[Peculiarities of hypnotic effect and pharmacokinetics of hemisuccinate 3-hydroxyphenazepam (levana)].

The pharmacodynamics and pharmacokinetics of hemisuccinate 3-hydroxyphenazepam (HS-3-HPh, levana)--a new hypnotic 1,4-benzodiazepine derivative--have been studied. It is established that HS-3-HPh in doses of 0.05, 0.1 and 2 mg/kg produces reliable hypnotic action (shortens the period of falling asleep, reduces the number of awakenings at night-time, and increases sleep duration) in the hexenal sleep potentiation test on mice. After a 7-day drug administration, no withdrawal syndrome has been observed. The concentration of 3-oxyphenazepam (3-OP, the main metabolite of HS-3-HPh) in brain after drug administration is significantly higher than the content of 3-OP upon its introduction. The content of 3-OP upon its introduction rapidly decreases, while that upon the administration of HS-3-HPh is retained on a stationary level for a rather long time (about 6 h). It can be suggested that a specific character of HS-3-HPh hypnotic action is determined by peculiarities of its pharmacokinetics, namely, easier entering the brain and subsequent hydrolysis with release of the active metabolite (3-OP).

[Biopharmaceutical classification system--experimental model of the prediction of drug bioavailability].

Biopharmaceutical classification system (BCS) is based on solubility tests; for various drugs they correlate with their bioavailability in human body. It is widely used in design and development of innovation drugs, new dosage forms (permeability amplifiers), in clinical pharmacology (drug-drug, drug-food interaction) and also by regulation agencies of several countries as the scientific approach, for testing of waiver on bioavailability. Review considers modern concepts and theoretical bases for prediction of bioavailability according to BCS. It gives characteristics of fundamental parameters of the system: absorption number, solubility number and the ratio of dose to the soluble part of the drug. Possible versions of BCS modification for its subsequent optimization are discussed.

[Comparative kinetics of 3-hydroxyphenazepam and its metabolism during transdermal and intravenous administration]. / Osobennosti sravnitel'noi kinetiki ékskretsii 3-hydroxyphenazepama i ego metabolitov pri transdermal'nom i vnutrivennom vvedeniiakh.

The kinetics of excretion of 2-(14)C-3-hydroxyphenazepam and its metabolites were studied upon a single transdermal and intravenous administration in mice. The main fraction of the total radioactivity (approximately 80%) was eliminated within approximately 84 h upon intravenous injection and within approximately 360 h after transdermal introduction. In the latter case, the ratio of lipophilic and hydrophilic metabolites is modified as well: the former fraction increases by a factor of 1.75, while the latter decreases by a factor of 1.2 as compared to the case of intravenous drug administration.

[Biochemical mechanisms of realization of antiviral and interferon-inducing activity of amixine and its analogs]. / Biokhimicheskie mekhanizmy realizatsii protivovirusnoi i interferonindutsiruiushchei aktivnosti amiksina i ego analogov.

Antiviral and interferon inducing activity of the amixine and its some derivatives, as well as their influence on the proteolytic enzymes activity, monooxygenase activity of the microsomal fraction, level of the lipids peroxidation were studied. Lack of correlation between antiviral and interferon inducing activity in the investigated series of compounds was found. Vice versa, the good correlation between interferon inducing activity and the elastase-like activities inhibition ability of the compounds was observed. It allows to state the assumption, that only one ability of compounds to induce of an interferon doesn't suffice for obtaining of high titres of interferon, and while their rather high antiproteolitic activity is necessary. It's shown, that except for one compound the influence of amixine and its derivatives on the red-ox enzymes activity well correlates with their ability to the interferon-inducing. All presented above allows to attribute amixine and its derivatives to polymodal antiviral agents.

[Effect of enomelanin on lipid peroxidation and the glutathione system in rat lung tissue exposed to NO2]. / Vliianie 'enomelanina na perekisnoe okislenie lipidov i sistemu glutationa v legochnoi tkani krys pri deistvii NO2.

