmacokinetic parameters of selective blocker of TRPA₁ ion channels from the group of substituted pyrazinopyrimidinones

Search considerations evaluation of pharmacodynamic and pharmacokinetic parameters of selective blocker of TRPA₁ ion channels from the group of substituted pyrazinopyrimidinone

PHYSICO-CHEMICAL PROPERTIES OF MONTMORILLONITE CLAYS AND THEIR APPLICATION IN CLINICAL PRACTICE (REVIEW)

The review is devoted to the medical application of montmorillonite clay minerals. Properties and mechanisms of action of enterosorbents. The properties of the enterosorbents include an absorption capacity and active surface. The mechanisms of action include the sorption of toxins in the gastrointestinal tract, the contact effect on the mucosa, enhancing the release of toxins in the gastrointestinal tract, increasing the metabolism and excretion of toxins. Physico-chemical properties of montmorillonite. Montmorillonite is a layered silicate from the smectite group, with the structure of 2:1. Its specific area is 173 m2/g and sorption capacity is 370 mg/g. The application of montmorillonite clays in medicine. Smectites are used as excipients, active substances or dispersants. Oral effects of smectite. The smectite based enterosorbents have antacid, mucocytoprotective, antidiarrheal effects, a high sorption activity against bacterial and viral particles. Analysis of the clinical use of the smectite based enterosorbents. Diosmectite has a high strength of recommendations and security (class B). The analysis is based on the results of the randomized clinical trials. According to different authors, from 22 to 84% of European doctors prescribe smectite for acute diarrhoea. Smectite reduces the duration of diarrhea by 22-42%, significantly reducing the number of bowel movements in comparison with placebo (

ION CHANNEL TRPA1 IS A PROMISING THERAPEUTIC TARGET FOR TREATMENT OF PAIN

TRPA1 is an ankyrin receptor of TRP family. It is a non-selective, calcium-permeable cation channel that is highly expressed by a subset of small diameter sensory neurons with cell bodies in the dorsal root, trigeminal, nodose and jugular ganglia. In the last time information about the role of TRPA1 in pain and cold sensitivity, as well as in the formation and maintenance of inflammation is increasing in scientific literature. Given this information, the interest for search and study of pharmacological agents, which selectively blocked of TRPA1 and reduced the severity of pain and inflammation is increasing

PRECLINICAL STUDY OF PHARMACOLOGICAL ACTIVITY OF ENTEROSORBENTE ON THE BASIS OF MONTMORILLONITE

Introduction: At present, enterosorbents based on mineral raw materials are in high demand among the population. However, there are no enterosorbents on the Russian pharmaceutical market on the basis of domestic mineral raw materials. Objectives: to study the pharmacological activity of enterosorbent based on montmorillonite of Russian origin under experimental conditions. Methods: The methodological approach was based on the implementation of a complex of theoretical, pharmacological, toxicological, histological, biochemical, statistical methods. Models of experimental diarrhea, acute and toxic liver damage, acute experimental pancreatitis were selected. Results and discussion: Enterosorbent based on montmorillonite Crim_04 has a dose-dependent antidiarrhoeal effect, which is manifested in an increase in the time of onset of diarrhea from 50.4% to 82.6% with various models of diarrhea, a reduction in the number of defecations from 50.4% to 64.4% liquid in them. Enterosorbent on the basis of montmorillonite has a high sorption activity to E.coli enterotoxin, inhibiting the outflow of fluid into the luminal cavity by 95.1%. In addition, the use of enterosorbent Crim_04 significantly improves biochemical indices in the blood serum of rats when modeling acute and chronic liver damage and acute pancreatitis. Conclusion: The enterosorbent under the Crim_04 cipher has a dose-dependent anti-diarrhea, detoxification activity, high sorption activity for E.coli enterotoxin, high therapeutic efficacy in experimental pancreatitis, most pronounced at a dose of 3320 mg / kg. It can be recommended for further complex toxicological studies and clinical trials

MOLECULAR SCREENING OF PROSPECTIVE CANDIDATES FOR TRPA1 ION CHANNEL SELECTIVE ANTAGONISTS

TRPA1 is an ankyrin receptor of TRP family. It is mostly expressed in the smalldiameter nociceptors with cell bodies located in the dorsal roots, as well as in trigeminal, nodose and jugular ganglia. Recently, more and more information has been found in the literature on the role of TRPA1 in the realization of cold and pain sensitivity, and also in the formation and maintenance of inflammation. Subject to these data there is an increasing interest in finding and studying pharmacological agents able to selectively block the TRPA1 receptors and thereby reduce the severity of pain and inflammation. Using the molecular modeling techniques, we analyzed spectra of biological activity of a series of promising candidates for selective antagonists of TRPA1 ion channel in order to find potentially active compounds against pain and inflammation. Substances that showed in high throughput screening the percentage of the cellular calcium response inhibition above 50% - 3*SD maximum and its own agonistic activity less than 10% + 3*SD minimum were identified as hits. The value IC50 for hits was determined immediately after re-testing at 10 μM concentration and repeatedly after the determination of the leading chemical series. As the result of the studies, the biologically active molecules of leading chemical series have been confirmed. The research was partially supported by the grant of the President of the Russian Federation №MD-4711.2015.7 and МК-6135.2016.4

STUDY OF THE ANALGESIC AND ANTI-INFLAMMATORY ACTIVITY OF A NEW NON-OPIOID ANALGESIC BASED ON A SELECTIVE INHIBITOR OF TRPA1 ION CHANNELS

