ENDOTHELIUM AND CARDIOPROTECTIVE EFFECTS OF HMG-CO-A-REDUCTASE IN COMBINATION WITH L-ARGININE IN ENDOTHELIAL DYSFUNCTION MODELING
Denisyuk T.A., Lazareva G.A., Provotorov V.Ya., Shaposhnikov A.A.
Using the combined application of L-arginine with HMG-Co-A reductase inhibitors simvastatin, atorvastatin, rosuvastatin and nanoparticulated rosuvastatin on the background of modeling of sepsis-induced disease through the introduction of strain 603 Staphylococcus aureus shows endotelio- and cardioprotective effects, manifesting itself in preventing the proliferation of endothelial dysfunction coefficient (CED), adrenoreactivity, maintenance of myocardial reserve and the normalization of biochemical markers values (Total NO, eNOS expression, C-reactive protein, IL-6, TNF). In this case, the combined therapy was so effective that the values obtained thereunder did not differ from those obtained from control animals.
ENDOTHELIOPROTECTIVE PROPERTY OF THE COMBINATION OF THE THIOCTIC ACID AND ROSUVASTATIN SHOWN IN THE ENDOTHELIAL DYSFUNCTION MODELS
Molchanova O.V., Pokrovskaya T.G., Povetkin S.V., Reznikov K.M.
During the experiment, the modeling of endothelial dysfunction of male rats was performed by intraperitoneal administration of L-NAME at a dose of 25 mg/kg for 7 days, and the same of female rats was performed by bilateral ovarioectomy and further intraperitoneal administration of L-NAME at a dose of 25 mg/kg for 7. The deficiency of nitric oxide as a result of the NO-synthase blockade was accompanied by the impairment of the endothelium- dependent and independent vasodilatation estimated in the pharmacological tests, which was expressed in the increasing coefficient of endothelial dysfunction. As a result of the research it was discovered that the combined application of thioctic acid at a dose of 50 mg/kg/day with antioxidant features and rosuvastatin at a dose of 0.85 mg/kg/day, which is a lipid-lowering drug, has endothelioprotective effect on the models of L-NAME-induced and hypoestrogen-L- NAME-induced deficiency of nitric oxide, which is expressed in prevalence of endothelium- dependent relaxations of vessels and decreasing coefficient of endothelial dysfunction, as well as prevention of increase in nitric oxide production.
ENDOTHELIO- AND CARDIOPROTECTIVE EFFECTS OF VITAMIN В6 AND FOLIC ACID IN MODELLING METHIONINE-INDUCED HYPERHOMOCYSTEINEMIA
Provotorov V.Y., Korokin M.V., Pokrovskii M.V., Povetkin S.V., Lazareva G.A., Stepchenko A.A., Bystrova N.A.
The endotelio- and cardioprotective effects of vitamin B6 (2 mg/kg) and folic acid (0.2 mg/kg) upon modeling of methionine-induced hyperhomocysteinemia via methionine intragastric administration at a dose of 3 g/kg were studied. It was shown that the combined use of vitamin B6 and folic acid allows on the background of a significant reduction in homocysteine concentrations normalizing the endothelial dysfunction coefficient and the parameters of maximum left ventricular pressure in response to intravenous administration of adrenaline.The research was partially supported by the grant of the President of the Russian Federation№MD-4711.2015.7.
STUDY OF THE INFLUENCE OF L-NORVALINE, ROSUVASTATIN AND THEIR COMBINATION ON THE LEVEL OF MICROCIRCULATION IN BONE TISSUE IN EXPERIMENTAL OSTEOPOROSIS AND FRACTURES ON ITS BACKGROUND
Rajkumar D.S.R., Gudyrev O.S., Faitelson A.V., Stepchenko A.A., Dolzhikov A.A., Povetkin S.V.
