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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↗
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↗
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↗
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↗
PubMed1979

[Mechanisms of hexobarbital anesthesia potentiation by hydrocortisone].

The authors carried out studies on white rats of Wistar strain and investigated some of the mechanisms, metabolic and central, by means of which hydrocortisone affected hexobartital sleep. They established that hydrocortisone in dose of 25 and 50 mg, administered singly, together with hexobarbital or after a 30-minute interval, potentiated hexobarbital sleep significantly. The concentrations of hexobarbital in blood serum and in brain on the 30th minute after its administration were higher in the experimental animals, treated with hexobarbital in comparison with the controls of both sexes. The experiments with determination of the activity of liver microsomal hexobarbital enzymic system showed convincingly a considerable inhibition of enzymic activity (with 53%) of hydrocortisone after 20 minutes after its application in vivo. Subthreshold sreep dose of hexobarbital, determined by the method of Lewy, was lowered than that of the experimental group and higher in the control rats. Hexobarbital concentrations in blood serum and in brain at the moment of waking were lower in experimental animals, treated with hydrocortisone, and higher in the control animals. The obtained results gave foundations to the authors to assume that metabolic and central nervous mechanisms participated in potentiation of hexobarbital sleep.

Anesthesia↗
PubMed1977

Hexobarbital pharmacokinetics in rats after ligation of the common bile duct.

Rats, with and without bile duct ligation (BDL), were injected with hexobarbital (i.p. and i.v.) and blood concentrations measured as a function of time. Analysis of these curves using a single-compartment model showed that BDL altered hexobarbital pharmacokinetics in a manner dependent upon the duration of BDL and the route of administration of hexobarbital. Clearance from the blood and the rate constant for elimination (K) were reduced after 72-hour BDL but not after 12-hour BDL. The absorption of hexobarbital after intraperitoneal injection was slowed by 12- and 72- hour BDL. Seventy-two-hour BDL also increased the volume of distribution of hexobarbital but only when the drug was administered intraperitoneally. These data are consistent with previously reported data showing impairment of hepatic microsomal drug metabolism after 72-hour BDL, but not after 12-hour BDL. We also confirmed earlier speculations that BDL decreased the absorption of intraperitoneally-administered hexobarbital, although this does not appear to be a significant factor in prolonging hexobarbital sleeping time.

Animals↗
PubMed1977

[Metabolism of hexobarbital in patients with acute hepatitis and cirrhosis (author's transl)].

16 patients with acute hepatitis, 18 patients with cirrhosis and a total of 21 volunteers and patients with normal liver function received 7.32 mg/kg hexobarbital by linear intravenous infusion within 60 min. Hexobarbital was determined gaschromatographically in serial blood samples and the hexobarbital-clearance was calculated from the plasma concentration curve versus time. Additional experiments were performed in rats suffering from so called "galactosamine hepatitis". In half of the patients with acute hepatitis a normal hexobarbital clearance could be found. In the other patients this was distinctly reduced but not correlation was found to other liver function tests. Patients with cirrhosis were subdivided into two groups. The patients in group 1 were well compensated. The patients in group 2 had a decompensated state with ascites and oesophageal varices. In nearly all patients with cirrhosis the hexobarbital-clearance was diminished. This was more pronounced in group 2. Ketohexobarbital excretion in healthy subjects was in the range of 40-60% of dose. Patients with acute hepatitis excreted only 10-20% of dose and patients with liver cirrhosis only about 5% of dose. In rats with "galactosamine hepatitis" hexobarbital clearance in vivo was distinctly reduced and this could be explained by diminished microsomal cytochrome p 45- and hexobarbital oxidation rate.

Acute Disease↗
PubMed1976

The binding of hexobarbital and aniline to cytochrome P-450 of liver microsomes from control and phenobarbital-treated rats of different ages.