The aim is to study the analgesic and anti-inflammatory activity of an innovative molecule under the ZC02-0012 laboratory code belonging to the group of selective blockers of the TRPA1 ion channel.Materials and methods. The study of the ZC02-0012 analgesic activity was carried out by the hot plate and acetic acid writhing tests. The hot plate test was performed on white laboratory mice. ZC02-0012 substance was administered in doses of 1, 3 and 9 mg/kg. Ketorol at a dose of 3.48 mg/kg was chosen as the reference drug. To study the analgesic effects in the hot plate test, intact white laboratory mice were placed on a preheated at 55°C plate to determine the base level of pain sensitivity. Then the test substances were administered to the animals divided into groups, and the hot plate test was repeated after 30, 60, 90 and 120 minutes. To study the analgesic effects in the test of acetic acid writhing, white laboratory rats were injected with the ZC02-0012 substance at doses of 0.46, 1.38, and 4.15 mg/kg. Ketorol at a dose of 1.6 mg/kg was chosen as the reference drug. 30 minutes after intramuscular injection and 60 minutes after intragastric administration, the intraperitoneal administration of a 0.75% solution of acetic acid was carried out at the rate of 1 ml per 100 g of animal weight. Counting the number of writhings started 15 minutes after the injection of acetic acid and continued for 30 minutes. The anti-inflammatory effects of the ZC02-0012 substance were studied using a model of acute exudative inflammation in response to the subplantar introduction of 0.02 ml of 2% formaldehyde aqueous solution into the right hind paw of the mouse. 4 hours after the phlogistic introduction, the mass of the edematous paw was evaluated. ZC02-0012 substance at doses of 1, 3 and 9 mg/kg and the Diclofenac reference drug at a dose of 13.91 mg/kg were administered intragastrically or intramuscularly 45 minutes before the introduction of phlogistic. The presence and severity of anti-inflammatory activity was judged by the inhibitory effect, expressed in percentage.Results. The analgesic activity of ZC02-0012 is found to exceed that for Ketorol in both the intramuscular and intragastric ways of administration according to the results of hot plate tests in doses of 3 and 9 mg/kg and acetic acid writhing in doses of 1.38 and 4.15 mg/kg, while the anti-inflammatory activity of ZC02-0012 at doses of 3 and 9 mg/kg is shown to be comparable to that of Diclofenac. Conclusion. The innovative molecule under the ZC02-0012 laboratory code is established to exhibit a pronounced analgesic and anti-inflammatory activity, thus being prospective for further research.Conflict of interest: the authors declare no conflict of interest

Correction of retinal ischemic injuries by using non-selective imidazoline receptor agonists in the experiment

Introduction: Retinoprotective effects of non-selective imidazoline receptor agonists: potassium salt of С7070; sodium salt of С7070; С7070 processed with CO2 – were investigated in comparison with C7070 on the retinal ischemia-reperfusion model in rats. Materials and methods: The protective effects of the substances were evaluated by using ophthalmoscopy, laser Doppler flowmetry, electroretinography, histological and morphometric studies of retinal layers. Results and discussion: The most pronounced retinoprotective effect was observed in potassium salt of C7070 at a dose of 10 mg/kg, which expresses in approaching the normal eye fundus image, achieving the target values of the retinal blood flow, b/a coefficient, and reaching the norm values of morphometric indicators. A less pronounced protective effect was found in sodium salt of C7070 at a dose of 10 mg/kg, which expresses in a 71% decrease (p < 0.05) in semi-quantitative assessment of the eye fundus changes, an increase in the retinal blood flow level by 70.4% (p < 0.05), in b/a by 94% (p < 0.05) in comparison with the group without correction, and reaching the norm of the morphometric indicators. A retinoprotective effect of the substance C7070 processed with CO2 at a dose of 10 mg/kg is inferior to that of the sodium salt of C7070. Conclusion: The retinoprotective activity of the substances is expressed in descending order: potassium salt of С7070 (10 mg/kg) ≈ С7070 (50 mg/kg) > sodium salt of С7070 (10 mg/kg) > С7070 processed with CO2 (10 mg/kg) ≈ С7070 (10 mg/kg). Injections of glibenclamide leveled the neuroretinoprotective effects of the substances to varying degrees, which confirmed the participation of ATP-dependent potassium channels in the implementation of these effects

Retinoprotective Effect of 2-Ethyl-3-hydroxy-6-methylpyridine Nicotinate

An important task of pharmacology is to find effective agents to improve retinal microcirculation and resistance to ischemia. The purpose of the study is to pharmacologically evaluate the retinoprotective effect of 2-ethyl-3-hydroxy-6-methylpyridine nicotinate in a rat model of retinal ischemia&ndash;reperfusion. A retinal ischemia&ndash;reperfusion model was used, in which an increase in intraocular pressure (IOP) to 110 mmHg was carried out within 30 min. The retinoprotective effect of 2-ethyl-3-hydroxy-6-methylpyridine nicotinate at a dose of 3.8 mg/kg, in comparison with nicotinic acid at a dose of 2 mg/kg and emoxipine at a dose of 2 mg/kg, was estimated by the changes in the eye fundus during ophthalmoscopy, the retinal microcirculation level with laser Doppler flowmetry (LDF), and electroretinography (ERG) after 72 h of reperfusion. The use of 2-ethyl-3-hydroxy-6-methylpyridine nicotinate prevented the development of ischemic injuries in the fundus and led to an increase in the retinal microcirculation level to 747 (median) (lower and upper quartiles: 693;760) perfusion units (p = 0.0002) in comparison with the group that underwent no treatment. In the group with the studied substance, the b-wave amplitude increased significantly (p = 0.0022), and the b/a coefficient increased reliably (p = 0.0002) in comparison with the group with no treatment. Thus, 2-ethyl-3-hydroxy-6-methylpyridine nicotinate has established itself as a potential retinoprotector