Attempt at modification of the pharmacological and toxic effects of cocaine]

The increase in locomotor activity induced by cocaine (15 mg/kg, i.p.) in the mouse was antagonized by pretreatment with compounds which inhibited monoanimergic receptors such as phenoxybenzamine, chlorpromazine or methysergide. On the contrary, the lethal dose of cocaine in rats and mice was not reduced by these substances. These data suggest that monoamines are involved in mediating the motor activity of cocaine but not implicated in the toxic effect of the drug.     

Microcalorimetric study of the toxic effect of selenium on the mitochondrial metabolism of cyprinus carpio liver

The metabolic thermograms and heat output of mitochondria isolated from carp liver have been determined by using an LKB bioactivity monitor. The thermogram can be divided into four parts: the lag phase, active recovery phase, stationary phase, and decline phase. The thermokinetic equation was established for the active recovery and decline phase of metabolism as follows: dP/dt =k _mP (1-SP). The rate constantsk ₁ andk ₂ of two phases of active recovery and decline phase have been also calculated. The metabolism activity of mitochondrial inhibited by a high concentration of trace element selenium has been studied. The metabolic heat released, time of each phase, and rate constants can be significantly influenced by excess of selenite added. These results suggested that a high concentration of selenium can damage the structure and function of mitochondria, and thus influence their metabolism.     

Microcalorimetric study of the toxic effect of sodium selenite on the mitochondria metabolism of Carassius auratus liver

The fundamental thermogenesis curves of the metabolic process of liver mitochondria from Carassius auratus and the toxic effect of Na₂SeO₃ on it were studied by using an LKB-2277 bioactivity monitor, ampoule method, at 28°C. From the thermogenesis curves, the thermokinetic equations were established under different conditions. The kinetics show that a low concentration of Na₂SeO₃ (1–4 mg/L) had promoting action on the metabolism process of Carassius auratus liver mitochondria, but that a high concentration of Na₂SeO₃ (8–16 mg/L) inhibited the mitochondria metabolism.     

Effect of cadmium chloride on polyphosphoinositides content in the rat liver and kidneys

The influence of cadmium chloride on the content of some fractions of polyphosphoinositides in the liver and kidneys of rats has been investigated in the work. We have reported that a single administration of sublethal dose of cadmium chloride leads to the long-term elevation of the content of diacylglycerol, which is responsible for the activation of protein kinase C. The increase of triphosphoinositides fraction content may be connected with activation of phosphoinositid-3-kinase and with accumulation of phosphatidylinositol-3,4-diphosphate and phosphatidilinositol-3,4,5-triphosphate, which are known as activators of some protein kinase C isoforms and also play an important role in the mitogen-activated protein kinase signaling pathway. The lipids fractions content changes were similar in the liver and kidneys, but had different time of response.     

Lack of mutagenic and toxic effects of low dose potassium bromate on kidneys in the Big Blue rat

Potassium bromate (KBrO3) has been classified as a genotoxic carcinogen based on positive results in the Ames test, and chromosome aberration and micronucleus tests. The purpose of the present study was to investigate the dose-response relationship for in vivo mutagenic and toxic effects of KBrO3 in the kidneys of Big Blue rats. In experiment 1, male Big Blue rats were divided into 8 groups. KBrO3 was dissolved in tap water and administered to groups 1-8 at concentrations of 0, 0.02, 0.2, 2, 8, 30, 125 and 500 ppm, respectively, for 16 weeks. Experiment 2 was performed to investigate the effects of KBrO3 at the 0.002 ppm dose approximately contained in the tap water on rat kidneys. Ten Big Blue rats were divided into 2 groups and given distilled water and tap water, respectively, for 16 weeks. In experiment 1, treatment with 500 ppm KBrO3 significantly increased the mutant and total mutation frequencies and frequency of GC to TA transversion of the lacI gene in the kidney compared to non-treatment control group, but 125 ppm and lower doses of KBrO3 had no effects. Histopathologically, renal toxic changes were observed in groups administered KBrO3 at 30 ppm or higher in a dose-dependent manner. PCNA positive cell indices in renal tubular cells were significantly increased in the kidney at doses of 125 and 500 ppm, but not at 30 ppm or lower doses, as compared to the control group. Furthermore, 8-hydroxy-2'-deoxyguanosine formation, a marker of oxidative stress, was significantly increased at 500 ppm. In experiment 2, there were no differences in any parameter between the distilled water and tap water groups. These results suggest the existence of no-effect levels for in vivo mutagenic and toxic effects, proliferation stimulus, and oxidative stress of KBrO3 in rat kidneys.     

Mechanisms of physiological and pharmacological sex hormone action on the mammalian liver

Androgen and oestrogen receptors have been demonstrated in mammalian liver, but since it is generally accepted that they are probably non-functional at endogenous steroid concentrations, it is not apparent how they mediate physiological influences on this organ. Nor is it certain to what extent pharmacological actions of sex hormones reflect overstimulation of physiological routes or whether alternative mechanisms become available once threshold values have been reached. In this presentation an attempt has been made to answer some of these questions using data obtained from a study of the regulation of the activities of microsomal 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSDH) and 5 alpha-reductase in rat liver. Androgens exert their primary physiological and pharmacological influences at the level of the hypothalamus. Oestrogens can elicit three different types of effect-physiological, antiandrogenic and pharmacological--of which the first two involve primary effects on the pituitary. Hepatic oestrogen receptors only become activated when oestrogen concentrations reach pharmacological levels. Progestins probably have no physiological influence on the livers of non-pregnant rats. Their pharmacological actions may either be traced back to secondary androgenic (e.g. medroxyprogesterone acetate, levonorgestrel) or oestrogenic (e.g. norethynodrel, lynestrenol) properties, involving the routes described above, or to independent effects on the central nervous system (e.g. cyproterone acetate modulation of 5 alpha-reductase activity).     

