Anaesthetic effects of pregnanolone in combination with allopregnanolone, thiopental, hexobarbital and flurazepam: an EEG study in the rat.
The anaesthetic interactions of the steroid, 3 alpha-hydroxy-5 beta-pregnan-20-one, in male rats were investigated in different fixed binary combinations with the steroid allopregnanolone (3 alpha-hydroxy-5 alpha-pregnan-20-one), two barbiturates (thiopental and hexobarbital) and the benzodiazepine, flurazepam. Anaesthetic effects were determined using an EEG threshold method. Interactions were assessed using an isobolographic method. The interaction between the two steroids, pregnanolone and allopregnanolone, showed an anaesthetic effect significantly less than additive (antagonistic). The interactions between pregnanolone and the two barbiturates and the benzodiazepine showed an anaesthetic effect significantly greater than additive (potentiation) in all tests performed. These results could be explained by a pharmacodynamic interaction at the hypothetical GABA-benzodiazepine-barbiturate-steroid complex in the CNS. (+info)
Pharmacological properties of some xanthone derivatives.
A series of aminoalkanolic derivatives of xanthone were examined in some experimental models of epilepsia, i.e., pilocarpine, aminophylline and pentetrazole-induced seizures. A final objective of this research was to examine the action of these compounds on the central nervous system, namely on spontaneous locomotor activity, amphetamine-induced hyperactivity and narcotic sleep induced by hexobarbital, as well as their influence on the gamma-aminobutyric acid (GABA) level and glutamic acid decarboxylase (GAD) activity in mice brain. The most interesting were the pharmacological results of (R)-2-N-methylamino-1-butanol derivative of 7-chloro-2-methylxanthone [Id], which displayed protective activity against the seizures induced by maximum electroshock and pentetrazole induced seizures; moreover, this compound had a relatively low toxicity and did not exhibit a neurotoxic effect. The influence on the locomotor activity as well as on the amphetamine-induced locomotor hyperactivity in mice was also seen for Id. Compound Id did not decrease the GABA level in mice brain. (+info)
Effect of repeated exposure to aniline, nitrobenzene, and benzene on liver microsomal metabolism in the rat.
Exposure of rats to aniline at daily doses of 50 mg/kg of body weight over a month stimulated the microsomal metabolism as manifested by (1) acceleration of p-hydroxylation of anilin and N-demethylation of aminopyrine in 9-000 times g postmitochondrial supernatant of the liver, (2) shortening the sleeping time after hexobarbital, and (3) reduction of the antipyretic effect of phenacetin. In the rats exposed to nitrobenzene in a similar manner to aniline, nitroreduction of nitrobenzene and p-hydroxylation of aniline remained unaffected; the antipyretic effect of phenacetin was decreased, whereas hexobarbital sleeping time remained unchanged. Exposure of rats to benzene (50 mg/kg of body weight daily for a month) had no effect on the rate of hydroxylation of benzene and N-demethylation of aminopyrine. In benzene-exposed rats hexobarbital sleeping time was prolonged whereas the antipyretic effect of phenacetin was unaffected. Microsomal metabolism of aniline, nitrobenzene, and benzene was stimulated and inhibited when the rats were pretreated with phenobarbital and SKF 525-A, respectively. (+info)
The metabolism of benzo(alpha)pyrene in isolated rat liver cells.
Isolated rat liver cells catalyze the metabolism of benzo(alpha)pyrene (BP) with the resulting formation of phenols, dihydrodiols, and conjugates. The rate of the primary oxidative step in the process was similar to that catalyzed by isolated rat liver microsomes in the presence of a reduced nicotinamide adenine dinucleotide phosphate-generating system and responded similarly to various inhibitors, including 2-diethylaminoethyl-2,2-diphenylvalerate, metyrapone, alpha-naphthoflavone, and hexobarbital. The level of cytoplasmic, reduced nicotinamide adenine dinucleotide phosphate was not rate limiting in liver cells isolated from either fed or fasted animals. The conjugates and dihydrodiols formed were readily excreted, whereas low concentrations of phenols accumulated intracellularly. The pattern of metabolites of BP was the same in isolated rat liver cells and in the isolated perfused rat liver. 3-Methylcholanthrene treatment of the rats caused a marked increase in cellular BP metabolism as well as in cytochrome P-450 concentration. The induced hemoprotein revealed characteristics similar to those previously established with isolated liver microsomes, i.e., increase in high-spin form, enhanced affinity for BP as revealed by a lower Michaelis constant, and sensitivity to the inhibitory action of alpha-naphthoflavone. After 3-methylcholanthrene treatment, phenols and dehydrodiols constituted a larger percentage of the total metabolites, indicating a more pronounced stimulation of the oxidative than of the conjugative step of BP metabolism by induction, and the dihydrodiols now tended to accumulate intracellularly. (+info)
Drug metabolizing function of isolated perfused liver.
