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Results for “Phenobarbital”

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PubMed1977

Phenobarbital actions in vivo: effects on extra cellular potassium activity and oxidative metabolism in cat cerebral cortex.

Extracellular potassium activity and changes in the reduction levels of intramitochondrial pyridine nucleotide (NAD) and cytochrome-a,a3 were monitored in the cerebral cortex of cats at rest and during electrical stimulation, before and after administration of sodium phenobarbital. Stimulation of the cortical surface evoked a transient increase in the level of oxidized NAD which was proportional in magnitude to the associated transient elevation of extracellular potassium. Phenobarbital (i.v.) produced, within minutes, a persistent shift in NAD to a more reduced level indicative of decreased oxygen consumption. Electrical excitability of the cortex also decreased within minutes, although there was no concomitant change in the resting extracellular potassium activity. Cortical stimulation produced transient elevations of [K+]0 and NADH oxidation and these responses returned to base lines more slowly following the barbiturate administration. However, the proportionality between NADH oxidation and [K+]0 elevation was not altered by phenobarbital. The kinetics of the cytochrome-a, a3 response to cortical stimulation mirrored those of NADH, implying that phenobarbital was not blocking electron transport in the respiratory chain between NADH and cytochrome-a, a3 even at doses where "resting" tissue oxygen consumption was decreased. The prolongation of recovery metabolism following phenobarbital was interpreted as being the result of protracted elevation of extracellular potassium activity. The slow return to "resting" levels of extracellular potassium is probably caused by interference with passive clearance mechanisms.

Animals↗

PubMed1975

Fluroxene toxicity induced by phenobarbital.

Because of reports of fluroxene toxicity in man, the effect of phenobarbital treatment on the toxicity and metabolism of fluroxene was studied in 9 rhesus monkeys. Six monkeys that were exposed to a mean calculated alveolar fluroxene concentration of 5.8% for 4-hr periods up to a total of 16 hr showed no evidence of toxicity. Two animals were sacrificed after a single 4-hr exposure to obtain control measures of fluroxene metabolites in tissues. Four monkeys that had previously survived received exposures to fluroxene and 3 monkeys that had no exposure to fluroxene died during fluroxene anesthesia after treatment with phenobarbital (mean time, 3 hr). Toxicity was manifested by arterial hypotension, pulmonary edema, and arterial hypoxemia. Phenobarbital treatment enhanced production of fluroxene metabolites, including the highly toxic trifluoroethanol. Concentrations of trifluoroethanol in mixed-expired gas, blood, and urine, and of total nonvolatile fluorine in blood, urine, and tissues of animals treated with phenobarbital were 2 to 10 times as in control animals. The results suggest that the rhesus monkey is a valuable model for the study of fluroxene pharmacology and that inclusion of an enzyme-inducing challenge in the evaluation of potential toxicity of other anesthetics seems warranted.

Anesthesia↗

PubMed1979

Comparative pharmacokinetics of coumarin anticoagulants. XLII: Effect of phenobarbital on systemic availability of orally administered dicumarol in rats with ligated bile ducts.

The purpose of this investigation was to determine if the previously demonstrated inhibitory effect of phenobarbital treatment on the systemic availability of orally administered dicumarol in rats is related to the known effect of phenobarbital on bile output. It was found that phenobarbital had no apparent effect on the systemic availability of an aqueous dicumarol suspension in rats with ligated bile ducts. Compared to results obtained previously on normal rats, bile duct-ligated rats absorbed and eliminated dicumarol much more slowly and absorbed much less of the anticoagulant. On the other hand, the relative inductive effect of phenobarbital treatment on dicumarol elimination was similar in normal and in bile duct-ligated animals. The latter exhibited substantial serum transaminase elevations, indicative of liver damage presumably secondary to cholestasis. These results demonstrate that a drug-drug interaction can depend markedly on the pathophysiological status of the animals.

Animals↗

PubMed1977

Induction of liver lysosomal enzymes during the autophagic phase following phenobarbital treatment of rat.

Phenobarbital was given to male rats as a single injection and as repetitive injections for 7 days. The effects of treatment on the lysosomal hydrolases acid phosphatase, cathepsin D, and aryl sulfatase were analyzed at different intervals ranging from 1 to 15 days after seven injections, and from 1 to 48 h after a single injection. In both cases, microsomal protein and NADPH-cytochrome c reductase were measured to ensure proper induction. After a single injection, a slight decrease in hydrolytic activities was observed. Repetitive administration of phenobarbital gave rise to a marked decrease of lysosomal enzyme activities 1 day after cessation of treatment. This decrease was followed by a continuous increase in activity up to day 3 and 4. One or 2 weeks after treatment, enzyme activities declined to control values. The increase in activity of lysosomal hydrolytic enzymes was correlated with the onset of induced autophagy of endoplasmic reticulum membranes described as occurring in liver upon cessation of phenobarbital exposure. It is concluded that phenobarbital treatment per se decreases lysosomal enzyme activities, whereas the induced autophagy following cessation of exposure is associated with enhanced levels of lysosomal hydrolases in rat liver.

