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At least 19 recordsLinked to original sources
PubMed1979

Influence of the acute intoxication with salts of some heavy metals on hexobarbital sleep and hexobarbital metabolism.

The effect of acute intoxication with salts of ten heavy metals on hexobarbital sleep and the dependence of this effect on the time of application and the dose of the heavy metal are studied in experiments on male albino rats. Two hours after subcutaneous injection of toxic doses, only cobalt nitrate significantly prolongs hexobarbital sleep. Significant prolongation of the sleep is observed at the 24th hour in intoxication with CuSO4, CdSO4, Co(NO3)2, Pb(CH3COO)2, ZnSO4, NiSO4, while As2O3, HgCl2, Bi(NO3)2 and SnCl2 do not change it. All heavy metals (with the exception of NiSO4) prolong significantly hexobarbital sleep 96 hours after the intoxication. At the 24th hour after intoxication with salts of heavy metals, the hexobarbital level in the blood serum at the 30th min after its administration is significantly higher for Co(NO3)2, CdSO4, NiSO4, and it tends to be higher for CuSO4 and Pb(CH3COO)2. This, together with the significant inhibition of the hexobarbital-oxidizing enzyme system in the case of Cu, Co, Cd and Pb, suggests that in the case of these heavy metals potentiation of the hexobarbital sleep is largely due to inhibition of the hexobarbital metabolism. No significant prolongation of hexobarbital sleep or changes in hexobarbital metabolism are found in intoxication with Hg, As, Bi and Sn salts. The definitely lower hexobarbital level in the blood serum and brain at the waking moment, as well as the lower threshold hypnotic doses, suggest the interference of pharmacodynamic mechanisms at the level of the central nervous system in the prolongation of hexobarbital sleep after acute intoxication with CuSO4, CdSO4 and NiSO4.

Acute Disease↗
PubMed1989

Inhibition of acute CNS-tolerance to hexobarbital and prolongation of hexobarbital anaesthesia by disulfiram treatment in rats.

In many studies disulfiram treatment has been found to prolong hexobarbital anaesthesia, but the underlying mechanisms have not been clarified. In the present study, the effect of disulfiram on the development of acute tolerance to hexobarbital was studied in 2 age groups of rats (80 and 130 days old). Acute tolerance was measured as the increase in the brain concentration of hexobarbital (in 4 brain regions) needed to keep the rats on a constant EEG-monitored anaesthetic level for 1 hr. The effects of disulfiram on the metabolism in vitro and elimination in vivo of hexobarbital were also measured. The results suggest that the prolonged hexobarbital anaesthesia found after disulfiram treatment was the result of an inhibition of at least two different mechanisms: (1) the ability of the brain to develop acute tolerance to hexobarbital, and (2) the metabolism of hexobarbital by the liver, the latter resulting in a decreased elimination of the anaesthetic from the brain. The impaired development of acute tolerance was apparent only in the older rats. The inhibition of hexobarbital metabolism was most obvious in the younger ones.

Age Factors↗
PubMed1980

Hexobarbital-binding, hydroxylation and hexobarbital-dependent hydrogen peroxide production in hepatic microsomes of guinea pig, rat and rabbit.

Cytochrome P-450 dependent oxygenase (3'-hydroxy-hexobarbital) and oxidase activities (hydrogen peroxide) have been measured in hepatic microsomes from guinea pigs, rats and rabbits. A sensitive gas-chromatographic assay was developed to measure the hydroxylated product 3'-hydroxy-hexobarbital. The kinetics of its formation were determined and correlated to hexobarbital type I binding and compared with oxidase activity: in the rat, Vmax for 3'-hydroxyhexobarbital formation was 5.1 and 2.6 nmoles/mg/min, resp. This was increased by phenobarbital treated rabbits, Vmax was 15.0 nmoles/mg/min for hydroxylation and 40.8 for H2O2 formation. Spectral affinity constants (Ks) in control animals were 0.12 mM (rats) and 0.14 mM (rabbits). Phenobarbital treatment decreased these affinity constants, which were similar for each activity measured. In guinea pigs, however, hydroxylation of exobarbital was low (3.1 nmoles/mg/min) and hexobarbital-dependent formation of H2O2 was higher than hydroxylation (Vmax: 7.0 nmoles/mg/min). Phenobarbital treatment led here to two affinity constnts for each activity measured, which however, were alike. The existence of low in addition to high affinity constants observed here might explain the difficulties seen hitherto in correlating hexobarbital binding and metabolism in this species. Total oxidase activity was higher than oxygenase activity in all species tested. It is suggested that oxygenase activity of cytochrome P-450 is not limited by binding but by a competition with oxidase activity for a common intermediary species. This might be peroxy-P-450 (substrate-Fe3+O2(2-), rendering either substrate-Fe3+ O for hydroxylation reaction, or oxidized cytochrome P-450-substrate and hydrogen peroxide as product of oxidase function.

