Approbation of a New Model of Secondary Damage after Traumatic Brain Injury Based on Reprogrammed Rat Embryo Fibroblasts.

The paper presents a new model of secondary injuries after traumatic brain injury. The model is based on the cultivation of rat embryonic fibroblasts reprogrammed to a neuronal phenotype in the presence of cerebrospinal fluid from injured rats. The presented model was used to test the therapeutic effect of inducers of the synthesis of chaperones from the classes of pyrrolylazines and indolylazines, which have neuroprotective properties.

Effects of Succinate-Containing Preparation on Characteristics of Rat Erythrocytes in Exhaustive Swimming with a Load.

We studied the dynamics of the red blood cell composition of Wistar male rats at rest and when swimming with a load (4% body weight) before and after administration of a succinatecontaining preparation (meso-2,3-dimercaptosuccinic acid). In rats receiving the succinatecontaining preparation, a decrease in the number of red blood cells and an increase in their volume and absolute and relative number of reticulocytes were observed at rest in comparison with vivarium control. In rats exposed to exhaustive swimming after preliminary administration of the test preparation (12 h before the test), we observed a decrease in hematocrit and erythrocyte diameter in comparison with the corresponding parameters in rats not treated with the preparation; the level of hemoglobin did not change. The pattern of changes in the cellular composition of red blood in rats at rest and during swimming against the background of treatment with the succinate-containing preparation in comparison with vivarium control is considered as a result of its effect on physical exercise under conditions of stabilization of hemoglobin and hematocrit levels, activation of proliferative activity of red bone marrow, and an increase in time of swimming to exhaustion by 2.8 times.

Indolyl- and Pyrrolylazine Derivatives Cause the Accumulation of Heat Shock Protein Hsp70 in Sh-Sy5Y Human Neuroblastoma Cells.

The heat shock protein Hsp70 is involved in cell defense from various types of stress, including the proteotoxic stress, which occurs during the development of many neurodegenerative diseases. This work presents data on the detection of small molecules, derivatives of indolyl- and pyrrolylazines, which can activate the synthesis of Hsp70 and cause its accumulation in the cell. The toxicity level of the new Hsp70 synthesis inducers was evaluated, and the safety of these compounds was demonstrated in experiments on SH-SY5Y neuroblastoma cell line. Derivatives of indolyl- and pyrrolylazines presented in this work can be potential therapeutic agents in models of neurodegenerative diseases that should be studied in more detail.

2-Morpholino-5-Phenyl-6H-1,3,4-Thiadiazine Corrects Metabolic Disorders during the Development of Alloxan Diabetes Mellitus in Rats.

Metabolic disorders were evaluated in rats with alloxan diabetes mellitus after administration of 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine (compound L-17). Administration of L-17 reduced the severity of metabolic disorders associated with diabetes mellitus. At the end of the experiment, the concentration of glucose, glycated hemoglobin, malonic dialdehyde, and catalase activity were significantly higher and peroxidase activity was significantly lower in the group of animals receiving L-17. The decrease of glycemia, glucose concentration, and glycated hemoglobin content was reached by the 3rd-4th week of the experiment. These data suggest that correction of biochemical parameters in rats with alloxan diabetes was reached after administration of L-17 for at least 3 weeks.

Alkyl 2-arylhydrazinylidene-3-oxo-3-polyfluoroalkylpropionates as new effective and selective inhibitors of carboxylesterase.

A series of alkyl 2-Arylhydrazinylidene-3-oxo-3-polyfluoroalkylpropionates was synthesized and their inhibitory activity with respect to porcine liver carboxylesterase (CaE, EC 3.1.1.1), human erythrocyte acetylcholinesterase (AChE, EC 3.1.1.7), and horse serum butyrylcholinesterase (BChE, EC 3.1.1.8) was studied. The molecular docking method was used to study the binding mode of the compounds in the active site of CaE. It was found that compounds containing the trifluoromethyl group in the third position of carbonyl chain are highly effective and selective inhibitors of CaE with nanomolar IC50 values, which agrees well with the results of molecular docking.

[Experimental comparative pharmacokinetics of levofloxacin, triazavirin, and related conjugate].

A comparative study of the pharmacokinetics of levofloxacin and triazavirine as well as 2-methylthio-6-nitro-1,2,4-triazolo[5,1-ñ]-1,2,4-triazine-7(4Í)-ide (3S)-(-)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-7H-pyrido[1,2,3-d,e]-1,4-benzoxazine-6-carboxylic acid (conjugate 2) obtained by conjugation of triazavirine and levofloxacin, representing a new class of pharmacological agents, was carried out in experiments on rats. It is established that conjugate 2 in comparison to individual levofloxacin and triazavirine has a higher relative bioavailability and lower rate of elimination, which can lead to improved effectiveness of therapy at reduced dose and frequency of drug administration.

[Investigation of Therapeutic Efficacy of Triazavirin Against Experimental Forest-Spring Encephalitis on Albino Mice].