Acid Phosphatase↗

PubMed1977

Characterization of microsomal electron transport components from control, phenobarbital- and 3-methylcholanthrene-treated mice. II. Improved resolution and quantitation of major components in ammonium sulfate fractions from total liver microsomes.

Quantitation of microsomal components in ammonium sulfate fractions using a high-resolution sodium dodecyl sulfate-polyacrylamide gel electrophoresis system, and a comparison of these results with those from similar experiments on total liver microsomes has enabled us to identify and better characterize the interactions between microsomal electron transport components. It was found that: (1) phenobarbital decreased the amount of one protein component of approximately 50 000 molecular weight while increasing a component of very similar molecular weight; (2) only two proteins appeared to be associated with CO binding; (3) another protein of approximately 68 000 molecular weight, one of the glycoproteins found in liver microsomes, appears to be induced by phenobarbital pretreatment; (4) the induction of NADPH-cytochrome c reductase activity after phenobarbital pretreatment is not dependent on an increase in the known NADPH-dependent flavoprotein, but rather on the increase in some component found predominately in our most soluble sub-microsomal fraction. A very good separation of the above components was achieved by ammonium sulfate fractionation, e.g. simply on the basis of their solubility. This and the fact that the more-or-less soluble proteins were induced by phenobarbital or 3-methylcholanthrene respectively indicate that the solubility of membrane proteins plays a major role in the structure and function of microsomal membranes.

Ammonium Sulfate↗

PubMed1979

The mode of action of phenobarbital on the excitable membrane of the node of Ranvier.

Single myelinated nerve fibres of Rana esculenta were investigated under current and potential clamp conditions at 20 degrees C. Under 2.5 mM phenobarbital, the amplitude of the action potential was reversibly reduced to 85.5 +/- 5% (n = 6), and the threshold potential was raised by 32% of the control in Ringer solution. The resting potential remained constant. Solutions with 2.5 mM phenobarbital caused a decrease of the Na current to 38.3 +/- 5.6% (n = 10), when the fibre had its holding potential before the test step. The effect was reversible at wash out of the drug. The Na currents were only negligibly decreased (7 +/- 4.5%; n = 10) when the test pulse was preceded by a long lasting negative polarization to Em = -140 mV. The effect of the conditioning polarization could be described by two time constants, tau 1 = 7.1 +/- 2.0 msec and tau 2 = 44.5 +/- 9.5 msec (n = 5). Experiments with 500 msec conditioning pulses showed that the Na inactivation curve, h infinity(Em), was shifted in a negative direction along the potential axis. In the range between 0.5 and 5.0 mM phenobarbital there was a shift of 8 mV for an e-fold change in drug concentration. 15 mM Ca2+ caused a shift to the h infinity(Em) curve in a positive direction along the potential axis, while simultaneous application of 2.5 mM phenobarbital and 15 mM Ca2+ caused no shift of the h afinity(Em) curve. The undissociated drug seemed to be responsible for the effects (pK = 7.3).

Action Potentials↗

PubMed1979

The effect of phenobarbital dose upon a variety of drinking related response measures.

Amount of water ingested, total laps, duration of drinking, amount per lap, laps per minute, and running velocity were investigated as a function of phenobarbital dosage (0 to 60 mg/kg). Twenty-three and a half (23 1/2) hour water deprived females rats served in the experiment. Amount of water ingested, total laps, and duration of drinking all responded similarly to phenobarbital all rose and subsequently fell as a function of phenobarbital dose on the day of drug treatment, rose as a linear function of dose a day later, and had no significant relation with dose 2 days after drug administration. These measures significantly intercorrelate with each other on the day of drug treatment and the day thereafter though not 2 days thereafter. Running velocity largely declines as a function of drug dosage on the day of treatment but is unaffected by the drug thereafter. The other measures show no definite trend. However these measures, running velocity and amount/lap and laps/minute, intercorrelate significantly with each other on the day of treatment and not thereafter. The first group of response measures and the latter group do not consistently correlate with each other. It was concluded that there are two identifiable classes of variables: one motor, which is largely a decremental function of dose, the other uncharacterized, initially rising, then falling as a function of phenobarbital dose on the day of drug treatment.

