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Vol 18, No 2 (2020)

Role of extracellular vesicles in nephrology. Prospective use in therapy of kidneys and urinary tract diseases
Vashchenko V.I., Shabanov P.D.

Extracellular vesicles (EVs) represent heterogeneous population of the microparticles liberated by almost all live cages which are widely investigated recently in various biological and medical areas. They usually consist of two basic types (exosomes and microvesicles) and recently draw the increasing attention in quality mesenges of the cellular alarm system. Really, these vesicles can influence on cages-recipients, transferring and delivering difficult complexes of biomolecules (the lipids, proteins, coagulation factors, antigene, nucleinic acids), protected from enzymatic to degradation in environment. Importance EVs has been shown in pathophysiology several bodies, in particular, in kidneys where various types of cages нефрона allocate EVs which mediate their communication with underlaying cages urinogenous ways. By numerous researches it is established that EVs are involved in cellular communications during the regenerative and pathological processes occurring in a kidney. During the last years also it has been proved that vesicles play an important role in normal physiology of kidneys. Though many mechanisms EVs at illnesses are still studied insufficiently, in particular, in kidneys, opening of a role of additional mechanisms can help to throw light on the biological processes proceeding in kidneys. Eventually, extracellular vesicles, allocated with nephritic cages, collect in urine, becoming, thus, the big resource as markers of illnesses urinogenous a path and the perspective noninvasive diagnostic tool at nephritic illnesses. In the present review we discuss the latest data about a role EVs in pathophysiology of kidneys and their potential prospects in diagnostics and therapy of nephritic illness.

Reviews on Clinical Pharmacology and Drug Therapy. 2020;18(2):91-114
Original articles
Prospects for the use of new generation of anti-tuberculosis drugs in treatment of drug-resistant tuberculosis
Pavlova M.V., Vinogradova T.I., Zabolotnykh N.V., Ershova E.S., Sapozhnikova N.V., Chernokhaeva I.V., Archakova L.I., Vitovskaya M.L., Dogonadze M.Z., Starshinova A.A., Grishko A.N., Yablonsky P.K.

The aim of this work was an experimental and clinical study of increasing of the efficiency of therapy of respiratory tuberculosis with drug resistant pathogen by including a combination of anti-tuberculosis drugs of new generation – Bedaquiline (Bq) and Thioureidoiminomethylpyridi-nium perchlorate (perchlozone, Tpp) into treatment regimens. The presented results were obtained: in the experiment on a model of tuberculosis infection in 103 male C57black / 6 mice, reproduced by inserting into the lateral vein of the tail of a suspense of clinical strains of Mycobacterium tuberculosis with multi-drug resistance (MDR) and with various combinations of mutations in the genes; in the clinic – on the basis of examination and treatment of 148 patients with multidrug-resistant respiratory tuberculosis. It is shown that the application of the therapy schemes for multiple and broad drug resistant tuberculosis, containing Bq and Tpp in combination with drugs, selected taking into account the drug sensitivity of mycobacteria, allows to significantly reduce the periods of relief of symptoms of intoxication, regression of inflammatory changes, abacillation and achieving positive X-ray dynamics. Undesirable phenomena against the background of combined prescription of new generation drugs, as a rule, corresponded to light and moderate severity, and in frequency of development and expression did not differ from control groups of observation.

Reviews on Clinical Pharmacology and Drug Therapy. 2020;18(2):115-121
Features of the involvement of the dopamine and serotonin brain systems in positive and negative emotional states in rats
Bychkov E.R., Lebedev A.A., Efimov N.S., Kryukov A.S., Karpova I.V., Pyurveev S.S., Droblenkov A.V., Shabanov P.D.

The aim was to study the effect of rewarding and aversive stimulation of lateral hypothalamus on the turnover of monoamines in the terminal structures of the mesocorticolimbic and nigrostriatal systems: the nucleus accumbens (NAc) and striatum (St). The Wistar male rats were implanted electrodes in the lateral hypothalamus and further trained in self-stimulation test. Animals were also selected on aversive emotional reactions were observed after pressing the pedal for self-stimulation. Subsequently, forced stimulation was performed for 5 minutes and the animals were decapitated. The content of norepinephrine, dopamine (DA) and its metabolites 3,4-dioxiphenylacetic acid (DOPАС) and homovanilinic acid, serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in the nucleus accumbens and striatum were determined by high performance liquid chromatography with electrochemical detection. Positive and aversive stimulation of lateral hypothalamus decreased the level of DA in the NAc, however, only stimulation of the positive emotiogenic zone increased the DA and 5-HT turnover in the NAc, as evidenced by an increase in the DOPАС/DA and 5-HIAA/SER ratios, respectively. Rewarding and aversive stimulation decreased the level of 5-HT in St, however, only rewarding stimulation decreased the St level of 5-HIAA compared to control and animals with aversive stimulation. Rewarding stimulation increased the turnover of serotonin in St, as evidenced by the increase of 5-HIAA/5-HT ratios. The activity of the noradrenergic system did not change after rewarding and aversive stimulation. Thus, both rewarding and aversive electrical stimulation increases the turnover of DA and 5-HT in NAc and St. However, these changes are more significant after rewarding stimulation. DA turnover increases more in NAc, and 5-HT turnover – in St. The data obtained indicate the specificity of the dopaminergic and serotonergic involvement for the formation of a modality of emotional reactions. Data may provide guidance for developing treatment strategies for neuropsychiatric diseases related to the malfunction of the reward system.