The experiment was carried out in female white Wistar rats to investigate the effect of L-norvaline, rosuvastatin and their combination on parameters of blood supply to the bone tissue on models of experimental osteoporosis and osteoporotic fractures. It was found that the studied drugs prevent reduction of microcirculation in osteoporotic bone tissue as well as in callus tissue of experimental osteoporotic fractures and it positively influences the course of reparative regeneration of bone tissue.
PHARMACOLOGICAL PRECONDITIONING BY RECOMBINANT ERYTHROPOIETIN AS THE POSSIBILITY OF INCREASING THE STABILITY OF TISSUE OF THE RETINA TO REPERFUSION ISCHEMIA IN EXPERIMENT
Shabelnikova A.S., Peresypkina A.A., Gubareva V.O., Levkova E.A., Dolzhikov A.A., Nikolaev S.B., Stepchenko A.A.
Ischemic injury was formed in laboratory rats by applying mechanical pressure (110 mm Hg) to the anterior eye chamber for 30 minutes. The experiment revealed that the recombinant erythropoietin (50 IU/kg) prevents the development of degenerative changes in retinal layers caused by ischemic injury. Intensity of the protective effect of erythropoietin on the retina of rats was assessed after 1 hour and 72 hours of reperfusion after pathology simulation. The observed protective effect of erythropoietin with the development of ischemia was confirmed by laser Doppler flowmetry, electroretinography and histomorphometry. Identification and use of pharmacological agents with the preconditioning effect may be a new approach in the correction and prevention of retinal ischemia, which is the leading element in the pathogenesis of a number of ophtalmic pathologies. The possibility of pharmacological preconditioning of ischemic lesions of the retina with erythropoietin is essential for the development of anti-ischemic agents for the treatment and prevention of ischemic ophthalmic pathologies.
USE OF L-ARGININE IMMOBILISED ON ACTIVATED CARBON FOR PHARMACOLOGICAL CORRECTION OF ENDOTHELIAL DISFUNCTION
Shakhno E.A., Savitskaya T.A., Pokrovskaya T.G., Yakushev V.I., Pokrovskii M.V., Grinshpan D.D.
For the first time a complex of L-arginine sodium salt of sulfate of cellulose acetate on activated carbon. To investigate the processes of sorption-desorption of L-arginine in a model environment. In animal experiments it was shown that granulirovannye the form of a combined preparation in dosages of 30 mg/kg, 70 mg/kg and 200 mg/kg exhibits a pronounced anti-hypertensive, endothelioprotecive and cardioprotective activity in a dosage of 200 mg/kg.
PHARMACOLOGICAL CORRECTION OF L-NAME-INDUCED OXIDE DEFICIENCY WITH DERIVATIVES OF 3-(2,2,2- TRIMETHYLHYDRAZINIUM) PROPIONATE
Skachilova S.Y., Kesarev O.G., Danilenko L.M., Bystrova N.A., Dolzhikov A.A., Nikolaev S.B.
This paper deals with the study of correction of L-NAME-induced endothelial dysfunction by means of 3-(2,2,2-trimethylhydrazinium) propionate derivatives. We have shown that 3-(2,2,2-trimethylhydrazinium) propionate and its derivatives reduced the expression of NO- deficient endothelial dysfunction induced by intraperitoneal administration of N-nitro L-arginine methyl ester (L-NAME), improved the parameters of endothelium-dependent vasodilation in response to administration of acetylcholine, and reduced the coefficient of endothelial dysfunction. It was revealed that the 5-hydroxinicotinate 3-(2,2,2-trimethylhydrazinium) potassium propionate has the most pronounced endothelioprotective effect.
STUDYING DOSE-DEPENDENT ENDOTHELIO- AND CARDIOPROTECTIVE ACTIVITY OF SELECTIVE ARGINASE II INHIBITOR IN HYPERHOMOCYSTEINE-INDUCED ENDOTHELIAL DYSFUNCTION
Yakushev V.I., Filippenko N.G., Kizilova I.V., Korokin M.V., Beskhmelnitsyna E.A., Litvinova A.S.