The spectral changes due to the binding of hexobarbital and aniline to cytochrome P-450 of rat liver microsomes were investigated in 10-day- to 15-month-old rats. The Ks values for both substances and consequently the affinity for cytochrome P-450 do not change during ageing. Phenobarbital treatment does not alter the affinity of hexobarbital, but enhances the Ks value for aniline. The maximal spectral changes (delta A max) due to aniline are nearly equal in all age groups whereas delta A max due to hexobarbital is very small in young rats and increases considerably during ageing. The age-dependence of the hexobarbital-induced delta A max is similar to the development of drug-metabolizing reactions. delta A max due to hexobarbital and aniline is enhanced by phenobarbital treatment of the rats. The addition of aniline to microsomes enhances the Ks value and diminishes delta A max for hexobarbital.

Aniline Compounds↗
PubMed1975

Pharmacokinetics of hexobarbital in acute hepatitis and after apparent recovery.

The pharmacokinetics of hexobarbital were studied in 13 patients with acute hepatitis. Hexobarbital sodium was administered by zero order intravenous (iv) infusion, and plasma concentrations were determined regularly by gas chromatography. For each patient the data were fitted according to 2-compartment kinetics. The results were compared to those obtained for 14 healthy volunteers. The elimination half-life of hexobarbital was 490 +/- 186 min in the hepatitis patients and 261 +/- 69 min in the control group. Clearance was significantly reduced in the hepatitis group, whereas the volume of distribution at steady state was not significantly altered. For some patients the initial distribution volume was reduced. In 6 patients the experiment with hexobarbital was repeated after apparent recovery from hepatitis as judged by normal transaminase and bilirubin levels. Generally the half-life of hexobarbital was shorter and the clearance value was higher than during the acute illness, but the values had not yet returned to normal. Clinical recovery from liver disease is not accompanied by corresponding recovery of drug-metabolizing capability.

Adolescent↗
PubMed1978

Induction of microsomal drug-metabolizing enzymes caused by hexobarbital.

Hexobarbital was given to anaesthetized mice for a period of 7 h by repeated i. p. injection, first of 100 mg/kg,then several times of 50 mg/kg. A high level of hexobarbital was maintained in the liver. The activity of microsomal drug-metabolizing enzymes was induced by this treatment with hexobarbital. 30 min after a single i. p. injection of 100 mg/kg of hexobarbital, there was a significant inhibition of aminopyrine N-demethylase but none of cytochrome c and neotetrazolium reductases. Hexobarbital in vitro inhibits aminopyrine N-demethylase but not cytochrome c reductase.

Aminopyrine N-Demethylase↗
PubMed1975

Influence of cystamine on activity and biotransformation of hexobarbital.

Influence of cystamine on hypnotic potency and biotransformation of hexobarbital in rats was studied. Duration of hexobarbital-induced sleep was prolonged maximally by 42% on the first day after premedication, and by 37% on the third day. After six days, differences from the control group were within the limits of experimental error. Biotransformation of hexobarbital was only slightly inhibited in rats premedicated with cystamine, confirmed by determinations of hexobarbital oxidase activity. Excretion of hexobarbital and its metabolites was delayed.

Animals↗
PubMedDate not supplied

Studies on the cause of changes of reactivity to hexobarbital in spontaneously hypertensive rats (SHR).

The hypnotic action of hexobarbital is weaker in spontaneously hypertensive rats (SHR) than in Wistar rats. The difference does not appear in young rats (up to the sixth week of life) and appears gradually concomitantly with maturation of animals. There was no correlation between the changes of reactivity to hexobarbital and development of hypertension. The rate of metabolism of hexobarbital was similar in SHR and Wistar rats. There is a close relationship between the changes in reactivity to hexobarbital and psychomotor activity: both are significantly higher in SHR than in Wistar rats. The results suggest that the main cause of a weaker action of hexobarbital in SHR is higher intensity of stimulatory processes in the central nervous system.

Aging↗
PubMed1978

Effect of subacute intoxication with some heavy metals on hexobarbital sleep and metabolism.

