Taloximine, a new respiratory stimulant with brochodilator properties. (33/71)

1. A novel phthalazine analogue taloximine (1-hydroxyimino-4(2-dimethyl-aminoethoxy)-1,2-dihydrophthalazine monohydrochloride monohydrate) stimulated respiration in conscious rabbits at doses of 7 mg/kg and above.2. Taloximine antagonized the depressant action of morphine on respiration in rabbits at doses of 10 mg/kg. At high doses it resuscitated rabbits after they had been given lethal doses of sodium pentobarbitone.3. In in vitro preparations of the trachea or bronchus taloximine was about equiactive with aminophylline. In the Konzett-Rossler preparation the intravenous ED50 for taloximine was about 18% of that of aminophylline, whereas after oral administration the two drugs were equiactive.4. Taloximine, unlike aminophylline, did not protect guinea-pigs against anaphylactic microshock to egg albumen.5. Taloximine shortened the duration of the loss of righting reflex in mice due to hexobarbitone more effectively than bemegride, nikethamide or vanillic acid diethylamide.6. In the dose required to stimulate respiration taloximine had only slight cardiovascular effects. Up to four times this dose produced no evidence of general excitation of the central nervous system.  (+info)

Hepatic drug-metabolizing enzyme activity in rats pretreated with (-)-emetine or (plus or minus)-2,3-dehydroemetine. (34/71)

1. Pretreatment of female rats with (-)-emetine or (+/-)-2,3-dehydroemetine (at 18mumol/kg body wt. for 24h) prolongs the hexobarbital-induced sleeping-time of the treated animals. 2. This effect is not observed on pretreating animals with other compounds closely related to (-)-emetine, such as (-)-isoemetine or (+)-O-methylpsychotrine. 3. Liver microsomal drug-metabolizing enzyme activity in vitro as measured by N-demethylation of aminopyrine and azo-reduction of Neoprontosil is inhibited in rats pretreated with (-)-emetine or with (+/-)-2,3-dehydroemetine. 4. These inhibitory effects on drug metabolism in vitro are not observed in corresponding experiments involving pretreatment of rats with (-)-isoemetine or (+)-O-methylpsychotrine. 5. Co-administration of emetine or 2,3-dehydroemetine and sodium phenobarbital or 1,1-dichloro-2-o-chlorophenyl-2-p-chlorophenylethane to rats abolishes or greatly diminishes the stimulation of drug-metabolizing enzyme activity in vitro usually obtained by the administration of phenobarbital or 1,1-dichloro-2-o-chlorophenyl-2-p-chlorophenylethane alone. 6. Further, in rats pretreated with sodium phenobarbital and subsequently injected with emetine or 2,3-dehydroemetine the pre-stimulated drug-metabolizing enzyme activity in vitro is diminished. 7. The inhibitory effects on drug-metabolizing enzyme activity after pretreatment with (-)-emetine or (+/-)-2,3-dehydroemetine do not appear to be related to NADPH generation.  (+info)

A rapid micro-method for the screening and measurement of barbiturates and related compounds in plasma by gas-liquid chromatography. (35/71)

A rapid gas-chromatographic method has been developed for the determination of butobarbitone, amylobarbitone, hexabarbitone, pentobarbitone, quinalbarbitone, phenobarbitone glutethimide, and methaqualone in ;finger-prick' samples of plasma. This has been applied to the analysis of some of these drugs in plasma taken from patients after therapeutic dosage and over-dosage.  (+info)

Pyran and polyribonucleotides: differences in biological activities. (36/71)

Maleic anhydride-divinyl ether copolymer (pyran) and the polyribonucleotides are both large polyanions with potent antiviral activity. However, they are biologically quite different. Interferon levels of 100 units or more/ml were associated with antiviral activity of polyribonucleotides. Interferon induction by pyran compounds was not primarily involved in antiviral resistance because preparations that did not induce interferon possessed antiviral activity equal to that of interferoninducing preparations. Both polyriboinosinic-cytidylic acid [poly (rI.rC)] and pyran increased the immune response to sheep erythrocytes in the Jerne hemolytic plaque-forming cell (PFC) assay, but their modes of immunoadjuvant action differed. On peak day, poly (rI.rC)-treated mice demonstrated 5.1 x 10(4) PFC/spleen (557 PFC/10(6) nucleated cells) and pyran-treated mice exhibited 4.5 x 10(4) PFC/spleen (299 PFC/10(6) nucleated cells), as compared with 2.7 x 10(4) PFC/spleen (261 PFC/10(6) nucleated cells) in controls. The compounds also differed in phagocytic alteration; polyribonucleotides did not affect phagocytosis whereas pyran produced a biphasic response. Both polyanions exhibited toxic inhibition of liver microsomal enzyme metabolism of type I and type II drugs. However, whereas pyran sensitized mice 50-fold to the lethal effects of endotoxin, the polyribonucleotides did not significantly sensitize mice to endotoxin.  (+info)