Reviews on Clinical Pharmacology and Drug Therapy. 2020;18(2):123-130
Pharmacological analysis of the effects of the neuropeptide Y antagonist BMS 193885 on the emotional, intraspecies behavior and reinforcing properties of ethanol in rats
Moskalyev A.R., Abrosimov M.E., Vetlugin E.A., Pshenichnaya A.G., Tissen I.Y., Ivankov A.S., Bychkov E.R., Lebedev A.A., Shabanov P.D.

Purpose. Our previously data on orexigenic peptides (orexin, ghrelin) showed antagonists of peptides receptors as correctors of the emotional-motivational and cognitive spheres. Currently, a close relationship between ghrelin and orexin with neuropetide Y has been shown in feeding and emotional behavior.

The aim of this work was to analyze the effect of the NPY antagonist Y1R BMS 193885 on emotional and intraspecies behavior, as well as on the reinforcing properties of ethanol in rats.

Methods. We used the “open field” test, “elevated plus-maze”, Porsolt’s forced swimming test, “resident – intruder” test, conditional place preference (CPP). BMS 193885 1 mg/ml, 20 μl intranasally did not cause an anxiogenic effect in the “elevated plus-maze”.

Results. In the Porsolt’s test, there was also no increase in the level of depression. Moreover, there was a significant decrease in the number and time of dives, as an indirect indicator of a decrease in the level of depression. At the same time, in the “resident – intruder” test were decreased protective behavior, as an indicator of a decrease in the stress of intraspecific interaction in the absence of aggression. Moreover, local movements were increased in the “open field” test as an indicator of the animal’s activity impaired by fear. BMS 193885 had no effect on the expression of the CPP of ethanol.

Conclusion. Thus, it was previously shown that the BMS 193885 is a powerful, selective, brain-penetrating Y1 receptor antagonist, it reduces food intake and body weight in animal models of obesity both after acute and chronic administration. Our data indicate that the decrease in food intake is not associated with the level of anxiety, depression, or with a change in intraspecific interaction. It has been previously shown that NPY reduces alcohol consumption. Our data indicate that the Y1R antagonist of the neuropeptide Y BMS 193885 does not cause a change in the CPP of alcohol.

Reviews on Clinical Pharmacology and Drug Therapy. 2020;18(2):131-138
Ontogenetic peculiarities of the effect of dantrolene and caffeine on the cardiac, respiratory and motor performance of intact and poisoned by physostigmine of rats
Kuznetsov S.V., Kuznetsova N.N.

Activities of the somatomotor (MA), cardiovascular and respiratory systems were investigated in conditions of activation and blockade of ryanodine receptors (RyR) impaired cholinergic regulation in rat pups aged 3, 16 and 30 days. It was found that blockage of RyR by dantrolene has a negative chronotropic effect, the severity of which decreases with age, reduces the respiratory rate in rats on P3 and practically does not change in older animals. The amplitude of EMG and the power of motor bursts decreases in rats on P3-P16 and increases on P30. The duration of MA in the activity- rest cycle remains unchanged at P3 and decreases at P16-P30, which indicates a different change in the pattern of MA in rats of different ages after the blockade of RyR. Caffeine-induced activation of RyR is accompanied by an increase in heart rate and respiratory rate in rats on P30 and does not cause significant changes in these parameters on P3-P16. There has been an increase in all MA indices, especially in P3. Certain age-related regularities were revealed in the conditions of acetylcholinesterase inhibition by physostigmine, carried out against the background of RyR inhibition or activation. Maximum sensitivity to such effects was found in rats on P3. It was shown that in early postnatal ontogenesis of rats the sensitivity of RyR, including RyR2, to dantrolene is higher than in adult animals. Changes in RyR activity level do not prevent the development of pathological forms of heart rhythm that developing in rats after the physostigmine injection.