Animals↗
PubMed1991

Inhibition and induction of drug metabolism by psoralens: alterations in duration of sleep induced by hexobarbital and in clearance of caffeine and hexobarbital in mice.

1. Hexobarbital (100 mg/kg i.p.) sleeping times in male CD-1 mice pretreated (-1 h) with a single i.p. injection of 150 mumol/kg of psoralen or coumarin analogues were increased, most markedly (6-fold) by linear, methoxy-substituted psoralens. 2. Hexobarbital sleeping times of mice which received three daily injections (231 mumol/kg; 50 mg/kg) of 8-methoxypsoralen (8-MOP) were 44% of controls (corn oil). 3. The whole-body half-life of caffeine (1 mg) in mice was 10.2, 1.2, and 0.37 h following 8-MOP (50 mg/kg per day) x 1, vehicle, and 8-MOP x 3 respectively. 4. The whole-body concentrations of hexobarbital (100 mg/kg dose) in mice 30 min after dosing were 14.3 +/- 0.9, 8.4 +/- 0.3, and 5.2 +/- 0.5 micrograms/ml (1 mouse = 150 ml) following 8-MOP (50 mg/kg per day) x 1, vehicle, and 8-MOP x 3 respectively. 5. It is concluded that, administered acutely, psoralen analogues inhibit hexobarbital metabolism in mice; and 8-MOP administered acutely inhibits the metabolism of caffeine and hexobarbital, but administered repeatedly increases their metabolism.

Animals↗
PubMed1986

Effects of methylmercury on hypnotic action of hexobarbital, liver hydroxylase and cytochrome P-450 in mice.

The effects of methylmercury hydroxide (MeHgOH) on the hypnotic action of hexobarbital was investigated in adult 129/SvSl mice of both sexes. It was found that there was no sex difference in the response to MeHgOH treatment. The action of MeHgOH was intimately related to the interval between MeHgOH administration and the test of hexobarbital hypnosis. A biphasic effect was observed. An initial dose-dependent prolongation of hexobarbital hypnosis was observed in animals pretreated with MeHgOH 24 h earlier. If the interval was extended from 24 h to 1 week, a shortening of sleeping time was observed in MeHgOH treated animals. The animals recovered from the effects of MeHgOH in 3 weeks. The initial effect of MeHgOH was found closely related to the decrease in the rate of hexobarbital metabolism in the liver through lowering of cytochrome P-450 concentration. On the other hand, the delayed shortening of hexobarbital hypnosis was not related to the rate of hexobarbital metabolism. It is assumed that the delayed effect of MeHgOH on the hexobarbital hypnosis is due to MeHgOH acting on the central nervous system to decrease its sensitivity to hexobarbital via interaction with the barbiturate receptors on the GABA-chloride ionophore complex. In animals exposed in utero to MeHgOH, it was found that the duration of hexobarbital-induced sleeping time was significantly longer in the offsprings tested for hexobarbital hypnosis 3.5 months after birth following prenatal exposure to MeHgOH. Repeated administration of hexobarbital to adult offsprings prenatally exposed to MeHgOH and to control mice shortened hexobarbital sleeping time, however, the maximum shortening capacity was smaller in the treated group. It is concluded that the hypnotic action of hexobarbital in mice can be altered by MeHgOH exposure both prenatally and postnatally. The effects of prenatal exposure to MeHg were observed in adult offsprings, indicating that MeHg may have a functional teratogenic effect on barbiturate-induced hypnosis in the absence of gross anomalies.

Animals↗
PubMed1975

Heredity of hexobarbital sleeping time and efficiency of drug metabolism in Wistar and Sprague-Dawley rats.

