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Background: To evaluate acute toxicity and local anaesthetic activity of a formulation containing a novel dimethylacetamide derivative, antioxidant, and vasoconstrictor in rats with chronic periodontitis., Methods: Novel anaesthetic dimethylacetamide-containing formulation LHT-15-32 was studied as 2% water solution. Its acute intravenous and subcutaneous toxicity was determined in mice. Pain sensitivity threshold of the upper second molar was determined in rats with experimental periodontitis. Oxidative stress activity and total antioxidant capacity were determined in rats' gingival mucosa by induced chemiluminescence. Local changes were evaluated in periodontal tissue by morphological examination. Tissue IL-1 β , IL-10, and TNF-α concentration was quantitatively assessed by an enzyme-linked immunosorbent assay. LHT-15-31 Na-blocking activity was studied on isolated neurons of Limnaea stagnalis ' parapharyngeal ganglion. Isolated sciatic nerve of Rana radibunda was perfused with different concentrations of LHT-15-32 to assess its conductivity. Statistical analysis was used, and continuous variables were presented as mean ± square deviation. The normality of distribution was determined using ANOVA. Newman-Keuls parametric criterion was used for intergroup comparison. LD 50 indexes were calculated by probit analysis., Results: LHT-15-32 acute intravenous and subcutaneous toxicity was lower than that of its active substance. The formulation by infraorbital administration induced deep dental anaesthesia which lasted over 70 min and activated the local antioxidant defense system and decreased IL-1 β level in gingival tissue. LHT-15-32 triggered tissue reparation around the impacted upper molar in rats assessed five days after administration. At 10 -6 to 10 -3  M concentration, LHT-15-32 inhibited sciatic nerve conductivity and blocked Na + channels of isolated neurons in a dose-dependent manner., Conclusions: The formulation may be considered as an effective and safe approach to anaesthetize upper molars with periodontitis., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2020 Ekaterina V. Blinova et al.)

Novel anaesthetic formulation LHT-15-32 was studied. The experimental study involved 66 white mice, 15 Rana radibunda frogs and 50 male Sprague Dawley rats. Its acute intravenous and subcutaneous toxicity was determined in mice. Pain sensitivity threshold of upper second molar was determined in rats with experimental periodontitis. Oxidative stress activity and total antioxidant capacity were determined in rats' gingival mucosa by induced chemiluminescence. Tissue IL-1β, IL-10 and TNF-a concentration was quantitatively assessed by ELISA. LHT-15-32 Na-blocking activity was studied on isolated neurons of Limnea stagnalis para-pharyngeal ganglion. Rana radibunda isolated sciatic nerve was perfused with LHT-15-32 to assess its conductivity. LHT-15-32 acute intravenous and subcutaneous toxicity was lower then that of its active substance LHT-4-00. The formulation infraorbital administration induced deep dental anaesthesia lasted longer than 70 min, activated local antioxidant defence system and decreased IL-1β level in gingival tissue. At 10 -6 to 10 -3 M LHT-15-32 inhibited sciatic nerve conductivity and blocked Na + -channels of isolated neurons in dose-dependent manner. LHT-15-32 proved to be less toxic than active substance and lidocaine. The agent provides deep and prolonged anesthesia of the upper molar of rats in chronic apical periodontitis, lowers tissue concentration of pain cascade cytokines and oxidative stress activity and suppresses the action potential amplitude of a sensory nerve due to Na-blocking activity.