Reviews on Clinical Pharmacology and Drug Therapy. 2020;18(2):139-148
Studying the anticonvulsive activity of new ligands of NDMA-receptor complex – imidazole-4,5-dicarbonic acid derivatives
Jakovleva E.E., Foksha S.P., Brusina M.A., Kubarskaja L.G., Piotrovskij L.B., Bychkov E.R., Shabanov P.D.

NMDA receptors were proven to play a significant role in the processes of epileptogenesis. Experimental data indicate a significant anticonvulsant effect of NMDA receptor antagonists, but the use of the studied NMDA ligands remains limited due to their low efficiency and toxic effects. The aim of the study was to investigate the anticonvulsant effect of new ligands of the glutamate NMDA receptor complex – imidazole-4,5-dicarboxylic acid (IDA) derivatives on a model of NMDA-induced convulsions in mice. The tested agents (IEM2258 and IEM2248) were injected into the lateral ventricles of a waking mouse brain at doses of 0.1–0.5 mmol in 5 µl 15 minutes before the convulsant (NMDA). Valproic acid was used as a comparator drug. The results of the study showed that IDA derivatives exhibit anticonvulsant activity of various degrees of severity. A pronounced anticonvulsant effect was established for IEM2258 at a dose of 0.4 mmol: a significant reduction in the duration of convulsions (compared to the previous dose of the tested substance) and a total absence of NMDA-induced deaths. IEM2248 showed anticonvulsant activity at a dose of 0.2 mmol, in 100% of cases preventing fatal outcomes and completely protecting animals from the convulsions. Thus, the data obtained in this study showed dose-dependent anticonvulsant effect of new IDA derivatives (IEM2258 and IEM2248) due to the blockade of the NMDA receptor complex, that indicates the promising aspect for the development of these agents and further searching for effective and safe anticonvulsants among this pharmacological class.

Reviews on Clinical Pharmacology and Drug Therapy. 2020;18(2):149-154
Correction of experimental dislipoproteinemia by the intranasal administration of an original enzyme preparation
Klyueva N.N., Okunevich I.V., Parfenova N.S., Shabanov P.D.

The article is devoted to the experimental study of the specific pharmacological activity of the original microbial cholesterol oxidase enzyme preparation obtained from Streptomices lavendulae. In the condition of modeling dyslipoproteinemia, a pronounced alimentary hyperlipidemia in rats with the intranasal route of administration, a dose-dependent lipid-lowering effect of the domestic enzyme preparation of microbial origin of cholesterol oxidase was detected. In moderate alimentary hyperlipidemia, based on the selection of animals with a difficultly developed conditioned drinking reflex, this original preparation of cholesterol oxidase in an effective dose has a hypolipidemic effect and normalization of the serum lipoprotein spectrum. Further studies are needed to finally clarify the question of the character, efficacy and hypolipidemic action of the natural-produced cholesterol oxidase test drug in other types of animals.

Reviews on Clinical Pharmacology and Drug Therapy. 2020;18(2):155-160
Discussion to modern points of pharmacology
Medications and bruises: past, present, and future
Urakov A.L.

The literature review shows that modern standards of treatment of diseases, as well as forms of statistical reporting of medical institutions do not include bruising as an independent disease and/or complication of drug therapy. Ancient and modern textbooks and reference books on drugs do not contain indications of the presence of drugs that cause bruising and/or vice versa, discoloring the skin in the area of bruises. Official medicine does not offer medications for urgent skin discoloration in the area of bruises. However, bruises have been known for a long time, and people have been fighting them for a long time, but without much success. It is shown that bruises are blood-stained areas of the skin that often occur when hitting hard objects in everyday life, injuries and wounds, as well as when injecting drugs and using drugs that thin the blood. Usually bruises disappear on their own after 5 to 8 days. The true bruising is most likely to occur when bites of snakes such as Gyurza and Viper, when injecting drugs such as heparin and its substitutes, as well as when injecting donor blood and when through-piercing veins with injection needles. Throughout the history of mankind, these facts have not been used sufficiently to analyze the causes of bruising, the possibilities of their diagnosis, prevention and elimination. This was done at the beginning of the 21st century in Russia. At the same time, the biological and clinical essence of the bruises was revealed. This scientific discovery made it possible to explain the absence of bruises in the list of diseases, offer a clinical classification of bruises, and discover drugs that can immediately discolor the skin in the area of bruises. This group of drugs has received names such as “bruising bleachers”, “oxygen-alkaline bleachers”, “oxygen-alkaline bleach cleaners”, “blood bleachers” and “bleaching agents” over the years. Their main ingredients are water, hydrogen peroxide, and sodium hydrocarbonate.

Reviews on Clinical Pharmacology and Drug Therapy. 2020;18(2):161-170

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