The comparative study of the therapeutic efficacy of Triazavirin against experimental Forest-Spring encephalitis on albino mice vs. the active drug Ribavirin® showed that in high doses (200-400 mg/kg) Triazavirin moderately protected the infected animals. A significant increase of the animal lifespan in the test groups (from 4.1 to 4.8 days) and a statistically (p ≤ 0.05) valid decrease of the virus accumulation in the target organ (the brain) were observed.

[Investigation of Triazavirin antiviral activity against tick-borne encephalitis pathogen in cell culture].

The efficacy of Triazavirin against the tick-borne encephalitis virus was estimated in the sensitive cell culture vs. the active drug Ribavirin. In a concentration of 128 mcg/ml Triazavirin was shown active in inhibition of the tick-borne encephalitis virus reproduction (strain Sofiin) by accumulation in the SKEV cell culture.

[The antiaggregant action of 2-morpholino-5-(thienyl-2)-6-H-1,3,4-thiadiazine in in vitro and ex vivo experiments].

The influence of 2-morpholino-5-(thienyl-2)-6-H-1,3,4-thiadiazine (H-29) on the platelet aggregation has been studied in experiments on donor plasma in vitro. It is established that H-29 causes a decrease in the platelet interaction induced by ADP and arachidonic acid. The influence of H-29 on platelet aggregation was also studied in ex vivo experiments with intravenous and oral administration, and some parameters of plasmatic hemostasis were evaluated.

[A new antiviral drug Triazavirin: results of phase II clinical trial].

The results of the clinical trial testing the efficacy of a new anti-influenza drug Triazavirin are presented in this work. The data of the trial were gathered during the 2010 influenza season. The treatment with oral Triazavirin significantly reduced the duration of the main clinical symptoms of influenza (intoxication, fever, respiratory symptoms), decreased the incidence of the influenza-related complications and the use of symptomatic drugs. The re-isolation rate of the influenza A and B viruses was significantly lower in the patients who were using Triazavirin. The analysis of the clinical data showed that the optimal prescribed dosage was 250 mg 3 times a day.

[Toxicity of triazavirin, a novel Russian antiinfluenza chemotherapeutic].

The study of the toxicity of triazavirin, a new antiinfluenza agent, showed that the maximum concentration of the drug, inducing no microscopically visible changes in the structure of the monolayer and the cells of the MDCK and SKEV cell cultures, was 128 and 100 mcg/ml respectively. The maximum drug dose for single intraperitoneal administration inducing no signs of acute intoxication in albino mice weighing 10-12 g was 1000 mg/kg. In investigation of the chronic toxicity it was shown that oral administration of the drug (by 0.05 ml) to the albino mice in a dose of 200 mg/kg (maximum possible concentration by the solubility) daily for 10 days was well tolerated by the laboratory animals. The maximum tolerable dose of triazavirin for the albino mice was > or = 200 mg/kg.

Development of Drugs with Direct Antiviral Action Based on Azaheterocyclic Systems.

This article discusses the results of studies carried out in recent years by a team of scientists from the Postovskii Institute of Organic Synthesis, Ural Branch, Russian Academy of Sciences, in cooperation with the First President of Russia Boris Yeltsin Ural Federal University, Ural State Medical University, Volgograd State Medical University, and other scientific and production organizations of the country to create triazavirin (riamilovir) and other direct etiotropic antiviral drugs based on azaheterocyclic derivatives.

[Therapeutic efficacy of Triazavirin, a novel Russian chemotherapeutic, against influenza virus A (H5N1)].

Therapeutic activity of Triazavirin against experimental influenza A was studied on albino mice intranazally infected with influenza virus A/Chicken/Kurgan/Russia/02/05 (H5N1) vs. reference drugs (Oseltamivir, Remantadin and Arbidol). The study showed that in a therapeutic dose of 1 mg/kg Triazavirin was efficient in protection of the animals from death. Its protective therapeutic efficacy (36.7+/-1.7%) was close to that of Oseltamivir (50.0+/-0.0%), comparable with that of Remantadin (38.3+/-1.7%) and higher than that of Arbidol (11.7+/-1.7%). During the whole observation period (up to the terminal phase) Triazavirin inhibited the influenza virus A accumulation in the lungs of the infected albino mice by more than 3 lg.

1,2,4-Triazoloazine derivatives as a new type of herpes simplex virus inhibitors.

A new class of inhibitors of herpes simplex virus replication was found. The compounds under study are derived from condensed 1,2,4-triazolo[5,1-c][1,2,4]triazines and 1,2,4-triazolo[1,5-a]pyrimidines, structural analogues of natural nucleic bases. Antiherpetic activity and cytotoxicity of the compounds were studied. The corresponding triphosphates of several active compounds were prepared and tested as inhibitors of DNA synthesis catalyzed by herpes simplex virus polymerase. The potential mechanism of their action is blocking of DNA dependent DNA polymerase, a key enzyme of viral replication.

[Influence of new 1,3,4-thiadiazines on platelet aggregation in vitro and ex vivo].

