[Sex-related differences in the antinociceptive effect of some non-narcotic analgetics in rats: the role of biotransformation].

Non-narcotic analgetics sodium diclofenac, indomethacin, naproxen, nimesulid, ketorolac, and celebrex (cytochrome P-450(2)c substrates) produce more pronounced and prolonged analgesic effect in pubertate female rats than in males. This can be related to the slower elimination of drugs from the female organism. The liver of females is characterized by a lower content of cytochrome P-450 and by less pronounced activity of amidopyrine-N-, indomethacin-O-, and naproxen-O-demethylase activity. No sex-related differences in pharmacodynamics were observed for meloxicam, and ethoricoxib, benzofurocaine, and amison, and acetylsalicylic acid, which are the substrates predominantly for CYP3A.

[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.

[Enterosorbents in the treatment of atherosclerosis]. / Enterosorbenty v lechenii ateroskleroza.

The article lists, characterizes, and discusses the mechanism of the action of endosorbents possessing hypocholesteremic and hypolipidemic effects. Among them are natural endosorbents--food fibers (cellulose, hemicellulose, pectins, gum, mucus, lignin and chitin compounds, etc.); artificial specific affinin and nonspecific carbonic enterosorbents (carbonitrate family, granulated, fibrous), as well as silica (aerosil, polysorb). The effectiveness and pathogenetic expediency of correcting disorders of lipid metabolism in atherosclerosis with enterosorbents is substantiated.

[The activity of the lipid peroxidation processes in the mucosa of the rat small intestine and its morphofunctional state under acute irradiation and the administration of combined preparations created on a base of highly dispersed silica]. / Aktivnost' protsessov perekisnogo okisleniia lipidov v slizistoi obolochke tonkoi kishki krys i ee morfofunktsional'noe sostoianie v usloviiakh ostrogo oblucheniia i vvedeniia kombinirovannykh preparatov, sozdannykh na osnove vysokodispersnogo kremnezema.

Morphofunctional and biochemical studies were carried out on bastard male rats (weight 200-240 g). The results showed that X-ray irradiation had induced structural alterations and elevation of lipid peroxidation in small intestine. Using of complex preparations defended this organ against pathological damages. The first preparation provided rat organisms with 100 ml/kg of silica, 2 mg/kg of beta-carotene, 30 mg/kg of alpha-tocopherol and 0.2 mg/kg of natrium selenite. The second preparation provided 100 mg/kg of silica, 10 mg/kg of dry Rhodiola extract, 0.1 mg/kg of tincture of Lagochilus [correction of Ladohilli] inebrians and 0.05 ml/kg of tincture of Aralia mandshurica. The third preparation provided organism with 100 mg/kg of silica and 20 mg/kg of thiobenzimidazole derivative. All these preparations had produced marked pharmacological effect.

[The possible means for the pharmacological correction of lipid metabolic disorders in atherosclerosis]. / Vozmozhnye puti farmakologicheskoi korrektsii narushenii lipidnogo obmena pri ateroskleroze.

The main trends of contemporary pharmacology of hypolipidemic and hypocholesterolemic agents were analysed. A list of drugs capable of correcting lipid metabolism disorders is given: cholesterol absorption inhibitors, stimulators of bile acid synthesis, inhibitors of cholesterol synthesis, analogs of fibroic acid and other inhibitors and correctors of hypertriglyceridemias, stimulators of reverse cholesterol transport and synthesis of high-density lipoproteins, etc. The latest theoretical and experimental elaborations of gene therapy of dyslipoproteinemias in atherosclerosis are discussed.

[The antinociceptive effect of tramal when combined with nonsteroidal anti-inflammatory preparations]. / Antinotsitseptivnyi éffekt tramala v usloviiakh ego kombinirovaniia s nesteroidnymi protivovospalitel'nymi preparatami.

The antinociceptive effect of tramal and its combinations with nonsteroidal anti-inflammatory drugs (ortophen, indomethacin, naproxen, acetylsalicylic acid, and ibuprofen) was studied in 110 male albino rats on models of electric and thermal stimulation. Possessing their own antinociceptive activity, nonsteroidal anti-inflammatory drugs potentiated the analogous effect of tramal. In vitro tramal was intensively demethylated by the rat liver microsomal fraction. In therapeutic concentrations ortophen and naproxen suppressed the rate of tramal demethylation by the rat microsomes. The potentiating effect of nonsteroidal anti-inflammatory drugs in relation to tramal is apparently connected with the delay in its biotransformation and conversion to inactive metabolites.

