DRUG DEVELOPMENT BY IN SILICO METHODS.

Multicenter studies of the last decade have confirmed the direct relationship between the spatial structure of drug compounds and their biological activity. Aim - the relevance of this topic, on the one hand, is explained by the rapid development of new technologies, on the other hand, by a large number of researches works devoted to the study of the influence of stereoisomeric factors on the therapeutic effect and side effects of drugs. In recent decades, computational approaches have been used to reveal the relationship between the biological properties of substances and their structure and to quantitatively describe this relationship. Quantitative Structure - Activity Relationships (QSAR) is widely used in modern drug chemistry. In combination with molecular modeling techniques, this trend has been commonly referred to as in silico methods, which implies a preliminary search for drugs by computer only, prior to experimental screening. Hundreds of QSAR and molecular modeling programs have been developed around the world: dozens of specialized scientific journals are published dedicated to computer-based methods of searching for biologically active substances. Thousands of articles have been published demonstrating the results of successful application of QSAR methods in the search for new biologically active substances. There are currently more than 101 million known organic compounds in the world, and the known number of biological activities exceeds 25,000, so global experimental testing of all substances is impossible. Thus, the use of in silico methods to search for drugs, in particular, for the preliminary selection of unpromising compounds is super relevant.

[SURGICALLY CAUSED INJURY AND WOUND-HEALING PROPERTIES OF BETULIN (EXPERIMENTAL STUDY)].

According to the experimental data a triterpene alcohol betulin have anti-inflammatory, wound- and burn-healing activity. Previous data reports, that betulin was used in not less than 5% concentrations. That is why studying less concentrations is of major interest. The goal of this investigation is to study anti-inflammatory properties of betulin-containing ointments on models of full-thickness skin and burn wounds. Betulin activity was studied on 170 white outbred rats with a back full-thickness skin wounds and 15 rabbits with ear skin burns. Efficiency of preparations was estimated according to a speed of wound (burn) surface reduction, time of a scab rejection (for wounds), character of hyperaemia reduction (for burns), histological data of wound (burn) preparations on the 7, 14 and 21 (3, 8 and 13) days and complete healing time of wound. Betulin-containing 0,2%, 0,5% and 5% ointments were studied. The highest wound-healing activity has shown 0,5% betulinic ointment. Burn-healing effects of 0,5% betulin-containing ointment were also more expressed, than in other groups. Full epithelization of wounds was seen on the 7 day (p=0,02). Speed of burn surface reduction of treated with 0,5% betulinic ointment was equal to that treated with «Pantenol¼, and even surpassed it according to histological data.

THE SELECTIVE SEROTONIN REUPTAKE INHIBITORS AND BEHAVIOUR OF ADULT DANIO RERIO IN EXPERIMENTS.

Depression is one the most common form of mental diseases. Due to epidemiological studies, it is common in different age groups including young people. Depression pathogenesis from the point of system perspective view consists of morphofunctional and pathopsychological components. The former can be divided into neuroanatomical, neurophysiological, neurochemical parts. Laboratory animals as experimental models are an invaluable tool for investigating pathogenesis of depressive disorders and creating potential treatments. Aim of study - to elucidate behavioral differences in Danio rerio exposed to selective serotonin reuptake inhibitors (SSRI). In our study Danio rerio was used as an experimental model of depression. In fish forming schools during separation in pairs, anxious and aggressive behavior towards each other was manifested. It contributes to formation of dominant-subordinate relationships. Before administration of fluoxetine and sertraline in all the groups studied, the lower level of fish swimming was observed. They were hyperactive. Aggressive behavior towards each other was not observed. On the third day of the experiment behavior of the fish in groups with fluoxetine and sertraline was different. In group with sertraline 25% of fishes come up to average level. In group with fluoxetine fishes remained at the bottom of the aquarium. On the fifth day of the experiment in the group with sertraline 25% of fishes had an abnormal craniocaudal position of the body in space.

[PRACTICE OF MANAGEMENT OF PATIENTS WITH INFECTIOUS ENDOCARDITIS IN CONDITIONS OF LOW FREQUENCY OF ETIOLOGICALLY SIGNIFICANT PATHOGENS IN THE RUSSIAN FEDERATION].

The article presents the results of a multicenter study of the etiology, antibiotic sensitivity and pharmacoepidemiology of infective endocarditis in the Russian Federation. The purpose of this study is to analyze the current practice of management of patients with infective endocarditis in conditions of low frequency of etiologically significant pathogens in the Russian Federation. The study included patients of both sexes of all age groups with definite and probable infective endocarditis. 406 cases of infectious endocarditis (240 in retrospect and 166 in the prospective part) were analyzed. Etiologically significant pathogen was isolated in 144 cases (35.5%). The structure of pathogens was dominated by gram (+) cocci (90.3%), most often - Staphylococcus aureus (46.5% of all isolated pathogens). Aminoglycosides (22.8%), parenteral cephalosporins of the III generation (22.1%) and glycopeptides (14.5%) were most frequently used in the course of starting antimicrobial therapy. When changing the mode of antimicrobial therapy, glycopeptides (18.6%), aminoglycosides (15.3%), fluoroquinolones (11.2%) and parenteral cephalosporins of generation III (9.5%) were most often prescribed.

PRO-INFLAMMATORY EFFECTS OF EXPERIMENTAL HYPERTHYROIDISM IN COLON OF MICE (IMMUNOHISTOCYTOCHEMICAL STUDY).

