[Various mechanisms of the depriming effect of bacterial endotoxin on drug metabolism]. / Nekotorye mekhanizmy deprimiruiushchego vliianiia bakterial'nogo éndotoksina na metabolizm lekarstvennykh veshchestv.

The effect of an endotoxin from Sh. Boydii on the biotransformation of amidopyrine and acetanilide, the activity of microsomal monooxygenases, hemoxygenase, and xanthine oxidase, the lipid peroxidation (LPO) intensity, the phospholipid spectrum, and the solubilization of microsomal membrane components was studied by intraperitoneal injections (2.5 mg/kg) in rats. It was found that the endotoxin inhibits the reactions of C- and N-acetanilide hydroxylation, N-amidopyrine demethylation, acetanilide hydrolysis at the amide bond, conjugation of aminophenol metabolites with glucuronic acid and sulfate, and 4-aminoantipyrine binding to acetate. The endotoxin effect reached maximum 24 h after injection and was observed for 96 h. The inhibition of metabolism of the test preparations is related to a decrease in the content of cytochrome P-450 and in the activity of 1A2, its 2B, 2C, 3A, and 2E1 isoforms. This is obviously caused by activated LPO and enhanced nitric oxide synthesis, as evidenced by a tenfold increase in the content of NO metabolites (nitrites and nitrates) in the blood of test animals. In clinical practice, it is necessary to take into account the possibility of a significant biotransformation of drugs in the acute period of bacterial infection, which may lead to changes in the pharmacological effect and toxicity of some drugs.

[Vitamin A and enzyme systems of metabolic activation of genotoxic compounds]. / Vitamin A i fermentnye sistemy metabolicheskoi aktivatsii genotoksichnykh soedinenii.

The study was undertaken to study the effects of N-nitrosodimethylamine (NDMA) on the formation of single-strand DNA breaks and gamma-glutamyltransferase-positive knots, the status of the enzymatic systems involved in NDMA metabolism and some other biochemical parameters when rats were on retinol-deficient diets and when they were given excessive vitamin A. The action of retinol on NDMA effects were analyzed by evaluating the activity of glutathione-S-transferase (EC 2.5.1.18), glutathione-reductase (EC 1.2.1.1), aldehyde-dehydrogenase and aldehyde-oxidase (EC 1.2.1.3 and EC 1.2.3.1, respectively), p-450 reductase NADPH cytochrome (EC 1.6.2.4), the demethylase and hydroxylase activities, levels of malonic dialdehyde and the rate of ascorbate-dependent lipid peroxidation, the contents of proteins, phospholipids, cysteine, redox glutathione, glucuronides, sulfates. The level of vitamin A in the animals was found to substantially affect the magnitude of the genotoxic action of NDMA. The supplementary administration of vitamin A reduced the effect of the carcinogen. The mechanism of protective action of retinol was largely explained by the mediated activity of cytochrome-P-450 and glutathione-dependent systems involved in the biotransformation of NDMA. Based on the data available in the literature and their own data, the authors analyzed the effects of retinol on the metabolism of genotoxicants and described possible mechanisms of its antimutagenic and anticarcinogenic action. It is concluded that the effective protection of the body from unfavourable environmental influences may be provided only by supplementary (more than the optimum) intake of vitamin A against the background of a damaging factor.

[The influence of modulators of enzyme activity on the pharmacological effect of thiopental sodium and ketamine and on the pharmacokinetics of thiopental sodium]. / Vliianie moduliatorov aktivnosti fermentov na farmakologicheskii éffekt tiopentala-natriia i ketamina i farmakokinetiku tiopentala-natriia.

The rat experiments studied the impact of inductors and inhibitors of enzymatic activity of xenobiotic metabolism on the pharmacological activity of sodium thiopental and ketamine and on the pharmacokinetics of sodium thiopental. Cocarboxylase, cobalt chloride and cimetidine enhanced the pharmacological action of sodium thiopental, but failed to exert any action on the effect of ketamine. The preparations of vitamin K, particularly vikasol and menadione sodium bisulfite, and phenobarbital attenuated the effects of these anesthetics, but tocopherol unchanged it. Phenobarbital and vikasol accelerated blood elimination of sodium thiopental, whereas cimetidine and cocarboxylase slowed down this process.