Effect of preliminary intraperitoneal injection on the state of the glutathione system and lipid peroxidation intensity in the lungs of rats subjected to NO2 has been studient. This compound is shown to decrease significantly all lipid peroxidation processes and to inhibit completely glutathion oxidation. These effects are supposed to be a result not only of antioxidant properties of enomelanin, but also of its ability to promote a decrease in the activity of glutathione-depending enzymes subjected to NO2.

[Biochemical mechanisms of protective action of enomelanin during hemic hypoxia caused by carbon monoxide]. / Biokhimicheskie mekhanizmy zashchitnogo deistviia énomelanina pri gemicheskoi gipoksii, vyzvannoi ugarnym gazom.

Prophylactic injection of enomelanine has been studied for its effect on hemic hypoxia and on different parts of breathing system. The enomelanine was shown to be effective for decreasing the level of carboxyhemoglobin and for protection from succinate dehydrogenase and cytochromoxidase. The authors think that these effects of enomelanine are conditioned not only by its anti-hypoxia abilities, but also by the capacity to activate the alternative protective mechanisms of the cell.

[Anti-edematous action of EDTA, its effect on lipid peroxidation intensity and various components of the antioxidant system of the lungs in rats exposed to NO2]. / Protivootechnoe deistvie EDTA i ee vliianie na intensivnost' perekisnogo okisleniia lipidov i nekotorye komponenty antioksidantnoi sistemy legkikh krys pri vozdeistvii NO2.

It has been studied how preventive administration of EDTA influences toxic NO2- induced pulmonary edema and disturbances in antioxidant systems. The compound in question, being preventively administered, has exerted a significant antiedematic effect as a result of a decrease in lipid peroxidation intensity and protection of the most important substrate components of the nonenzymatic antioxidant system from the oxidation effect.

[Correction of lipid peroxidation intensity and glutathione system by derivatives of polygalacturonic acid after exposure to nitrogen dioxide]. / Korrektsiia proizvodnymi poligalakturonovoi kisloty intensivnosti perekisnogo okisleniia lipidov i sistemy glutationa pri vozdeistvii dioksida azota.

Influence of intraperitoneal administration of polygalacturonic acid derivatives at a dose of 100 mg/kg on the glutathione system and lipid peroxidation in the rat lung after treatment with NO2 was studied. A considerable decrease of lipid peroxidation intensity by these derivatives was caused not only by ability of these compounds to the chelate formation and absorption of free radicals, but also by the substantial activation of the glutathione system.

[Reduction of cytochrome p-450 content and activity by porphyrins after damage to the microsomal membrane by tetrachloromethane]. / Vosstanovlenie porfirinami soderzhaniia i aktivnosti tsitokhroma P-450 posle povrazhdeniia mikrosomal'noi membrany tetrakhlormetanom.

Natural porphyrin (hemin and its synthetic analogue--tetraphenylporphyrin with iron TPP-Fe3+) has been studied for its effect on activity of monooxygenase responses and cytochrome P-450 content against a background of introduction of four-chlorine carbon in the in vitro experiments. The reducing effect of hemin and TPP-Fe3+ on cytochrome P-450 and dependent enzymes: N-demethylase, n-hydroxylase and benz(a)pyrene hydroxylase has been noticed; the synthetic analogue of heme was more efficient.

[Biokinetics of a new prodrug gidazepam and its metabolite]. / Biokinetika novogo prolekarstvennogo preparata--gidazepama i ego metabolita.

Pharmacodynamics and pharmacokinetics of a novel tranquilizing agent--gidazepam (I), a prodrug, and its physiologically active metabolite--7-bromo-5-phenyl-1,2-di-hydro-3H-1,4- benzodiazepine-2-one (II) in mice organism were studied. The form of relationship was determined between the dynamics of the anticonvulsant effect of labelled (2-14C-) I and II and the kinetics of the content of 14C-compounds in the experimental animals brain. It was noted that the biophase of the effect and the effector fragment of the scheme of biokinetics for I and II are identical. The effector prognosis of pharmacokinetics of I was realized. The comparison of the main characteristics of biokinetics for the prodrug (I) and drug (II) allowed us to reveal the nature of the quantitative differences of these pharmacological effects.