[The modification of the pharmacokinetics and analgesic effect of naproxen by cimetidine, phenobarbital and thiamine diphosphate]. / Modifikatsiia farmakokinetiki i anal'geticheskogo éffekta naproksena tsimetidinom, fenobarbitalom i tiamindisfosfatom.

Phenobarbital in a dose of 70 mg/kg (one-time daily intraperitoneal administration for 5 days) promotes naproxen elimination from rat blood and reduces its analgesic activity. Cymetidine (intragastric one-time daily administration in a dose of 100 mg/kg for a week) inhibits naproxen elimination from blood and increases it analgesic effect. Thiamine diphosphate administered intraperitoneally in a dose of 10 mg/kg (one time a day for a week) does not change pharmacokinetic and analgesic effect of naproxene.

[The influence of retinol, tocopherol and cimetidine on the ulcerogenic effect of Orthofen, indomethacin and naproxen]. / Vliianie retinola, tokoferola i tsimetidina na ul'tserogennyi éffekt ortofena, indomtatsina i naproksena.

The influence of retinol, alpha-tocopherol, and cimetidine on ulceration induced by ortophen, indomethacin, naproxen was studied on rats. It was shown that alfa-tocopherol, retinol, and cimetidine reduce the damaging effect of these drugs on the gastroduodenal mucosa of rats thus normalizing the phospholipid content. The influence of alpha-tocopherol and retinol on the side-effects of ortophen was studied in children with rheumatoid arthritis. Ortophen was found to cause gastroduodenal side-effects in more than 30% of patients and decrease the levels of vitamin A and E in children. The use of retinol and alpha-tocopherol in cotherapy decreases the frequency and severity of side-effects and reduces the vitamin deficiency.

[Effect of thiamine and riboflavin derivatives on the activity of xenobiotic-metabolizing enzyme and on the pharmacologic effect of analgesics]. / Vliianie proizvodnykh tiamina i riboflavina na aktivnost' metabolizma ksenobiotikov i farmakologicheskii éffekt anal'getikov.

Riboflavin deficiency decreases the activity of rat hepatic microsomal enzymes, addition of riboflavin and flavin mononucleotide stimulates their activity. At the same time thiamine deficiency induces xenobiotic metabolic enzymes and excessive addition of thiamine, thiamine diphosphate in particular, suppresses their activity. Flavin mononucleotide and thiamine diphosphate considerably modify the pharmacological effect of the agents which are actively metabolized by the hepatic microsomal system. Thiamine diphosphate enhances the pharmacological activities of orthophen, indomethacin, and tramal while flavin mononucleotide slightly diminishes them.

[New functional properties of albumin]. / Izuchenie novykh funktsional'nykh svoistv al'bumina.

Effects of albumin on N-demethylation reactions of substrates in rat liver microsomes were studied in vitro. Albumin was found both to accelerate and to inhibit the reaction of demethylation. The interaction between ligand and albumin appears to be responsible for these effects. The role of the effect in the metabolism of either xenobiotics or endogenous substances is discussed.

[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.

[Effect of polysorb on adhesion of a gauze dressing to the wound surface]. / Vliianie polisorba na adgeziiu marlevoi poviazki k ranevoi poverkhnosti.

Under the influence of polysorb in its application, adhesion of a gauze dressing to the wound surface reduces 3-fold. The in vitro investigations have shown that polysorb had a stimulating effect on fibrinolysis.

[Biotransformation and toxicity of xenobiotics in various routes of administration of vitamin A into the rat body]. / Biotransformatsiia i toksichnost' ksenobiotikov pri razlichnom postuplenii vitamina A v organizm krys.

Deficiency of vitamin A in rats caused a decrease in metabolic rate of acetanilide as well as in elimination of voltaren from blood plasma, while excess of the vitamin (3,000 IU/kg) stimulated voltaren elimination and increased excretion with urine of aminophenol conjugates of acetanilide with sulfuric and glucuronic acids. Under conditions of vitamin A deficiency formation of acetanilide toxic metabolites was increased as a result of which excretion of mercapturic acids with urine was elevated but excess of vitamin A and its hyperdose inhibited these reactions. At the same time, deficiency of vitamin A amplified the paracetamol and voltaren toxicity and its excess exhibited protective effects.

[Effects of vitamin A on the activity of glutathione system enzymes of liver detoxication after administration of nitroso-compound precursors to rats]. / Vliianie vitamina A na aktivnost' fermentov glutationovoi sistemy detoksikatsii pecheni pri vvedenii predshestvennikov nitrozosoedinenii krysam.