[The prolonged use of calcium antagonists in myocardial infarct in rats: their effect on hemodynamics and the contractile function and morphology of the heart muscle]. / Dlitel'noe primenenie antagonistov kal'tsiia pri infarkte miokarda u krys: vliianie na gemodinamiku, sokratitel'nuiu funktsiiu i morfologiiu serdechnoi myshtsy.

Experiments on rats with myocardial infarction induced by occlusion of the left coronary artery were made to explore the influence of calcium antagonists injected intraperitoneally for a long time (daily, for 21 days) on hemodynamics, contractile function and morphology of the heart muscle. It has been shown that verapamil (0.5 mg/kg), diltiazem (2 mg/kg) and nimodipine (20 micrograms/kg) do not exert under those conditions any noticeable effect on pump and contractile heart functions. Administration of verapamil in a doze of 2 mg/kg enhanced heart failure. The drugs under study normalized the response of contractile heart function to volumetric load, which is related to a considerable measure to the acceleration of reparative processes in the myocardium.

[A preclinical study on the safety of a new antialcoholic drug inmecarb]. / Doklinicheskoe issledovanie bezopasnosti novogo protivoalkogol'nogo preparata inmekarba.

A preclinical study on safety of a new antialcoholic drug inmecarb was carried out on three species of experimental animals (rats, guinea pigs, dogs) receiving the drug at different doses including a subtoxic one (1/5 of LD50) for 6 months. The authors concluded that on the basis of a relatively low toxicity and the absence of specific toxicity and long-term side effects the drug may be recommended for clinical use as an antialcoholic agent.

[Toxicological characteristics of teturam in an alcoholic intoxication model in rats]. / Toksikologicheskaia kharakteristika teturama na modeli alkogol'noi intoksikatsii u krys.

Study of toxicological characteristic of teturam (200 mg/kg, administered into the stomach through a tube daily for 2 weeks) on the model of alcoholic intoxication in rats (ethanol, 8 g/kg, administered into the stomach through a tube daily for 1 month) confirmed the literature data on the drug's ability to enhance or maintain ethanol-induced pathological changes in the blood and internal organs.

[Experimental verification of the use of lithium oxybutyrate for the drug prevention of alcoholism relapses]. / Eksperimental'noe obosnovanie primeneniia litiia oksibutirata dlia farmakoprofilaktiki retsidivov alkogolizma.

It was found that lithium oxybutyrate suppresses voluntary consumption of 5% ethanol solution in rats with preliminarily formed alcohol motivation, slows down the formation of alcohol addiction under conditions of forced consumption of 5% ethanol solution and exerts a positive effect on general state of the animals subjected to a long-term action of ethanol by improving the conditioned reflex activity of the central nervous system and stimulating defensive-adaptational mechanisms of the organism.

[Electrophysiological and morphological analysis of the cardiotoxic action of ethanol in rats]. / Elektrofiziologicheskii i morfologicheskii analiz kardiotoksicheskogo deistviia étanola u krys.

The experiments on male rats showed that oral ethanol administered in a dose of 8 g/kg (2/3 of LD50) daily for a month produces toxic heart damage whose electrophysiological and morphological characteristics are similar to clinico-anatomical manifestations of human alcohol myocardiodystrophy. It was concluded that the model may be used for the search of new pharmacological agents for the treatment and prevention of alcohol myocardiodystrophy.

[Effect of cefuroxime on embryonic and fetal development in an experiment]. / Vliianie tsefuroksima na razvitie émbriona i ploda v éksperimente.