This paper deals with the study of endothelio- and cardioprotective activity of arginase II selective inhibitor, the substance under the code ZB49-0010C in the model of hyperhomocysteine-induced endothelial dysfunction. The results of the studies prove the presence in the arginase II selective inhibitor, the substance under the code ZB49-0010C, dose- dependent endothelioprotective and cardioprotective activity, which expression increases with the increase in dose and is maximum at a dose of 10 mg/kg.The research was partially supported by the grant of the President of the Russian Federation№MD-4711.2015.7.
ANALYSIS OF DYNAMICS OF ANTIBIOTIC RESISTANCE OF PATHOGENS IN PATIENTS WITH DIABETIC FOOT SYNDROME UNDERGOING IN-PATIENT TREATMENT
Batishcheva G.A., Malorodova T.N., Pokrovskaya T.G., Kazakova E.E., Urojevskaya J.S., Zhernakova N.I., Osipova O.A.
Persistent ulcers in patients with diabetic foot syndrome in 85% of cases lead to amputation because of secondary infection and growing gangrene that significantly worsen the prognosis. In the course of our study, the data were obtained on the role of the staphylococcus, Pseudomonas aeruginosa infections, Enterobacteriaceae isolates, and, in a small percentage of cases, Candida fungusin diabetic foot syndrome. It was shown that in case of incomplete eradication of the pathogen the structure of pathogens and its sensitivity to antibiotics undergo changes. In this case, methicillin-resistant staphylococci and Pseudomonas aeruginosa are detected. In this paper we discuss the approaches to the choice of antibiotic therapy, subject to the sensitivity of these microorganisms to antibiotic therapy in the surgical department of St. Joseph Belgorod Regional Clinical Hospital. The obtained data state that III-IV generation pseudomonas cephalosporins and fluoroquinolones can be used for empirical therapy. And, in case of staphylococcal infections, - vancomycin.
DEVELOPMENT AND VALIDATION OF METHODS OF QUANTITATIVE DETERMINATION OF THE NEW ANTIDIABETIC DRUG IN THE BLOOD PLASMA OF RATS BY HIGH PERFORMANCE LIQUID CHROMATOGRAPHY WITH MASS SPECTROMETRIC DETECTION
Buzov A.A., Kulikov A.L., Avtina T.V., Pokrovskii M.V., Osipova O.A.
We developed a method of quantification of the new antidiabetic drug 3-(1h-benzimidazole-2-yl)-1,2,2-trimethyl-cyclopentane-carbonic acid (c7070) in the blood plasma of rats by high-performance liquid chromatography with mass-spectrometric detection. The analytical range of the method was 0.02-3876.0 μg in 1 ml of blood plasma. The research was partially supported by the grant of the President of the Russian Federation№ MD-4711.2015.7 and МК-6135.2016.4.
TEST-SYSTEM FOR ESTIMATION OF ACTIVITY OF GSK-3 INHIBITORS AS ANTIHYPOXANTS AND DIFFERENTIATION OF ENDOTHELIAL PROGENITORS IN VITRO
Burda Y.E., Nadezhdin S.V., Zubareva E.V., Pokrovskii M.V., Faitelson A.V., Burda S.Y., Shirina M.S.
A model test-system was developed for validation in vitro of antihypoxic and endothelio-differentiating activity of newly created glycogen synthase kinase-3 inhibitors in comparison with the reference drug β4-thymosin.
MOLECULAR SCREENING OF PROSPECTIVE CANDIDATES FOR TRPA1 ION CHANNEL SELECTIVE ANTAGONISTS
Kravchenko D.V., Beskhmelnitsyna E.A., Korokin M.V., Avtina T.V., Sernov L.N., Tishin A.N., Kostina D.A.
TRPA1 is an ankyrin receptor of TRP family. It is mostly expressed in the small- diameter 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.