Experimental study on chemotherapeutic efficacy, acute toxic action and nephrotoxicity of combinations of eremomycin with tobramycin

Chemotherapeutic efficacy of eremomycin in combination with tobramycin was investigated on a model of experimental sepsis of albino mice caused by Staphylococcus aureus cultures resistant to methicillin. Eremomycin is a novel original antibiotic of the glycopeptide structure isolated in the USSR and tobramycin is an aminoglycoside. Acute toxicity of the combination with a wide range of the dose fixed proportions was studied on mice and the nephrotoxic action of the antibiotics and their combinations administered intravenously for 5 days was studied on albino rats. The experiments showed that the chemotherapeutic effect of eremomycin in combination with tobramycin was of synergistic nature. Acute toxicity of the combined drugs mainly summed up and somewhat increased when the proportion of tobramycin and eremomycin was 1:2.4 or 1:3.6. Eremomycin had a dose-depended nephrotoxicity. Summing up of the nephrotoxic action of the drugs on their combined use was observed.     

Experimental study of antibacterial activity, therapeutic effectiveness and toxic properties of the combination of tobramycin and carbenicillin

Tobramycin combination with carbenicillin was studied experimentally. Tobramycin is a new aminoglycoside antibiotic prepared at the Institute of New Antibiotics, the USSR Academy of Medical Sciences. It was shown that the combination had mainly synergistic action (67 per cent) on clinical strains of Pseudomonas aeruginosa which was confirmed in treatment of experimental sepsis caused by the organism. In acute experiments with albino mice there was observed summation of the general toxic action of the antibiotics used in the combination. The level and nature of the nephrotoxic action of the tobramycin combination with carbenicillin were shown in experiments with rats to be the same as those of the nephrotoxic action of tobramycin used alone. The presence of carbenicillin in the combination did not increase the inhibitory effect of tobramycin on excitement transmission in the neuromuscular synapses.     

Intracellular localization of thiamine-binding proteins in the liver and kidneys of rats

The distribution of thiamine-binding and thiamine triphosphatase activity typical of thiamine-binding proteins was studied in intracellular structures of rats liver and kidneys. It was found that the fraction of microsomes has the highest rate of specific thiamine-binding activity amide fractions of subcellular structures that was isolated using differential centrifugation in the both organs. Hydrolysis of thiamine triphosphate (pH 7.4) was also extremely active in these structures. The results of our research allow to make a conclusion that subcellular structures precipitated as fraction of microsomes (endoplasmic reticulum and vesicled parts of plasma membranes) are the sites of the most probable localisation of thiamine-binding proteins of liver and kidneys.     

Effect of NAD and ADP on glycolysis in the kidneys and liver of rats during ischemia

Experiments on albino rats have shown that kidney ischemia and its simulation by the anaerobic incubation of postmitochondrial kidney homogenate fraction without a substrate induce a considerable damage of the glycolytic system at the stage of the glucoso-6-phosphate transformation into fructoso-1.6-diphosphate and a less pronounced damage in the fructoso-1.6-diphosphate transformation into lactate. Administration of adenosine diphosphate (ADP) and nicotinamide adenine dinucleotide (NAD) to rats before kidney vessel occlusion or their addition to the postmitochondrial fraction before the anaerobic incubation without a substrate decreased a degree of the glycolytic system damage. The damage of the glycolytic system and protective action of NAD are also detected under simulation of liver ischemia. Possible mechanisms of the ischemic damage in the glycolytic liver and kidney tissue system are discussed.     

Effect of hemosorption on the ultrastructure of hepatocytes in toxic liver damage

Extracorporeal perfusion of toxic blood via carbonic sorbents is an effective method for correcting severe disturbances of hemostasis. Ultrastructural alterations in hepatic cells were studied in experimental toxic liver injury before and after hemosorption. It was established that after hemosorption the processes of intracellular regeneration were significantly activated in the liver parenchyma. The number of crysts in the mitochondria increased as did the electronic density of the matrix. At the same time the number of lysosomes rose as well. However, in persistent unresolved cholestasis, destructive alterations in the hepatic tissue progressed despite the performance of hemosorption.     

Experimental study of the morphogenesis of nutmeg fibrosis of the liver]

Partial structure of the inferior vena cava over the diaphragm carried out experimentally in dogs let to blood stasis in the liver. Biopsy material obtained at different experimental periods demonstrated that fibrosis began to develop from the central and collective veins as a result of proliferation of the fibroblasts of the vein adventitita and "emigration" of the fucsinophilic fibers into the adjacent parenchyma. In parallel there occurred a neoformation of the connective tissue in the areas of hemorrhages and necroses associated with proliferation of the Kupffer's cells. Nutmeg fibrosis proved to have a cellular genesis and as associated with increased tropocollagen activity of fibroblasts.     

Experimental study of the use of colchicine in alcoholic liver diseases

Rats kept on a standard diet were subdivided into several experimental groups: group 1, control; group 2, animals receiving ethyl alcohol for 10 days; group 3, animals receiving ethyl alcohol for 3 months; group 4, animals receiving colchicine; group 5, animals receiving alcohol in combination with colchicine; group 6, animals receiving alcohol in combination with carbon tetrachloride (CCl4); and group 7, animals receiving alcohol in combination with CCl4 and colchicine. Electron microscopy of the rat liver has shown that colchicine inhibited significantly the onset of hepatic fibrosis and degenerative changes in hepatocyte organells induced by hepatotoxins (alcohol alone or alcohol in combination with CCl4). Colchicine also inhibited monooxygenase activity in the liver homogenate of experimental rats. Possible mechanisms of hepatoprotective colchicine effect are discussed.