The direct and indirect effects of cefuroxime on the embryo and fetus were studied in vitro and in vivo at different gestation times. The placenta, liver and kidneys of the mother and fetus were investigated morphologically. It was shown that in a dose of 250 mg/kg the antibiotic did not induce disorders in the fetus development. The histological examination of the fetus placenta and liver revealed no changes as compared to the controls. However, in the renal tubules of the mother and fetus, pathological lesions in the form of the cytoplasm granular degeneration and nucleus swelling, lysis and necrosis were observed. These lesions were of a dose-dependent character. The possible nephrotoxic effect of cefuroxime prevents its use as a drug of choice in treatment of gestation pyelonephritis.

[Use of automatic cytophotometric analysis for assessing the hepatotropic action of ethanol]. / Primenenie avtomaticheskogo tsitofotometricheskogo analiza dlia otsenki gepatotropnogo deistviia étanola.

It has been shown in experimental chronic intoxication that there is a close correlation between the dose of ethanol, microscopic appearance of the liver, the content of DNA, RNA, protein, glycogen in hepatocytes and structural parameters of nuclear chromatin of these cells. It is concluded that automatic cytophotometric analysis of the structure of hepatocyte nuclei holds promise for an accurate quantitative evaluation of the hepatotropic action of chemical substances and drugs.

[Quantitative informational estimation of the degree of liver damage on a model of chronic alcoholic intoxication]. / Kolichestvennaia informatsionnaia otsenka stepeni porazheniia pecheni v modeli khronicheskoi alkogol'noi intoksikatsii.

In the rat liver at a chronic alcoholic intoxication produced with various doses of ethanol, a double phased picture of informational characteristics has been revealed in the cellular nuclei under a linear increase of the dose. An analysis of corresponding distribution of the hepatocytic nuclei has been performed according to their size and informational characteristics. On this base, the limiting dose of ethanol is estimated for development of the hepatic alcoholic lesion.

[Reparative regeneration of the liver as a model for the preclinical study of the hepatotropism of anti-alcohol agents]. / Reparativnaia regeneratsiia pecheni kak model' dlia doklinicheskogo izucheniia gepatotropnosti protivoalkogol'nykh sredstv.

It has been established that administration of teturam (200 mg/kg) per os once a day for 14 days retards reparative regeneration of the liver in rats following partial hepatectomy and exerts an additional damaging action on the population of regenerating hepatocytes. Administration of potassium orotate (100 mg/kg) per os once a day for 14 days speeds up, on the contrary, organ regeneration. The combined use of the drugs potentiates paradoxically the negative hepatotropic effect of teturam. It is concluded that experimental reparative regeneration of the rat liver can be applied to the assessment of hepatotropism of the antialcoholic drugs.

[Toxicological characteristics of an experimental model of alcoholism in rats]. / Toksikologicheskaia kharakteristika éksperimental'noi modeli alkogolizma u krys.

The morphological appearance and morphometric indicators (the content of RNA, protein, glycogen and fat) of the internal organs of random-bred male rats were studied 10 days, 6 and 12 months after voluntary consumption of 15% ethanol. Alcohol consumption for 12 months provoked marked pathological alterations of the animals' internal organs, similar to organ pathology in alcoholic patients. The time course of these changes was marked by stages which correlated with the stages of experimental alcoholism formation, classified according to the behavioral criteria. The conclusion is made about adequacy of the model in question for screening and study of the pharmacological agents fit for the treatment of alcoholism.

[Chronic alcoholic intoxication in animals as a model for the study of the safety of new anti-alcohol agents]. / Khronicheskaia alkogol'naia intoksikatsiia u zhivotnykh kak model' dlia izucheniia bezopasnosti novykh protivoalkogol'nykh sredstv.

Experiments on 200 noninbred male rats have demonstrated that daily administration of ethanol per os in a dose of 8 g/kg (2/3 LD50) for a month produced pathological changes in organs and systems of the body, which were similar to the manifestations of chronic alcoholic intoxication in man. It is concluded that the model under consideration may be used during preclinical study of the safety of new antialcoholic agents.

[Effect of phenazepam on the body organs and systems of rats subjected to prolonged ethanol exposure]. / Vliianie fenazepama na sostoianie organov i sistem organizma krys, podvergnutykh dlitel'nomu vozdeistviiu étanola.