[Effector modeling of the action of ligands of the GABA receptor complex: functional interactions of muscimol and exogenous modulators of the complex]. / Effektornoe modelirovanie deistviia ligandov GAMK-retseptornogo kompleksa: funktsional'noe vzaimodeistvie mustsimola i ékzogennykh moduliatorov kompleksa.

In comparison with the literature data the pharmacological effects of muscimol (MS) on mice organism were studied under the condition of administration of the exogenic ligands of GABA-receptor complex GABA antagonist bicuculline (BC), chloride ionophor blocking agent pentylenetetrazole (PZ), phenazepam (BD), sodium barbital (BB) and GABA synthesis antagonist--thiosemicarbazide (TS). Antagonism of MS to the anticonvulsant effect of BB and BD at the administration of BC to the animal was observed, while no effect was observed at the administration of PZ. However at the administration of TS to the experimental animals MS exhibits anticonvulsant effect. The observed properties (partial agonism/partial reverse agonism) of MS at its effect to the whole system are probably determined by the level of endogenic GABA and its changes due to the administration of TS and functional state of GABA--receptor system modified with the exogenic ligand BC.

[Conformational properties of biologically active melanostatin analogs]. / Konformatsionnye osobennosti biologicheski aktivnykh analogov melanostatin.

On the basis of the two-dimensional 1H NMR studies the conformation of melanocyte inhibiting hormone (HCl.Pro-Leu-Gly-NH2, MIF) and its five analogues with p-substituted phenylalanine has been determined. Structure-antidepressant activity relationship (examined by the Porsolt test) of MIF and its analogues has been estimated by means of the multivariate statistical analysis, the vicinal spin coupling constants, which determine phi and chi dihedral angles of the second amino acid and phi and dihedral angle of glycine, being selected as structural parameters. It is shown that a biologically active conformation (10-membered beta-turn II) is realized for the considered peptides.

[The effect of tilorone on peroxidation systems and antiperoxidation defense under normal conditions and in hypoxia]. / Vliianie tilorona na sistemy perekisnogo okisleniia i antiperekisnoi zashchity v norme i pri gipoksii.

Modifying effects of widely used immunomodulator tylorone on lipid peroxidation and the state of antioxidant system were studied under conditions of normal state as well as in subacute poisoning with carbon monooxide. Multiple effects of tylorone on these reactions were found in various tissues. The drug increased content of reduced glutathione in liver tissue, while amount of the substance was decreased in kidney and heart muscle. Content of diene conjugates and of SH-groups in blood, content of ascorbate in adrenal glands and activity of glucose-6-phosphate dehydrogenase in liver tissue were found to decrease. After administration of tylorone alterations of the most patterns studied under hypoxic conditions were similar to those of normal state. At the same time, the oppositely directed alterations were detected in content of reduced glutathione in heart muscle and in activity of glucose-6-phosphate dehydrogenase in liver tissue under conditions of carbon monoxide poisoning.

[Mechanisms in the modulation of the reactions of immune splenocytes by macroheterocyclic compounds]. / Izuchenie mekhanizmov moduliatsii reaktsii immunnykh splenotsitov makrogeterotsiklicheskimi soedineniiami.

The effect of macroheterocyclic compounds possessing immunostimulating properties in vivo on the reactions of the immune splenocytes in vitro has been studied. It has been shown that the cell activity is determined by the medium ionic composition. In the medium with the optimal content of the bivalent cations the azacrown ethers decrease the intensity of the immune splenocytes reactions depending on the dose. In the media of the modified ionic composition the studied compounds in concentration 10 microM activate all the reactions of the spleen cells, in concentration 100 microM they suppress or do not change them.