Nature of considerable variability of hexobarbital sleeping time and drug metabolism efficiency within a single strain of rats were investigated. Wistar or Sprague-Dawley rats with shorter than average hexobarbital sleeping time had also higher rates of in vitro hepatic microsomal metabolism of hexobarbital, aminopyrine, aniline and benzene, higher liver weight, microsomal protein content and P-450 level, and faster hexobarbital blood level decline (but similar volumes of distribution) after intraperitoneal hexobarbital sodium than those with relatively longer hexobarbital sleeping time, but awakened with the same hexobarbital blood level. The differences were maintained throughout the life of rats and inherited in their offspring. It indicated a possible genetic control of hexobarbital sleeping time and efficiency of drug metabolisms with apparent differences in selection response for Type I and Type II substrates (hexobarbital and aminopyrine vs aniline): it might indicate different heredity mechanism for these types of substrates. Stronger hexobarbital narcotic effect in females was associated with the rate of hexobarbital metabolism, but also with higher brain sensitivity. Hexobarbital sleeping time pattern indicated more general pattern of drug metabolism (better for Type I substrates) and success of selection of rats for different efficiency of drug metabolism (up to 8-fold differences in F5 generation) suggested considerable genetic non-homogeneity of two common strains of laboratory rats.

Aminopyrine↗
PubMed1976

The interaction between pilocarpine and hexobarbital in male rats.

The interaction between pilocarpine and hexobarbital was studied in male rats. Hexobarbital was infused continously. The dose needed to obtain an EEG criterion (the "silent second") was determined. The ensuing anesthesia times after these equi-anesthetic doses were also recorded. At different times prior to the hexobarbital threshold determination the rats were pretreated with 25-200 mg/kg of pilocarpine. In most experimental series pretreatment with methylatropine (2 mg/kg s.c.) was also given to reduce the effects of pilocarpine on peripheral cholinergic sites. In the dose-response study pilocarpine was given 1 h prior to the hexobarbital threshold determination. Pilocarpine in doses of 25-50 mg/kg increased the amount of hexobarbital needed to obtain the "silent second". With higher doses of pilocarpine, increases in hexobarbital thresholds were seen if no convulsion had been induced by the pilocarpine treatment. If a convulsion was recorded the dose of hexobarbital was reduced. Similar results were obtained in the time-effect studies where more convulsions tended to appear if the time between the dose of pilocarpine and the dose of hexobarbital was increased. In animals without convulsions the effect of pilocarpine on the dose of hexobarbital was counteracted by atropine (8 mg/kg i.p.). The ensuing anesthesia times were increased in the pilocarpine pretreated animals, which could be due to either the pilocarpine dose, the increased dose of hexobarbital needed to obtain the "silent second", or both. No regression between body temperature and dose of hexobarbital was found, but there was a regression with the ensuing anesthesia times. The effects of pilocarpine with an increase in hexobarbital threshold is similar to the changes seen in the threshold in the abstinence after chronic barbital treatments. More important, however, is that both increases are reduced by convulsions. Could pilocarpine be a model for the changes in the abstinence after barbital?

Anesthesia↗
PubMed1977

[Hexobarbital-oxidation in vivo and in vitro in rats after phenobarbital-pretreatment or after portacaval anastomosis (author's transl)].

Male rats were pretreated with phenobarbital for 5 days or received portacaval anastomosis 3 weeks before. Hexobarbital was applicated intravenously and hexobarbital plasma concentrations were followed up gaschromatographically in arterial blood samples. Hexobarbital clearance was calculated from the plasma concentration curve versus time. Liver microsomes were prepared and cytochrome P 450 and the hexobarbital oxidation rate was determined. After portacaval shunt the animals showed a small liver, a reduced cytochrome P 450 and diminished hexobarbital oxidation rate. Hexobarbital clearance in vivo was reduced, too. After phenobarbital pretreatment liver weight increased and cytochrome P 450 and hexobarbital oxidation rate were distinctly enhanced. The hexobarbital clearance in vivo were increased. Since the plot of hexobarbital clearance in vivo versus cytochrome P 450 or versus hexobarbital oxidation rate in vitro gave a good correlation, it is concluded that hexobarbital clearance in vivo may be a good estimate for hepatic cytochrome P 450 and hepatic hexobarbital oxidation rate.

Animals↗
PubMed1990

Polymorphism in hydroxylation of mephenytoin and hexobarbital stereoisomers in relation to hepatic P-450 human-2.