Experiments made on 80 randombred male rats have demonstrated that the tranquilizer phenazepam in a daily dose of 1 mg/kg administered per os to intact animals for 14 days produces no adverse changes in the hematological, biochemical and morphological indicators that characterize the status of the most important organs and systems of the body. Administration of phenazepam to rats preexposed to ethanol (4 g/kg per os once a day for a month) has been found to retard the elimination of morphological alterations in the liver and brain induced by ethanol. The results obtained allow recommending the use of appropriate experimental models in the preclinical study of the safety of new antialcoholic agents.

[Mechanism of the toxic action of alcohol on reparative regeneration of the liver]. / Izuchenie mekhanizma toksicheskogo deistviia alkogolia na reparativnuiu regeneratsiiu pecheni.

Administration of ethanol in a dose of 4 g/kg (1/3 of the LD50) from the 1st to the 14th day after partial hepatectomy retards the reparative regeneration of the rat liver. At the cell level this effect is realized at the expense of the reduced cell division followed by mitosis replacement by intracellular pattern of regeneration as hypertrophy and polyploidy of hepatocytes. It is suggested that the revealed mechanism of ethanol toxic effect determines the progressing character of alcoholic liver injury.

[Toxicity of the new antidepolarizing curare-like drug diadonium]. / O toksichnosti novogo antidepoliarizuiushchego kurarepodobnogo sredstva diadoniia.

It has been shown in acute experiments on rats, rabbits and cats that under extracorporeal pulmonary ventilation, the animals could tolerate the 50-100 fold apnoeic doses of diadonium. Chronic experiments have demonstrated that administration of the subapnoeic doses of diadonium to rats, rabbits, and dogs and the apnoeic doses to rats (under extracorporeal respiration) for 10-14 days exerts no significant effect on the peripheral blood, the main biochemical characteristics of blood serum, histological structure of the internal organs, and does not possess local irritant or hemolytic action. The data obtained indicate the safety of diadonium as a myorelaxant.

[Effect of a physical load on the toxicological characteristics of sodium oxybutyrate]. / Vliianie fizicheskoi nagruzki na toksikologicheskie kharakteristiki natriia oksibutirata.

Toxicity of sodium hydroxybutyrate administered for a long time was studied in freely moving animals and in those exposed to intense exercise (daily swimming for 30 min). Hematological, biochemical and morphological analyses demonstrated the drug to be little toxic. Intense exercise did not entail the increased toxicity of sodium hydroxybutyrate. On the contrary, the biochemical parameters (the content of creatinine, protein and protein fractions) altered by exercise returned to normal as a result of a prolonged administration of the drug.

[Reactivity of the hypothalamo-hypophyseal neurosecretory system of rats preferring and refusing alcohol]. / Izuchenie reaktivnosti gipotalamo-gipofizarnoi neirosekretornoi sistemy krys, predpochitaiushchikh i otvergaiushchikh alkogol'.

Rats were kept for one and six hours in a thermal chamber at a temperature of -4 degrees C under conditions of free choice between 5% ethanol and water. Study of the morphological picture of the supraoptic and paraventricular nuclei of the hypothalamus and neurohypophysis of rats that preferred alcohol or rejected it has shown an inverse relationship between marked initial preference of alcohol and resistance of the hypothalamohypophyseal neurosecretory system of the animals to hypothermal exposure that exhausts the neurosecretory function.

[Embryotropic action of phenazepam in mini pigs, a new species of experimental animals]. / Izuchenie embriotropnogo deistviia fenazepama v opytakh na minisvin'iakh - novom vide eksperimental'nykh zhivotnykh.

It has been established in experiments on mini pigs of Siberian origin that phenazepam given at a dose of 1 mg/kg per os during organogenesis has no embryotoxic or teratogenic action. The drug content in the blood of pregnant animals was determined simultaneously. A conclusion is drawn about perspectiveness of using mini pigs for testing embryotoxic activity of drugs.