Context: Exploration of the biological property of programmed death-ligand 1 (PD-L1) signaling that may impact bladder tumor growth in humanized animals and cell culture., Aims: The aim of this study is to evaluate how PD-L1 signaling involves bladder cancer growth and progression., Settings and Design: This study design involves experimental in vivo and in vivo study., Subjects and Methods: A role of PD-L1 signaling pathway inhibition for bladder cancer growth was assessed in humanized immunodeficient animals carried main molecular subtypes of bladder carcinoma patient-derived xenografts and provided with selective anti-PD-L1 treatment; bladder cancer cells invasiveness was evaluated in mixed RT112/84 cells + CD4 + cells culture incubated with PD-L1 blocker durvalumab. We used two-tailed Student's t -test to explore differences between main and control subgroups. Significance of intergroup comparison was measured with one-way ANOVA followed by the Tukey's or Newman-Keul's criterion. Survival curves were analyzed with Gehan's criterion with the Yate's correction. Differences were considered statistically significant at P < 0.05., Results: Anti-PD-L1 intervention increased survival of the animals carried both primary and relapsed luminal noninvasive, muscular invasive, and relapsed luminal bladder cancer xenografts. There was significant retardation of tumor volume duplication time in aforementioned subgroups correlated with PD-L1 expression. Durvalumab treatment in concentration-dependent manner inhibited tumor cells invasiveness of mixed RT112 + CD4 + culture cells with its maximum at the highest studied concentration (10 μM)., Conclusions: Obtained data constituted the pivotal role of programmed cell death-1/PD-L1 signaling pathway in bladder cancer development and progression. The results will have major implications for further clinical investigations., Competing Interests: There are no conflicts of interest.

The effect of a cerebroprotective agent magnesium bis-aminoethanesulfonate (laboratory code FS-LKhT-317) on intracellular calcium concentration was studied by the fluorescent imaging technique on neuroglial cell culture from Spraque-Dawley rat hippocampus. The substance produced a pronounced inhibitory effect and suppressed NMDA receptor activity in concentrations of ≥50 μM. The observed effects were reversible or partially reversible and were detected by a decrease in Ca 2+ signal amplitude in neurons in response to NMDA applications in a Mg 2+ -free medium and by inhibition of Ca 2+ pulses in magnesium-free medium (elimination of magnesium block).

2-Amino-4H-chromene derivatives possess anticancer property proved on different in vivo and in vitro models of malignancies such breast, nasopharyngeal, bladder, ovary carcinomas, astrocytoma, and osteosarcoma. We assumed it might be effective to apply one of the derivatives as promising approach to lung carcinoma treatment. to evaluate how novel 4-aryl substituted 2-amino-4H-chromene derivative AX-554 impacts tumor growth and progression, as well as possible mechanisms for anticancer effect development on in vivo patient-derived heterotopic xenograft model of lung carcinoma in mice. This was an experimental in vivo study. 40 nu/nu BALB /c female mice were randomly allocated into four equal groups: Intact, control, reference, and main group. Animals of three latter groups were ingrafted with human-derived lung adenocarcinoma. Antitumor and antimetastatic action of AX-554 novel aminochromone derivative as a substance were studied. Mice survival was registered. Kinase of anaplastic lymphoma (ALK), tubulin Beta-3 (TUBB3), and c-mesenchymal-epithelial transition (MET) concentrations in the prime tumor nodes homogenates were determined by quantitative enzyme-linked immunosorbent assay. Dannet's parametric criterion and the nonparametric exact Fisher test were used. The normality of the distribution was determined using ANOVA. The survival curve was analyzed using Gehan's criterion with the Yates's correction. Aminochromone derivative possesses an inhibitory effect on human lung adenocarcinoma transplanted into nu/nu BALB /c female mice, as well as significant antimetastatic activity. About 50 mg/kg/day AX-554 intragastric course increases animals' life expectancy of more than 3.3 times when compared with the control and induces remission in 60% of cases. The anticancer effect of the derivative is due to anti-ALK-mediated activation of tumor cells apoptosis and suppression TUBB3-dependent cell proliferation., Competing Interests: There are no conflicts of interest.

Experiments on the model of immobilization stress in albino mice showed that a combination of mexidol, thymogen, and hyperbaric oxygenation reduced adverse effects of diazepam on behavioral response of animals in the black-and-white chamber and elevated cross maze tests and led to optimization of the blood gas composition as manifested by increased oxygen tension, normalization of the partial pressure of carbon dioxide, and restoration of the acid-base balance and blood bicarbonate level. The proposed combined treatment can be recommended for the treatment of patients with stress-induced pathology.