Stereoselective 4'-hydroxylations of R-(-)-mephenytoin and S-(+)-mephenytoin and 3'-hydroxylation of R-(-)-hexobarbital and S-(+)-hexobarbital were determined in liver microsomes of 14 Japanese subjects who were extensive metabolizers of mephenytoin and in five Japanese subjects who were poor metabolizers of mephenytoin. Content of P-450 human-2 assessed by Western blots was correlated to microsomal S-(+)-mephenytoin 4'-hydroxylation, R-(-)-hexobarbital 3' alpha-hydroxylation, and S-(+)-hexobarbital 3' beta-hydroxylation, and was less correlated to R-(-)mephenytoin 4'-hydroxylation, R-(-)-hexobarbital 3' beta-hydroxylation, and S-(+)-hexobarbital 3' alpha-hydroxylation. Antibodies raised against P-450 human-2 inhibited microsomal S-(+)-mephenytoin 4'-hydroxylation efficiently but was less efficient on R-(-)-mephenytoin 4'-hydroxylation in extensive metabolizers and on 4'-hydroxylation of mephenytoin enantiomers in poor metabolizers. The antibodies also inhibited R-(-)-hexobarbital 3' alpha-hydroxylation and S-(+)-hexobarbital 3' beta-hydroxylation but did not effectively inhibit the hydroxylation of the two other optical isomers of hexobarbital in extensive metabolizers and of four stereoisomers in poor metabolizers. These findings indicate the close relationship between polymorphic mephenytoin 4'-hydroxylation and two stereospecific hexobarbital hydroxylations, and they suggest that P-450 human-2 is a typical S-(+)-mephenytoin 4'-hydroxylase and a major hexobarbital 3'-hydroxylase in the livers of extensive metabolizers. The findings were further supported by the experiments that used P-450 human-2 complementary dexoyribonucleic acid-derived protein in yeast microsomes.

Cytochrome P-450 Enzyme System↗
PubMed1978

Evaluation of Dopram(R) and its effects on hexobarbital narcosis.

The effect of Dopram(R) on hexobarbital induced narcosis and hypothermia was determined. Sodium hexobarbital (70mg/kg, i.p.) sleeping times were assessed in saline, Dopram(R), 20 and 40 mg/kg, i.p., administered mice. A dose-response increase in sodium hexobarbital induced narcosis was produced by Dopram(R). The duration of Dopram(R) effect on hexobarbital narcosis was also assessed. Dopram(R) potentiated significantly hexobarbital sleeping times when administered two hours prior to sodium hexobarbital challenge. Dopram(R) also was observed to significantly increase the hypothermic response to hexobarbital. The effect of the individual components of Dopram(R) (doxapram hydrochloride and chlorobutanol) on hexobarbital narcosis and hypothermia was evaluated. It was found that doxapram hydrochloride (20 and 40 mg/kg, i.p.) and chlorobutanol (5 and 10 mg/kg, i.p.) potentiated sodium hexobarbital narcosis and hypothermia. It seems that doxapram hydrochloride and chlorobutanol are both responsible for the potentiation of hexobarbital narcosis and hypothermia by Dopram(R).

Animals↗
PubMed1981

Heme enhances hexobarbital metabolism in perfused rat liver after drug-mediated destruction of cytochrome P-450.

During mixed-function oxidation of allylisopropylacetamide (AIA), autocatalytic destruction of hepatic cytochrome P-450 leads to retarded elimination of this agent. After AIA-mediated destruction of cytochrome P-450, exogenously administered heme that has entered liver cells is directly incorporated into cytochrome P-450. This raises the hepatic content of this hemoprotein, enhances the activity of mixed-function oxidases and accelerates hepatic clearance of the inactivating agent, AIA. We have studied the metabolic consequences of these phenomena for the disposition of hexobarbital coadministered with AIA in the isolated perfused rat liver. AIA decreased perfusate fractional disappearance of hexobarbital by approximately 80%. This was attributable to destruction of cytochrome P-450 rather than to competitive inhibition of hexobarbital metabolism, since by increasing the molar ratio of hexobarbital to AIA in perfusate, hexobarbital elimination was not enhanced. Heme administered after AIA significantly accelerated hexobarbital disappearance from the perfusate, reflecting increased hexobarbital metabolism by reconstituted cytochrome P-450. In the absence of prior destruction of cytochrome P-450 by AIA, heme failed to alter the rate of hexobarbital elimination. These findings demonstrate that drug-mediated destruction of cytochrome P-450 results in impaired hexobarbital metabolism, which is reversible by administration of heme. Heme infusion may be useful in treatment of patients poisoned with drugs that destroy hepatic cytochrome P-450.