The activity of glutathione system enzymes exposed to nitroso-compound (NC) precursors in small doses for 12 months and preliminary injection of vitamin A have been studied. The histo- and biochemical examinations have revealed a pronounced increase in the enzyme activity exposed of NC precursors and a slight increase when injecting preliminary vitamin A.

[Activity of enzymes participating in xenobiotic metabolism and the condition of microsomal membranes of rat liver in vitamin K deficiency]. / Aktivnost' fermentov, uchastvuiushchikh v metabolizme ksenobiotikov, i sostoianie mikrosomal'nykh membran pecheni krys pri defitsite vitamina K.

Alimentary deficiency or vitamin K (vitamin K-poor diet) as well as the vitamin deficiency resulting from sinkumar administration are accompanied by a decreased activity of microsomal demethylases, hydroxylase, NADH- and nNADPH-reductases of dichlorophenolindophenol and neotrazolium. The activity of cytosolic enzymes (only glutathione-S-transferases, aryl- and allyl esterases) is diminished in a lesser degree. Vitamin K deficiency does not significantly interfere with the effect of the xenobiotic metabolism enzyme inducer (phenobarbital) or the cytochrome P-450 inhibitor (cobalt chloride). The changes in the enzyme activity result in a decrease of acetanilide biotransformation. A possible reason for the observed changes in the activity of microsomal enzymes is the weakening of hydrophobic and polar interactions in microsomal membranes. This hypothesis was confirmed by experiments with the use of membrane perturbants as well as by solubilization of membrane-bound enzymes.

[The effect of vitamin E deficiency on enzyme activity and the status of the membrane fraction of rat liver microsomes]. / Vliiane nedostatochnosti vitamina E na aktivnost' fermentov i sostoianie membran fraktsii mikrosom pecheni krys.

The vitamin E deficiency was studied for its effect on the activity of enzymes participating in metabolism of xenobiotics. Experiments with 54 rats have demonstrated that the maintenance of animals on the vitamin-E-deficient diet within 13-14 weeks decreases the activity of microsomal monooxygenases (demethylase and hydroxylase), NADH- and NADPH-reductases, aryl- and aliesterases in the liver and lungs, which is a result of disturbance of hydrophobic and polar interactions in microsomal membranes. Vitamin E deficiency makes the extent of solubilization of these enzymes higher under the influence of deoxycholate and trypsin and intensifies inactivation of these enzymes under the effect of urea. In the lungs and in the liver of the vitamin E deficient rats the content of reduced glutathione decreases as well as the activity of glutathione reductase, glutathione-S-transferase, aldehyde dehydrogenase, while the activity of gamma-glutamyltransferase increases; glutathione disulphide is accumulated.

[Modification of the pharmacokinetics of ortophen and its analgesic activity by inducers and inhibitors of xenobiotic metabolism enzymes and thiamine diphosphate]. / Modifikatsiia farmakokinetiki ortofena i ego anal'geticheskoi aktivnosti induktorami i ingibitorami aktivnosti fermentov metabolizma ksenobiotikov i tiamindifosfatom.

Phenobarbital administered in a dose of 70 mg/kg intraperitoneally (once a day for 4 days) was shown to accelerate ortophen elimination from blood of rats and to decrease its analgesic activity. Administration of cimetidine (100 mg/kg, intragastrically once a day for 5 days), cobalt chloride (10 mg/kg, subcutaneously twice) and thiamine diphosphate (10 mg/kg, intraperitoneally once a day for a week) was found to slow down elimination of ortophen from blood and to enhance its analgesic effect. Cimetidine slows down ortophen elimination from blood of the patients.

[Glutathione and ascorbic acid metabolism and antioxidant enzyme activity in the tissues of vitamin E-deficient rats]. / Obmen glutationa, askorbinovoi kisloty i aktivnost' antioksidantnykh fermentov v tkaniakh krys, defitsitnykh po vitaminu E.

In has been shown in the experiments on male rats that alimentary vitamin E deficit causes the decrease of reduced glutathione and ascorbic acid concentration in the liver and lungs and that of glutathione-S-transferase, glutathione reductase in the liver and lungs, catalase in the liver and glutathione peroxidase in the heart activity, but increases the amount of glutathione disulfide in the liver and lungs and superoxide dismutase and gamma-glutamyltransferase activity in the liver. The data obtained show the selective character of reaction participants of the antioxidant system of rats' organism to the deficit of one of the antioxidant factors--vitamin E and also testify to complex interrelation between separate members of this system.