Studies on cadmium-induced inhibition of hepatic microsomal drug biotransformation in the rat. (37/71)

Cadmium is a potent inhibitor of hepatic microsomal drug biotransformation in the rat. Male rats receiving a single intraperitoneal dose of cadmium exhibit significant decreases in hepatic microsomal metabolism of a variety of substrates. The threshold cadmium dose is 0.84 mg Cd/kg, and the effect lasts at least 28 days. Mechanistically, the inhibitory effect results from decreased cytochrome P-450 content since cadmium does not alter NADPH cytochrome c reductase activity. This effect is also observed following acute oral administration of cadmium in doses greater than 80 mg Cd/kg but is not observed following chronic administration of the metal via drinking water in concentrations of 5-200 ppm for periods ranging from 2 to 50 weeks. A tolerance to the inhibitory cadmium effect is observed if male rats are pretreated with subthreshold doses of the metal prior to the challenge cadmium dose. The degree of tolerance can be overcome by increasing the challenge dose of cadmium. Characterization of the tolerance phenomenon in terms of onset, duration, and intensity reveals a good correlation with the kinetics of metallothionein production, suggesting that the underlying basis for the tolerance phenomenon is likely the induction of metallothionein. A sex-related difference in the inhibitory effect of cadmium was observed. Cadmium did not inhibit the metabolism of hexobarbital or ethylmorphine in female rats but did inhibit that of aniline or zoxazolamine. Cadmium did not lower cytochrome P-450 content in female rats.  (+info)

Development of tolerance to the prolongation of hexobarbitone sleeping time caused by cannabidiol. (38/71)

1 The effects of acute and subacute cannabidiol (CBD) administration on hexobarbitone sleeping time and on some constituents of the hepatic microsomal drug-metabolizing system were assessed in the mouse.2 Acutely administered CBD prolonged sleeping time; but with subacute treatment, tolerance to the effect rapidly developed.3 Brain hexobarbitone concentration upon awakening was unchanged by either acute or subacute CBD treatment, which suggests that neither the prolongation of sleeping time nor the tolerance is the result of a change in sensitivity of the central nervous system to the barbiturate.4 Acute CBD treatment increased the half-time of hexobarbitone in the brain, which returned toward normal with the development of tolerance.5 Acutely, CBD caused a 30% decrease in hepatic cytochrome P-450 level; with tolerance, the cytochrome concentration returned to normal.6 The evidence suggests that the CBD-induced prolongation of barbiturate sleeping time and the tolerance to this effect are the result of changes in the rate of drug metabolism, which are related to changes in the amount of cytochrome P-450.7 The effects of CBD on the hepatic microsomal drug-metabolizing enzyme system are different from those attributed to SKF 525-A and piperonyl butoxide because the cannabinoid does not decrease cytochrome P-450 quantitatively by complex formation, it does not produce a recovery overshoot in the cytochrome concentration and, finally, it does not cause an induction of the hexobarbitone-metabolizing enzymes.  (+info)

Lead and methyl mercury: effects of acute exposure on cytochrome P-450 and the mixed function oxidase system in the liver. (39/71)

The rat liver mixed function oxidase system which is responsible for the metabolism of endogenous and exogenous compounds has been shown to be affected by lead and methyl mercury. Administration of these environmental pollutants to rats results in a decrease in cytochrome P-450 content and inhibition of in vitro N-demethylase and hydroxylase activities. The in vitro enzyme-inhibiting effects of the metals found pharmacological expression in the whole animal by prolongation of hexobarbital-induced sleeping times.  (+info)

The effects of anaesthetics on synaptic excitation and inhibition in the olfactory bulb. (40/71)

1. The effects of anaesthetics (pentobarbitone, hexobarbitone, halothane, urethane, chloralose, chloral hydrate and ethanol) on the extracellular field potentials of the olfactory bulb produced by lateral olfactory tract stimulation were analysed.2. Relatively large doses of all the anaesthetics (e.g. pentobarbitone, 40-70 mg/kg) depressed the synaptic excitation of granule cells.3. The antidromic invasion of mitral cell dendrites was only slightly less sensitive to the anaesthetics than was the synaptic excitation of granule cells.4. A wide dose range of anaesthetics (e.g. pentobarbitone, 3-60 mg/kg) prolonged the granule cell post-synaptic inhibition of mitral cells. All the anaesthetics, except ethanol, prolonged the inhibition.5. The action of anaesthetics on post-synaptic inhibition was due to a specific effect on the inhibitory synapses.6. Amino-oxyacetic acid, an inhibitor of GABA catabolism, had little effect on the synaptic inhibition or on the ability of hexobarbital to prolong the inhibition. This suggests that the prolongation seen with anaesthetics is not a result of interfering with GABA catabolism.7. The present results are compared with results obtained with anaesthetics in other areas of the nervous system and it is proposed that prolongation of ;gaba-ergic' inhibition might contribute to an agent's ability to produce general anaesthesia.  (+info)