[Correlation of the behavioral characteristics of animals with varying levels of alcohol motivation: motor activity, taste and electrical pain sensitivities]. / Korreliatsiia povedencheskikh kharakteristik zhivotnykh s razlichnym urovnem alkogol'noi motivatsii: dvigatel'noi aktivnosti, vkusovoi i élektrobolevoi chuvstvitel'nosti.

It is shown that rats with a high degree of orienting-investigatory behaviour, low thresholds of emotional and pain sensitivity consume considerably more ethanol and rejected substances--urea and mustard--in comparison with low-active, less electrical pain-sensitive animals with a low degree of alcohol motivation. It is suggested that studying of characteristics of specialized appetite can be an important factor for prognostication of behaviour and role of individual in population.

[Effector modeling of the action of ligands of GABA-receptor complex. Functional interaction of the hypothetic alcohol receptor with other subunits of the complex]. / Effektornoe modelirovanie deistviia ligandov GAMK-retseptornogo kompleksa. Funktsional'noe vzaimodeistvie gipoteticheskogo retseptora spirtov s drugimi sub"edinitsami kompleksa.

The types of the interaction of the pharmacological effects of ethanol and barbiturate antagonists--picrotoxin, bemegride and corasol--were determined. The effect of ethanol was determined as competitive--for the convulsant effects of bicuculline, and non-competitive--for the effects of thiosemicarbazide. The indices of the anticonvulsant effects of n-aliphatic alcohols were compared. It is suggested that n-aliphatic alcohols alter the functional status of the supramolecular GABA-receptor channel ensemble. The pharmacological properties and the elements of the structural similarity of picrotoxin and n-propanol (the presumptive ligand of the GABA-receptor channel ensemble) are discussed.

[Effector modelling of the action of ligands of the GABA-receptor complex, cooperativity of the processes and the type of modification of the complex by convulsants and their reversible agonists]. / Effektornoe modelirovanie deistviia ligandov GAMK-retseptornogo kompleksa, kooperativnost' protsessov i tip modifikatsii kompleksa sudorozhnymi agentami i ikh obratnymi agonistami.

The expression of cooperativity of pharmacological effects of convulsants--exogenic ligands of supramolecular GABA-receptor-channel ensemble (GABA-RC)--bicuculline, picrotoxin, pentylenetetrazole, bemegride at intravenous infusion to intact animals and against a background of administration of barbital-Na and phenazepam is determined. The supposed mechanism of bemegride effect is discussed. Analysis of principles of GABA-RC functioning in vivo on the base of pharmacological data (cooperativity coefficients and types of modulation of GABA-RC functions at the interaction of convulsants and their reverse agonists) suggests the formation of biosystem response at modification of structures adequate to one of four subunits of "quartet" (tetrameric) model of GABA-RC.

[Tetraphenylporphyrin-Sn4+ induction of cytochrome P-450]. / Induktsiia tetrafenilporfirinom-Sn4+ tsitokhroma P-450.

TPP-Sn4+ was administered intraperitoneally (25 mg/kg body weight). The study was performed for 1-30 days. A day after administration the increase in the hemoprotein level 1.4 times was observed, as well as an increase in the level of p-hydroxylation of aniline. On 7-14 days the greatest increase in cytochrome P-450 content was observed. To clarity the mechanism of TPP-Sn4+ effect on cytochrome P-450, we studied its effect on the activity of heme oxygenase and LP rate. This compound is an inhibitor of heme oxygenase activity and reduces the rate of LP in the microsomes which regulates porphyrin metabolism in the organism.

[The fenazepam demand by rats depending on the degree of alcoholic motivation]. / Potreblenie fenazepama krysami v zavisimosti ot stepeni alkogol'noi motivatsii.

Phenazepam stimulates the drinking behaviour of rats. Under free-choice conditions ethanol-preferring rats drank significantly greater amount of phenazepam solution than those not preferring ethanol. Intraperitoneal administration of phenazepam and ethanol eliminated differences between the animals of the two groups in consumption of each substance but had no cross effect.