How closely the isolated liver of the rat would simulate the in vivo function of the organ in terms of the metabolic pattern of the compounds such as bromosulphophthalein, p-nitrophenol, hexobarbital, and indocyanine green was investigated. In order to produce tissue with the stimulated function, the animal was pretreated with phenobarbital and, for the reverse purpose, with ethionine. Some of the indices of the function employed herein, such as the appearance pattern of the compound, the rate of biochemical transformation or the biliary excretion, showed that the perfused liver would generally well reflect the in vivo situation. The method with isolated and perfused liver could exclude the participation of other organs and also the influence of the factors unavoidable in an in vivo experiment. Thus, it is suggested that the isolated perfused liver is useful for studying directly the functional level of the organ as drug metabolizing tissue. (+info)
Energy wastage in rats given drugs that induce microsomal enzymes.
Metabolic efficiency was studied in rats given drugs known to induce hepatic microsomal enzymes. The presence of an increased metabolic rate was indicated by increases in oxygen consumption under various experimental conditions and by changes in body weight. The latter was not accounted for by increased losses of energy in excreta. The results support the hypothesis that hepatic microsomal enzyme induction can significantly alter the body's metabolic efficiency. (+info)
Prediction of compound signature using high density gene expression profiling.
DNA microarrays, used to measure the gene expression of thousands of genes simultaneously, hold promise for future application in efficient screening of therapeutic drugs. This will be aided by the development and population of a database with gene expression profiles corresponding to biological responses to exposures to known compounds whose toxicological and pathological endpoints are well characterized. Such databases could then be interrogated, using profiles corresponding to biological responses to drugs after developmental or environmental exposures. A positive correlation with an archived profile could lead to some knowledge regarding the potential effects of the tested compound or exposure. We have previously shown that cDNA microarrays can be used to generate chemical-specific gene expression profiles that can be distinguished across and within compound classes, using clustering, simple correlation, or principal component analyses. In this report, we test the hypothesis that knowledge can be gained regarding the nature of blinded samples, using an initial training set comprised of gene expression profiles derived from rat liver exposed to clofibrate, Wyeth 14,643, gemfibrozil, or phenobarbital for 24 h or 2 weeks of exposure. Highly discriminant genes were derived from our database training set using approaches including linear discriminant analysis (LDA) and genetic algorithm/K-nearest neighbors (GA/KNN). Using these genes in the analysis of coded liver RNA samples derived from 24-h, 3-day, or 2-week exposures to phenytoin, diethylhexylpthalate, or hexobarbital led to successful prediction of whether these samples were derived from livers of rats exposed to enzyme inducers or to peroxisome proliferators. This validates our initial hypothesis and lends credibility to the concept that the further development of a gene expression database for chemical effects will greatly enhance the hazard identification processes. (+info)
INFLUENCE OF METHYLDOPA ON CENTRAL EFFECTS OF RESERPINE.
Methyldopa potentiated hypnosis due to hexobarbitone in mice, as did reserpine, chlorpromazine and 5-hydroxytryptamine. Methyldopa antagonized the increase by reserpine of sleep due to hexobarbitone, but enhanced the potentiation by chlorpromazine and 5-hydroxytryptamine of hypnosis due to hexobarbitone. The sedative effect of reserpine in mice and the emetic effect in pigeons were also antagonized by methyldopa. However, the effects of reserpine on convulsions due to leptazol and in causing ptosis were not antagonized by methyldopa. It is suggested that some effects of reserpine (potentiation of hexobarbitone-sleeping time, sedation and emesis) are unrelated to changes in brain amine levels and that methyldopa, with its weak reserpine-like actions, is an antagonist to reserpine. (+info)