The influence of new original 1,3,4-thiadiazines on the human platelet aggregation in vitro was studied. All substances inhibited the platelet aggregation induced by both ADP and arachidonic acid. 1,3,4-Thiadiazines L-19, H-30 and L-37 were the most effective inhibitors. Effect of the intravenous injection of L-19 in various doses on platelet aggregation and some parameters of plasmatic hemostasis were studied ex vivo.

[Triazavirin prophylactic efficacy against influenza virus A (H5N1)].

The experimental study of the prophylactic efficacy of Triazaverin against the experimental form of the influenza virus A (H5N1) on albino mice intranasally infected with the influenza virus A/Chicken/Kurgan/Russia/02/05 vs. the reference drugs Tamiflu, Remantadin and Arbidol showed that in doses of 1 to 100 mg/kg it was efficient in the animal protection from death. The drug was also efficient in the urgent prophylaxis. Triazaverin effectively inhibited the influenza A virus multiplication in the lungs of the albino mice.

Silicon-hydroxyapatite‒glycerohydrogel as a promising biomaterial for dental applications.

Nanocomposite silicon-hydroxyapatite‒glycerohydrogel (Si-HA‒glycerohydrogel) with different hydroxyapatite (HA) contents of 0.75 and 1.75 wt.% and the same Si content (2.04 wt.%) was obtained by the sol‒gel method. Silicon tetraglycerolate in the form of glycerol solution was used as a biocompatible precursor and HА in the form of aqueous colloidal suspension - as a template and property modifier. Transmission electron microscopy was applied to demonstrate that there are nanoscale HA particles that are in the crystalline state. For the first time, using the atomic force microscopy method, the remineralizing properties of Si-HA‒glycerohydrogel were studied on human teeth extracted for orthodontic reasons. It was found that Si-HA‒glycerohydrogel containing 1.75 wt.% HA has a pronounced remineralizing effect. Immersion of tooth enamel samples in the gel for one month significantly reduces roughness and makes the enamel surface more uniform. Silicon contained in glycerolates in a biologically active and accessible form exerts an additional positive effect on the process of remineralization of tooth enamel. By the energy dispersive X-ray analysis, it was demonstrated that the tooth enamel had an increased silicon content; and the Vickers microhardness test showed greater microhardness values. The obtained data analysis allows the remineralizing Si-HA‒glycerohydrogel to be considered as a promising biomaterial for dental applications.

[Antiaggregant properties of new 1,3,4-thiadiazine derivatives].

A series of new 1,3,4-thiadiazine derivatives have been synthesized and their effect on the human platelet aggregation in vitro has been studied. All the tested substances inhibit the human platelet aggregation induced by ADP and arachidonic acid in a broad concentration range. The most active 1,3,4-thiadiazines (L-19, L-28 and L-31) effectively inhibit platelet aggregation at concentrations within 0.01-1 mM.

Effects of a compound from the group of substituted thiadiazines with hypothermia inducing properties on brain metabolism in rats, a study in vivo and in vitro.

The aim of the present study was to examine how administration of a compound of 1,3,4- thiadiazine class 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide (L-17) with hypothermia inducing properties affects the brain metabolism. The mechanism by which L-17 induces hypothermia is unknown; it may involve hypothalamic central thermoregulation as well as act via inhibition of energy metabolism. We tested the hypothesis that L-17 may induce hypothermia by directly inhibiting energy metabolism. The study in vivo was carried out on Sprague-Dawley adult rats. Two doses of L-17 were administered (190 mg/kg and 760 mg/kg). Brain metabolites were analyzed in control and treated groups using magnetic resonance spectroscopy, along with blood flow rate measurements in carotid arteries and body temperature measurements. Further in vitro studies on primary cultures from rat hippocampus were carried out to perform a mitochondria function test of L-17 pre-incubation (100 µM, 30 min). Analysis of brain metabolites showed no significant changes in 190 mg/kg treated group along with a significant reduction in body temperature by 1.5°C. However, administration of L-17 in higher dose 760 mg/kg provoked changes in brain metabolites indicative of neurotoxicity as well as reduction in carotid arteries flow rate. In addition, a balance change of excitatory and inhibitory neurotransmitters was observed. The L-17 pre-incubation with cell primary cultures from rat brain showed no significant changes in mitochondrial function. The results obtained in the study indicate that acute administration of L-17 190 mg/kg in rats induces mild hypothermia with no adverse effects onto brain metabolism.

[The estimation of the perspectives of the 1,3,4-thiadiazine derivatives as the protectors means for the health tissues under radiation therapy of malignant tumour patients].

We generalized the results of our own researches of the mechanisms, determined the high (90% BALB-line mice were survived) radioprotection activity by 1,3,4-thiadiazine derivatives. It was determined that this preparat achieves the highest concentrations in the critical for the acute radiation influence tissues. The preparate bind with the cell's membranes, nucleus and mitochondries, blockade the development of the radial reactions on the tissues level. Small quantity passes to the brain marrow, takes part in the regulative processes, which central nervous system is produced, reduces the metabolitical processes in the organism. It doesn't possess the election accumulation in the tumour and it is perspective for the prevention of damage health tissues under irradiation cancroid's therapy.