Allylisopropylacetamide↗
PubMed1991

Enantiospecific quantification of hexobarbital and its metabolites in biological fluids by gas chromatography/electron capture negative ion chemical ionization mass spectrometry.

A highly sensitive and specific assay based on gas chromatography/electron capture negative ion chemical ionization mass spectrometry has been developed for the analysis of the enantiomers of hexobarbital and its major metabolites in human urine and plasma. S-(+)-(5-2H3)hexobarbital and R-(-)-(5-2H3)hexobarbital were synthesized for clinical studies along with (+/-)-(1,5-2H6)hexobarbital and the deuterated major metabolites for use as internal and reference standards. Hexobarbital enantiomers and their metabolites were analyzed after pentafluorobenzyl and trimethylsilyl derivatization, following solid-phase extraction from plasma and urine. Intense negative ion spectra were observed for all of the derivatives. The base peak in the spectra corresponded to the M-pentafluorobenzyl anion [M-PFB]- except for 1,5-dimethylbarbituric acid, where M-. was the most abundant ion. The applicability of the method was demonstrated by following the plasma concentration-time profiles and urinary excretion in a male extensive metabolizer of mephenytoin who was given a pseudoracemic oral dose of hexobarbital containing equal 50 mg amounts of S-(+)-2(H0)hexobarbital and R-(-)-(2H3)hexobarbital. Marked stereoselective disposition was observed, with the R-(-)-enantiomer being more efficiently metabolized, primarily by alicyclic oxidation and ring cleavage.

Adult↗
PubMed1992

Influence of age on stereoselective pharmacokinetics and metabolism of hexobarbital in the rat.

The influence of age on stereoselective pharmacokinetics and in vitro metabolism of R- and S-hexobarbital was studied in the rat. After intravenous administration of the racemate, the plasma concentrations of S-hexobarbital are markedly lower than those of R-hexobarbital. For S-hexobarbital the half-life is somewhat shorter and the volume of distribution and plasma clearance is higher than for its antipode. For both enantiomers an increase in AUC and half-life, and a decrease in clearance are observed with aging. These changes occur mainly between the 3rd and the 12th month and are slightly more pronounced for R- than for S-hexobarbital, as appears from the S/R ratios. The volume of distribution shows no changes with aging. In vitro disappearance rate in 3-month-old rats is significantly higher for S- than for R-hexobarbital. There is for both enantiomers an increase in disappearance rate in 12-month-old rats as compared to younger or older rats, but this is significant only for the R-enantiomer. There are pronounced differences in the kinetics and metabolism of both hexobarbital enantiomers; changes with aging occur, but are only slightly and not always significantly more important for R- than for S-hexobarbital.

Aging↗
PubMed1993

Interaction of the competitive AMPA receptor antagonist NBQX with hexobarbital.

IP administration of hexobarbital to rats caused a mean sleeping time of 93.6 min (SD 21.5). IV infusion of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX) at a dose rate of 0.11 mg/kg/min starting 30 min after administration of hexobarbital prolonged the mean sleeping time to 132.2 min (SD 14.9). Dose rates of 0.33 and 1.10 mg/kg/min prolonged the mean sleeping times to 176.4 min (SD 33.3) and 444.1 min (SD 72.0), respectively. Measured 180 and 450 min after the start of the study, there were no differences in the plasma concentrations of hexobarbital in groups receiving hexobarbital alone compared to groups receiving the high-dose rate of NBQX starting 30 min after administration of hexobarbital. The present results demonstrate that by IV infusion NBQX dose dependently prolonged the sleeping time of hexobarbital. There were no indications of interactions on hexobarbital elimination of either isomer. It is therefore likely that NBQX acts synergistically with hexobarbital to depress the central nervous activity.

Animals↗
PubMed1979

Hexobarbital blood levels and effects on EEG in the presence and absence of caffeine.

The interaction of caffeine and hexobarbital in the rat with spinal cord transection was studied. Duration of hexobarbital effect on the brain was taken as the time from the injection of hexobarbital (i.v.) to the return of pre-injection cortical voltage. Hexobarbital distribution and elimination was estimated by application of a two-compartmental model to values for blood hexobarbital concentration (determined by a direct gas chromatographic method after extraction). Caffeine caused a shift in the dose-response curve for hexobarbital but no changes in hexobarbital distribution and elimination. Results are interpreted on the basis of a central interaction of caffeine with hexobarbital at a brain receptor level.

Animals↗