[The chemical toxicological analysis of sertindole].

Sertindole is an "non-typical" neuroleptic extensively used for the treatment of schizophrenic patients. The detection of intoxication with this medication implies the necessity of development of the optimal methods for its isolation from the biological materials and further identification. The objective of the present work was to study the influence of various factors on the efficiency of sertindole extraction from solutions, the elaboration of the methods for its isolation from biological objects, detection, and quantitative determination in the extracts from these objects. Investigations into the influence of various factors on the isolation of sertindole from solutions included characteristic of the chemical nature of the organic solvent and the electrolyte, measurements of pH, time and frequency of extraction with the use of UV spectrophotometry. Isolation of sertindole from the liver, kidneys, brain, heart, gastric and intestinal contents was carried out by the method of A.A. Vasil'ev. Moreover, we have developed an original method for the detection of sertindole in the extracts using TLC, UV spectrophotometry, and HPLC. The qualitative determination of sertindole in the extracts from the internal organs, blood plasma, and urine was performed by HPLC. The optimal conditions for sertindole liberation from the extracts have been found and TLC-screening conditions proposed. The TLC, UV spectrophotometric, and HPLC techniques specially modified for the determination of sertindole in the extracts were used. It was shown that the maximum amounts of sertindole were present in the liver and brain within 24 hours after acute poisoning. In the kidneys, stomach, and intestines, it accumulated in smaller quantities Extracts from the heart did not contain sertindole. Maximum efficiency of the sertindole extraction during 24 hours was achived from blood plasma.

[EXPERIMENTAL STUDY OF SPECIFIC ACTIVITY OF 1.3-DIAZINON-4 COM- POUND PYaTd1 DERIVATIVE IN VIVO].

AIM: Study anti-leprosy activity of.a 1.3-diazinon-4 compound derivative under the labora- tory code PYaTd1 on the model of intra-plantar infection of mice and evaluate the character of its antibacterial effect. MATERIALS AND METHODS: Study of specific activity was carried out in vivo on the experimental model of leprosy, proposed by Shepard C.C., that assumes execution of intraplantar infection of mice with a suspension of mycobacteria, produced from lepromas or autopsy tissue of a non-treated leprosy infected, or from tissues of experimental mice, previously infected with Mycobacterium leprae from non-treated patients. The study was carried out on 120 CBA line-mice infected with M.leprae (VIII passage) from patient M; Dapsone and PYaTdl compound were administered to animals next day after the infection with forage at a dose of 25 mg/kg for 4.5, 6, 9 and 11 months. The mice were split into 3 groups: control (infected.without treatment), com- parison (infected, receiving.dapsone), experimental (infected, receiving PYaTdl). After.the control term the mice were euthanized under chloroform anesthesia. Suspensions for quantification of mycobacteria were prepared from paw pads. Smears were stained by Ziehl-Nilsson. RESULTS: After 4.5 months the intensity of infect reproduction under, the effect of dapsone and PYaTd1 was reduced compared with control by 18 - 25 times. After a 6-mont course - by 50 - 75% and after 9 months - by 85 - 90%. After 11 months in mice that had received PYaTd1, an intensive suppression of microorganism reproduction as observed: the yield in paws was 70 times lower than in control. In the group that had received dapsone, a reduction of the number of mycobacteria by 20 - 25 times was detected, it was significantly less effective than under the conditions of PYaTd1 admnistration. CONCLUSION: A novel 1.3-diazinon- 4 derivative under the code PYaTd1 can actively supress reproduction of-M. leprae, that gives evidence regarding its specific anti-mycobacterial activity and determines perspectives of its further studies.

[INFLUENCE OF NATURAL COMPOUNDS WITH POLYPHENOL STRUCTURE ON THE VASODILATION FUNCTION OF CEREBROVASCULAR ENDOTHELIUM IN RATS UNDER FOCAL ISCHEMIA CONDITIONS.]

It was studied the effect of two natural compounds with polyphenol structure, green tea polyphenols (Sigma-Aldrich) and catechol hydrate (Sigma-Aldrich) in a dose of 100 mg/kg, on the vasodilating function of endothelium in brain vessels of rats with model ischemic damage. The focal ischemia was modeled by occlusion of the right middle cerebral artery. The vasodilating function of endothelium was estimated from NO synthesis modification determined by means of the Doppler sonography technique. It was established that at the focal brain ischemia leads to the pronounced endothelial dysfunction that is confirmed by the suppressed reactivity of brain vessels to the action of a vasodilating factor (acetylcholine, Ach) and by development of the L-arginine paradox phenomenon. Upon the treatment with polyphenolic compounds studied, the ability of brain vessels to vasodilatation upon ACh introduction is retained. The observed blood flow enhancement (relative to negative control group) in response to the introduction of L-arginine significantly decreases upon the administration of green tea polyphenols and catechol hydrate (by a factor of 3.15 and 2.29, respectively). This result, in turn, gives grounds to assume that the polyphenolic compounds studied possess endothelium protecting properties.