The goal: to investigate a preventive activity for novel medication magnesium 2-aminoethansulfonate in experimental hepatitis in pregnant rats., Material and Methods: The study has been conducted in firs week pregnant rats with paracetamol and ethanol-induced liver injury., Results: There has been found out that new domestic compound magnesium 2-aminoethansulfonate (laboratory name LBK-527) introduced daily at a dose of 28 mg/kg per os during 6 days, limits cytolysis and cholestasis caused by either paracetamol or ethanol intake in experiments in pregnant rats. Study shows that liver of the animals, that have been given LBK-527 simultaneously with either 500 mg/kg paracetamol or 10 ml/kg 40% ethanol, remains being structurally close to normal. The substance prevents acute toxic liver dystrophy and the organ's structure disintegration made by mentioned toxic agents. Having administered at a therapeutic dose LBK-527 isn't associated with faetotoxicity and embriototoxity in experiments in rats.

The new technology of hospital psychiatric care, developed and implemented in the Mordovia republican clinical hospital, permits resolving problems of hospitalism, lethality, pharmaceutical resistance and others. The essence of this technology is in staging of hospital care under condition of intensification and standardization of curative diagnostic process, implementation of complex approach to treatment of psychiatric disorders. The patient sequentially passes through three stages: intensive diagnostics and intensive treatment (intensive care department, intensive therapy department), supportive therapy (general psychiatric department); rehabilitation measures (curative rehabilitative department). The concentration of resources at the first stage, application of intensive therapy techniques permit in the shortest period to arrest acute psychotic symptomatic. The described new technology of hospital psychiatric care permits enhancing effectiveness of treatment, significantly shorten period of hospitalization (37.5 days), to obtain lasting and qualitative remission, to rehabilitate most fully social working status of patient and to significantly decrease lethality.

In the article there are presented the results of research on naturally conditioned insufficiency of trace elements, particularly iodine, in the Republic of Mordovia. Iodine deficiency disorders are referred to the most common non-infectious human pathology. According to WHO data, about two billion people on Earth live in conditions of in iodine deficiency. In the Russian Federation there are no areas in which the population would not be at risk for the development of iodine deficiency disorders. To these regions and the Republic of Mordovia is referred. The prevalence of diseases caused by iodine deficiency among the urban population accounted for 100-150, among rural--130-350. In some regions of endemic goiter rate reaches 800. Analysis of the morbidity rate of the population in the Republic of Mordovia, associated with the iodine deficiency, shows that in the structure of diseases related to micronutrient deficiency, by 2013 diffuse goiter plays a leading role, beingfollowed by a multi-node (endemic) goiter onward thyroiditis, subclinical hypothyroidism and hyperthyroidism. Thus, the analysis of indices of new cases of diseases associated with the iodine deficiency, allows to make the conclusion that diffuse goiter is the most significant pathology. In the structure of diseases related to the micronutrient deficiency, out of the most frequently detected iodine deficiency disorders, the greatest fraction are diffuse and multinodular goiter. The study was conducted with the support of the project, performed in the framework of the basic part of the State assignment (project 2859) and a RHSF grant.

A comparative study of the acute toxicity and antiarrhythmic activity of new domestic derivatives of dimethylacetamide showed that the introduction of amino and carboxylic acid residues into the structure of compounds is accompanied by reduction of the toxic properties of new substances on the average 2.73 times (p = 0.002) upon intraperitoneal introduction to animals. It has been established that the derivatives are able to prevent the formation of aconitine induced arrhythmias and eliminate the arrhythmia that occurs on the second day of myocardial infarction in dogs. Original derivatives of dimethylacetamide exhibit antiarrhythmic properties and their activity increases in proportion to the acute toxicity (r = 0.83, p = 0.0043).

Experiments on rats with myocardium infarction showed that intravenous administration of etoxidol in a dose of 14.2 mg/kg restricted the size of necrosis area and reduced the ratio of necrosis/ischemia zones. The test compound reduced the risk of rhythm and conduction disturbances induced by administration of toxic epinephrine doses to the mice, and increased mouse survival. Etoxidol administered intravenously to cats with acute myocardial ischemia reduced epinephrine concentration and intensity of free radical oxidation in zones of myocardial lesions against the background of the increase in norepinephrine concentration and antioxidant activity in the myocardium. By antiischemic and antioxidant activity, etoxidol was superior to its structural analogue mexidol.

Experiments on mice with streptozotocin-induced diabetes mellitus and stress-induced erosive ulcerous damage of the mucous membrane of stomach showed evidence of the preventive activity of deanol aceglumate in the course of peroral introduction at a dose of 250 mg/kg per 24 h during 4 days. This effect is accompanied by activation of the peristalsis of bowels and by an increase in the blood flow in the wall of stomach.