Thyroid hormones can exert responses in various immune cells affecting several inflammation-related processes. The interactions between the endocrine and immune systems have been shown to contribute to pathophysiological conditions. Aim of study - to answer the question if hyper- or/and hypothyroid state can be as provoking factor for inflammation in colon. The study was performed on 60 mature male mice of the inbred line C3H-A. On male mice was reproduced a model of experimental hyperthyroidism and hypothyroidism by oral intake of L-thyroxin and propylthyouracil, accordingly. By the 22nd week of the experiment all animals were sacrificed. The rectum was removed for histo- and immunocytochemical examination. In histological examination in hyperthyroid group the hypertrophy of the mucous membrane of the colon is detected. Simultaneously the frequency of cell mitosis is increased. Among the epithelium glands of the colon can clearly be seen apoptotic bodies. Moderate or expressed infiltration by lymphocytes and plasma cells is elucidated in mucous membrane of colon relatively to mucous membrane of colon of euthyroid group i.e. control one. In hyporthyroid group the hyportrophy of the mucous membrane of the colon was detected. The lymphocytic infiltration is not found. In immunocytochemical examination the frequency of CD20 and CD56 positive cells was significantly higher (>23%) in cytological preparation of membrane mucous of colon from hyperthyroid mice (p<0.01). Meanwhile CD20 and CD56 positive cells were detected in single cases in cytological preparation of membrane mucous of colon from hypothyroid mice. The same observation was done for healthy membrane mucous from control (euthyroid) group. It is possible that the thyroid status is one of the factors modulating the inflammation. This discussion is far from over, because it is unclear whether prolonged hyperthyroidism can actually activate pro-inflammatory reactions, which subsequently, in turn, activate carcinogenesis.

OX1R ANTAGONIST SB408124 ACTION AND EXTRAHYPOTHALAMIC CRF IN RATS AFTER PSYCHOTRAUMATIC EXPOSURE.

Corticoliberin (CRF) isn't only regulates hypothalamic-pituitary-adrenal axis activity, but also functions as a neurotransmitter in extrahypothalamic brain regions like amygdala, implicated in the emotional responses to stress. The CRF system provides an input to orexin neurons and can modulate the activity of orexinergic neurons in stress response. Some data showed the role of orexin-A in extinction of aversive memory. The orexin system was shown to participate in stress-induced behavior connected with the extended amygdala structures, like central nucleus of the amygdala. The objective was to study the effects of orexin-A antagonist SB-408124 in rats after predator-induced stress using behavioral tests and its effects on CRF level in amygdala. In this study 30 male Wistar rats were used. The animals received an intranasally selective antagonist of Orexin receptor 1 type SB-408124. Posttraumatic stress disorder was modelled by single predator exposure. A group of 10-12 rats were placed in a terrarium with an indian python. 7 days after exposure to the predator, the behavior of animals was tested in the Open Field and Elevated Cross-Maze tests. Free motor activity of animals was studied in the "open field" test. To assess stress, we used the "elevated cross-maze " test. CRF concentrations in brain structures were measured by solid-phase ELISA using the Corticotropin Releasing Factor (CRF) test system. In the group of stressed rats receiving intranasally SB-408124, the time of stay in the light arm was restored, but did not reach the control values, the number of runs was restored to the control level, and the number of grooming acts increased in comparison with both the control group and the stressed animals. In the "open field" in the group of stressed rats receiving saline solution, the number of sniffs and rearing were decreased, but the number of peeks into holes was increased. In the group of stressed rats receiving SB-408124 20 µg intranasally, the number of sniffs was increased and the number of hole peeking decreased in comparison with the stressed rats receiving saline solution. The CRF level in the homogenates of amygdala in stressed rats was lower (0.44±0.07 ng/mg protein vs. 0.61±0.01 ng/mg in the control group). In the intranasal administration of SB408124 group this decrease was not recorded and the CRF level in the amygdala was 0.57±0.01 pg/mg protein. Orexin A antagonist SB-408124 reduced anxiety after psychotraumatic exposure. Predator induced acute psychotraumatic exposure decrease CRF level in the rat's amygdala. Intranasal administration of selective orexin 1 receptor antagonist SB408124 restored it closely to normal and has an anxiolytic effect on animal behaviour.

UNEQUAL HORMONAL RESPONSE OF MALE AND FEMALE C3H-A MICE TO THE THYROID AND ANTITHYROID AGENT TREATMENTS.

The state of physiological functions of the whole organism, its vital activity and adaptation to various changes in the surrounding and internal environment is controlled by neurohumoral mechanisms. The main place in the implementation of those mechanisms belongs to hormones. A clinically relevant problem is currently the relationship between activity of thyroid gland and prolactin. Aim of study. - To elucidate further the relationship of thyroid-stimulating hormone, thyroxine and prolactin. The study was performed on virgin 30 mature male mice and 33 mature female mice of the inbred line C3H-A. On male and female mice was reproduced a model of experimental hyperthyroid and hypothyroid status by the administration to L-thyroxin and propylthyouracil, accordingly. The blood samples from animals were assayed for TSH, T4 (total) and prolactin. In the hyperthyroid male mice the level of T4 (total) was significantly higher as compared to the hypothyroid and control groups. No deference for the level of TSH and prolactin was found between the hyperthyroid and the hypothyroid groups. In the hypothyroid female mice the level of TSH and T4 (total) was significantly lower and the level of prolactin was significantly higher as compared to the hyperthyroid and the control groups. The male and female mice responded in different ways upon the administration to L-thyroxin and propylthyouracil on the level of TSH, T4 (total) and prolactin.