Endothelial dysfunction and Protein kinase C activity development interrelation at ischemic injury of a brain.

The ischemic stroke is the reason of high mortality and population disability worldwide and it is closely connected with endothelium dysfunction (ED). The endothelium carries out regulation of specific functions, generally the universal modulator - nitrogen oxide. A number of enzymes participates in a production of nitric oxide, but specific for an endothelium is endothelial NO synthase (eNOS), which violation of regulation is observed at an ischemic stroke. Significant role in activity of eNOS regulation plays protein kinase C (PKC). In this review the following processes were investigated: ED and nitric oxide interrelation at an ischemic stroke; some features of biological activity of nitric oxide depending on a place of synthesis and on time of ischemic damage; eNOS activity regulation by means of PKC; interrelation between ED and PKC activity at oxidative stress; the main alarm ways including activation of eNOS and PKC which regulate microvascular permeability and a tone of vessels of a brain. Being guided by the carried-out analysis of theoretical data, it should be noted that at development of ED the PKC hyperactivity is observed, therefore, the search of the substances possessing inhibiting influence on activity of PKC for treatment of the majority of cardiovascular diseases and an ischemic stroke has become particularly important and perspective.

[Investigations of the distribution of aripiprazole in the internal organs and biological fluids of the laboratory animals in case of acute intoxication].

Despite the present-day extensive application of aripiprazole, there are many cases of its overdose and of poisoning with this compound. The objective of the present study was to detect and quantify aripiprazole in the internal organs and biological fluids of the laboratory animals in case of acute intoxication. The experiments were carried out on white mice of both sexes weighing 20.5 and 25.7 g. Aripiprazole was isolated from the liver, kidneys, brain, and heart as described by A.A. Vasil'eva and from the plasma and urine by the newly developed original methods. Aripiprazole was identified and quantitatively determined in the extracts from the aforementioned organs and tissues with the use of HPLC. The data obtained on the completeness of extraction from the liver, kidneys , and brain of the laboratory animals indicate that aripiprazole accumulated in the highest concentrations in the brain and kidneys within 24 hours after acute poisoning. Ist content was significantly lower in the liver while no traces of aripiprazole were found in the heart of the mice. The methods for aripiprazole isolation from the urine and blood plasma are described. The maximum amounts of aripiprazole were detected in blood plasma within 24 hours after acute intoxication. It is concluded that the proposed methods for aripiprazole isolation from the biological fluids (blood plasma and urine) can be included in the scheme of the chemical toxicological analysis of this compound.

[Study of the influence of original multicomponent gels on the process of pathological scar formation using new methodological approach].

A new method of the quantitative macroscopic assessment of the process of a complex infected wound healing has been created. It was verified by example of the influence of original multicomponent gels consisting of cycloferon, amino acid glycine, glycyram (ammonium salt of glycyrrhizic acid), and vegetable oils on the process of infected wound healing and pathological scar formation. Simultaneously, the wound healing was monitored by the conventional histomorphological method. The proposed gels more effectively prevent the formation of pathological scars in comparison to reference preparation Contractubex.

[Modern notions about the role of taurine in the central nervous system].

Literature data concerning modern notions about the role of taurine in the central nervous system are analyzed. Mechanisms of the neuroprotective activity of taurine are described. Evidence showing the effects of taurine as neurotransmitter, neuromodulator, antioxidant, etc. is provided.

[Molecular targets for searching of endothelial-protective substances].

Endothelial dysfunction underlies the development of many cardiovascular diseases. Thus endothelium becomes an independent therapeutic target, and the search of new substances with endothelial-protective action to date is one of the promising tasks for pharmacotherapy and medicinal chemistry. Molecular modeling is an effective tool for solving this problem. Computer chemistry methods use is only possible in combination with detailed information on three dimensional structure and functions of molecular targets: receptors and enzymes, involved in signal transduction inside and outside of endothelial cells. Information on structure and function of various macromolecules involved in vascular tone regulation is collected in the review. The structure of endothelial NO-synthase (EC 1.14.13.39) (eNOS)--enzyme, responsible for the nitric oxide synthesis and involved in vascular tone regulation process is reviewed. The importance of eNOS substrate--L-arginine is underlined in the review in terms of this enzyme activity, regulation, the information on structure and functions of L-arginine transport system is provided. Also different ways of eNOS activity regulation are reviewed, among which are enzyme activation and concurrent inhibition by substances interaction with active center of enzyme, inhibition by caveoline binding with oxigenase domain, and also regulation by phosphorylation of certain amino acids of eNOS by proteinkinase and dephoshphorylation of them by phosphatases. The importance of membrane receptors of endothelial cells as targets for endothelial-protective substances is underlined. Among them are receptors of endothelin, platelet activation factor, prostanoids, bradykinin, histamine, serotonin and protease activated receptors. The important role of potassium and calcium ion channels of vascular cells in endothelial-protective activity is underlined. Macromolecules presented in the review finally are considered as targets for searching for medicinal substances with endothelial-protective activity using proposed ways and methods of molecular modeling.