In experiments on albino rats it is found that cobaltous dichloride, cadmium nitrate, nickel sulphate, copper sulphate and lead acetate, applied subcutaneously for 7 days, potentiate hexobarbital anaesthesia, while mercury dichloride and iron dichloride have no effect on it. A higher hexobarbital content is found in the blood serum of rats, treated with cobaltous dichloride, cadmium nitrate, nickel sulphate, copper sulphate and lead acetate, compared with the control animals. Treatment for 7 days with cobalt dichloride, cadmium nitrate, copper sulphate and nickel sulphate inhibits the activity of the liver microsomal hexobarbital-oxidizing enzyme system. The prolonged hexobarbital sleep in rats subjected to subacute intoxication with cobalt, cadmium, nickel, copper and lead is probably due to a considerable extent to the inhibition of the hexobarbital metabolism by these metals.

Animals↗
PubMed1976

[Sleeping time and awaking blood concentration of hexobarbital influenced by glucose and adrenaline in rats of both sexes].

Sleeping times in male and femal rats are prolonged after the simultaneous i.p. administration of adrenaline and hexobarbital sodium. The blood concentration of hexobarbital at awakening is unchanged in male rats, while in females this concentration is decreased. When adrenaline is given s.c., no change in sleeping times is observed in female and male rats, while the blood concentration of hexobarbital for the two sexes is decreased. Glucose, given p.o. or i.p., has no influence on sleeping times or on hexobarbital concentrations. The hexobarbital concentrations at awakening is higher in female than in male rats.

Animals↗
PubMed1976

Effect of water and food deprivation on hepatic microsomal metabolism of hexobarbital and aniline.

Water deprivation for 48 hr with its accompanying decrease in food intake significantly lowered the in vitro rate of hexobarbital metabolism by hepatic microsomes isolated from male rats. Pair-fed rats allowed water ad libitum had a significantly lower level of hexobarbital metabolism than those deprived of water. Rats starved for 24 hr with or without water also had levels of hexobarbital metabolism significantly lower than their controls; with those animals allowed water ad libitum, the level was significantly lower than for those deprived of water. In vivo hexobarbital "sleeping time" experiments were in general agreement with these results. The in vitro metabolism of aniline was increased in both male and female rats following 24 hr starvation and in female rats (but not males) the effect was greater when water was allowed than when deprived. The differences between hydrated and dehydrated animals were not attributable to reduction in concentration of microsomal protein or the water content of liver. It is concluded that water consumption accentuates the effect of food deprivation on hepatic microsomal metabolism.

Aniline Compounds↗
PubMed1975

The effects of sulphydryl reagents on the binding and mixed function oxidation of hexobarbital in rat hepatic microsomes.

1. The effects of the sulphydryl reagents p-chloromercuribenzoate, N-ethylmaleimide and iodoacetamide on the binding spectrum, oxygen consumption and formation of a suspected substrate-cytochrome P-450-oxygen complex for hexobarbital in rat liver microsomes were investigated. 2. The oxygen consumption caused by hexobarbital oxidation was inhibited non-competitively by all three agents, with 50% inhibition at 4 times 10(-5) M for p-chloromercuribenzoate, 3-7 times 10(-4) M for N-ethylmaleimide and 1-9 times 10(-3) M for iodoacetamide. Cysteamine protected and at least partially reversed this inhibition. 3. p-chloromercuribenzoate inhibited the formation of the cytochrome P-450-substrate-oxygen complex, while N-ethylmaleimide and iodoacetamide also inhibited the formation of this complex but to a lesser extent. The p-chloromercuribenzoate inhibition was protected against and reversed by cysteamine. 4. p-Chloromercuribenzoate and N-ethylmaleimide caused a 50% reduction in the magnitude of the hexobarbital-induced binding spectrum, and this was paralleled by the conversion of cytochrome P-450 to cytochrome P-420. Cysteamine protected against this effect but could not reverse it. Iodoacetamide had no effect on the binding spectrum of hexobarbital and failed to convert cytochrome P-450 to cytochrome P-420. 5. Points of attack within the reaction sequence of drug oxidation are tentatively ascribed to the sulphydryl reagents used in this study.

Animals↗