A complex pharmacological study of the new cytoprotector drug etoksidol in animals with the disturbances of cerebral blood circulation showed that the intravenous introduction of the drug restores autonomous nomotopic driver of rhythm, conductivity in the atria and atrioventricular connection, and refractoriness of the atrioventricular connection, which were violated a result of sharp cerebral ischemia. The new drug does not suppress the inotropic function of the heart in cats and limits the dimensions of the zone of necrosis in rats with the myocardial infarction on the background of deficiency of the cerebral blood flow.

Experiments on white mice under the model immobilization stress condition showed that a combined action of mexidole, diazepam, thymogen, and hyperbaric oxygenation (pathogenetic therapy) leads to optimization of the behavioral reactions, which is manifested by a decrease in the level of anxiety, increase in the locomotor and research activity, and normalization of the cortisole level. This effect is explained by a complex pharmacological action of all factors on the immune and endocrine mechanisms of the stress pathogenesis.

The results of electrophysiological investigation of the effects of LKhT-12-02 (a quaternary ammonium derivative of lidocaine) on the intact cat heart and the isolated ion channels of Lymnaea stagnalis snail showed that this compound belongs to class 1B antiarrhythmic agents (Vaughan - Williams classification). The drug does not suppress the automatic nonmonotonic rhythm driver, does not influence the conductance in ventricles, auricles, and atrioventricular node in the sinus rhythm, and does not elongate the effective refractory period of the auricles and atrioventricular node. LKhT-12-02 decreases the rate of fast depolarization of the action potential, while not reducing its duration. The compound does not influence the conduction of sodium ion channels.

Complex electrophysiological study of the effects of quaternidine carried out on intact hearts from cats, myocardial fragments from rats, and single ionic channels of large edible snail showed that quaternidine demonstrates properties of class 1B antiarrhythmic drug according to Vaughan-Williams nomenclature. This agent did not suppress nomotopic pacemaker automaticity, did not change conduction in ventricles, atria, and atrioventricular junction in hearts with preserved sinus rhythm, did not prolong refractoriness of the atria and atrioventricular junction, but prolonged efficient refractory period of heart ventricles. Quaternidine decelerated rapid depolarization of the action potential, but had no effect on its duration. It did not affect potassium conductance.

The investigation of electrophysiological parameters of the cardiac activity in cats showed that, a derivative of lidocaine with glutamic acid (anion), does not influence the cardiac pacemaker and the myocardial excitability of atrium and ventricles, but decreases the atrioventricular conduction and increases the refractory period of myocardium in the left ventricle of intact heart. Under the conditions of myocardial ischemia, LKhT-3-00 exhibits a negative chronotropic effect. Lidocaine glutamate increases the refractory period of atrium and decreases the excitability and refractory period of ventricles.

The results of experiments on cats showed that quaternidine, a quaternary ammonium derivative of trimecaine, does not induce significant variations in the hemodynamic parameters, being advantageous in this respect to some well-known antiarrhythmic drugs. LKhT-3-00 (dialkylaminophenylacetamide glutaminate)--a tertiary derivative of lidocaine--leads to a slight decrease in the heart rate, an insignificant decrease in the arterial pressure for 10 min, and a pronounced enhancement of the pumping ability of the left ventricle over a time period of 30 min.

The results of experiments on dogs showed that quaternidine, a quaternary ammonium derivative of trimecaine, produces a significant antiarrhythmogenic effect in cases of rhythm disorders in the late stage of a model myocardial infarction. For drugs administered in a single isotoxic dose, the therapeutic effect of quaternidine in animals with acute myocardial ischemia considerably exceeds the duration of action of lidocaine and trimecaine.

The results of experiments on cats and dogs showed that quaternidine, a quaternary ammonium derivative of trimecaine, exceeds the structural precursors (trimecaine and lidocaine), as well as the reference drugs quinidine and propranolol, in intensity of the antiarrhythmic action upon single administration on the occlusive and reperfusive arrhythmia models. The therapeutic effect of quaternidine in animals with acute myocardial ischemia lasts for about 8 h, which more than 20 times longer as compared to the duration of action of both lidocaine and trimecaine.