[Role of endothelial dysfunction in the development of vascular complications of diabetes].

The literature review discusses the main pathological factors (hyperinsulinemia, hyperglycemia, insulin resistance, oxidative stress, neurohormonal activation, disturbances in the synthesis system, allocation and availability of nitric oxide, etc.) that underlie the development of endothelial dysfunction in diabetes mellitus and determine their role in the development and progression of vascular complications of this disease.

[Endothelial protection drugs--a new class of pharmacological agents].

This review considers issues dealing with the role of nitric oxide and endothelial function/dysfunction in providing a number of physiological and pathophysiological processes and various body systems functioning. It also covers in details the possible ways of pharmacological management of endothelial dysfunction (ED) using drugs of different pharmacological groups (classes). Diverse pharmacological effects which have various degree of intensity and presented at various stages of ED pathogenesis are discussed. The value and urgency of search and development of agents with endothelial protection potential are studied in available experimental and clinical works on the considerable role of endothelial system in cardiovascular diseases and lack of specific means for prevention and treatment of endothelial dysfunction. Integrated morphological-functional approach to assessment of ED and endothelial protection of substances was developed and implemented in experimental practice in Cardiovascular Agents Laboratory of the Volgograd State Medical University Research Institute of Pharmacology. Various ED models were tested and most valid ones were selected. Endothelial protection of new compounds such as Salifen and Flavicin are considered and compared with cardiovascular drugs, antioxidants with metabolic effects, GABA derivatives. These drugs are assumed to belong to a new class of drugs--endothelial protection drugs.

[Effects of mexidol and sulodexide on the level of specific markers of endothelial dysfunction in animals with experimental diabetes mellitus].

Streptozotocin-induced diabetes leads to the development of endothelial dysfunction, as evidenced by decreased expression of endothelial nitric oxide synthase (eNOS) and increased expression of endothelin-1 as specific markers of endothelial disorders. All test substances showed endotelioprotective activity by increasing the concentration of eNOS and reducing the level of endothelin-1. With respect to the degree of impact on the eNOS and endothelin-1 levels, the compounds studied can be rated as follows: sulodexide > meksidol.

[Effect of cardiovascular drugs on vasodilating endothelial function in animals with experimental deficiency of sex hormones].

The influence of various cardiovascular drugs, including ACE inhibitors (lisinopril), beta-adrenoblockers (bisoprolol, nebivolol), calcium inhibitors (nifedipine), cholesterol-lowering drugs (simvastatin), and heparinoids (sulodexide), on the vasodilating endothelial function has been studied in animals with experimental deficiency of sex hormones. According to the expressiveness of a positive effect on endothelium-dependent vasodilatation in castrated rats, the tested drugs can be arranged in the following sequence: sulodexide > lisinopril > or = simvastatin > or = nebivolol > bisoprolol > nifedipine.

[Relationship between the antioxidant effect of flavonoids and their effect on the vasodilating function of endothelium under endothelial dysfunction conditions].

A relationship between the vasodilating activity of flavonoids under conditions of endothelial dysfunction in experimental diabetes and their antioxidant effect is established. Flavicin and quercetin show the maximum influence on the vasodilating function of endothelium and exhibit more pronounced antioxidant activity under conditions of endothelial dysfunction.

[Effect of flavicin on vasodilating and antithrombotic endothelial functions in animals with experimental diabetes mellitus].

It is established that flavonoid flavicin improves antithrombotic and vasodilating functions of blood vessels in rats with endothelial dysfunction caused by streptozotocin-induced diabetes.

[Development of endothelial dysfunction in sex hormone deficiency].

The review of literature deals with the implication of estrogen deficiency in the development of endothelial dysfunction and its related cardiovascular diseases.

[A new methodological approach to the experimental estimation of endothelial dysfunction].

A new methodological approach is proposed, which involves measurements of (i) the blood flow in vessels under the action of acetylcholine and nitro-L-arginine and (ii) the time of thrombus production as the reaction to iron chloride application on the wall of the vessel. Using this method, it is possible to estimate endothelial dysfunction in experiment.

[Comparative evaluation of the neuroprotective activity of phenibut and piracetam under experimental cerebral ischemia conditions in rats].

The neuroprotective properties of phenibut and piracetam were studied in rats with cerebral ischemia caused by bilateral irreversible simultaneous occlusion of carotid arteries and gravitational overload in craniocaudal vector. In addition, the effects of both drugs on microcirculation in brain cortex under ischemic injury conditions were studied. Phenibut and (to a lower extent) piracetam reduced a neuralgic deficiency, amnesia, and the degree of cerebral circulation drop, and improved the spontaneous movement and research activity deteriorated by brain ischemia.

[Effect of phenibut on the behavior of experimental animals under conditions of voluntary chronic alcoholism].

The effect of phenibut on the locomotor and orientation-research activity, as well as on the alcohol and food motivation, was studied on experimental animals under conditions of voluntary chronic alcoholism. Phenibut decreased the manifestations of alcohol-induced behavioral disorders and reduced alcohol motivation.