Animals↗

PubMed1979

Serum levels of phenytoin and phenobarbital in epileptic patients treated with mixture antiepileptic tablets, Comital-L or Hydantol-F.

Serum levels of both phenytoin and phenobarbital were determined by homogenous enzyme immunoassay in 59 epileptic patients treated chronically with either Comital-L or Hydantol-F tablets. The majority of the patients receiving Comital-L tablets showed low serum levels of phenytoin and high serum levels of phenobarbital, while patients treated with the usual daily dosage of Hydantol-F tablets showed adequate therapeutic serum levels of both phenytoin and phenobarbital. From the results obtained, the dose ratio of phenobarbital to phenytoin in Comital-L tablet seemed inappropriate to obtain adequate therapeutic serum levels of both drugs simultaneously. Since the dosage of each anticonvulsant drug used concurrently should be established individually, the use of such fixed-dosage mixture tablets of antiepileptic drugs as Comital-L or Hydantol-F in daily clinical practice should be reconsidered from the viewpoint of serum level monitoring of antiepileptic drugs.

Anticonvulsants↗

PubMed1975

Differential effects of phenobarbital and pentobarbital on isolated nervous tissue.

Epileptiform after discharges evoked by repetitive electrical stimulation of chronically isolated cortical slabs (cat) were shortened by low doses of phenobarbital but not affected by hypnotic doses of pentobarbital. Both pentobarbital and phenobarbital raised threshold and lowered spike amplitude in isolated sciatic nerves. The action of both drugs was increased by reducing Na in the medium and by decreasing the Ringer's pH. Similar to the action of other general anesthetics, the axonal effect of pentobarbital was enhanced by D2O replacement for H2O in the Ringer's (suggesting that tissue water is involved in pentobarbital action), whereas D2O replacement did not modify the action of phenobarbital or of local anesthetics. These results suggest that the varying in vivo effects of pentobarbital and phenobarbital may be due to a difference in their action upon excitable membranes (rather than to a different regional distribution in brain).

Animals↗

PubMed1976

[Effect of phenobarbital stimulation on morphological and cytoenzymatic changes in the liver of benzene intoxicated rats (author's transl)].

The experiments were carried out on male Wistar-Rats. They were divided into 2 groups. The rats of the control groups were treated to Phenobarbital intraperitoneally for 3 consecutive days. The animals of the experimental group were additionaly injected with Benzen intraperitoneally on the 4th day of experiment. It has been found that Phenobarbital brought about the formation of 2 types of bright and dark cells in the liver. The action of Phenobarbital is carried on by Benzene. The authors discuss morphological and functional evaluation of bright and dark cells from the point of view of stimulating action of Phenobarbital as well as the course of Benzene biotransformation in liver cells.

Adenosine Triphosphatases↗

PubMed1978

[Double-blind study on the anti-convulsive effect of phenobarbital and valproate in the Lennox syndrome].

In a double-blind crossover trial valproate was compared with phenobarbital with regard to anticonvulsive activity and tolerance in 17 epileptic children (mean age 55 +/- 26 months) with Lennox syndrome. Valproate in association with a phenobarbital dose reduced by about 40% proved to be to a statistically significant degree more active against epileptic seizures than phenobarbital alone. No difference in the effect on the EEG tracings was observed. Valproate appeared to be somewhat more active than phenobarbital with regard to behaviour, but the difference was not significant. Tolerance to both products was equally good.

Benzodiazepines↗

PubMedDate not supplied

Metabolic fate of phenobarbital in man. N-Glucoside formation.

1-(beta-D-Glucopyranosyl)phenobarbital was identified as the major metabolite of phenobarbital in man. Proof of structure was based on the comparison of the UV, NMR, and mass spectrometry and TLC data for the acetylated metabolite with an authentic compound. The previous erroneous structure assignment of this metabolite as N-hydroxyphenobarbital was based on insufficient data. After oral administration of 14C-labeled phenobarbital to two healthy male subjects, most of the radioactivity (87 and 78% of the dose) was recovered in urine over a period of 16 days. The N-glucopyranoside, p-hydroxyphenobarbital, and unchanged phenobarbital accounted for 30 and 24%, 18 and 19%, and 33 and 25% of the dose, respectively.

Acetylation↗

PubMed1979

Influx of glycyl-proline and free amino acids across intestinal brush border of phenobarbital-treated rats.

In a previous study the authors have shown that treatment with phenobarbital in the rat is followed by a generalized increase of amino acid concentration in the plasma. In order to better clarify this phenomenon, the effect of phenobarbital on intestinal protein absorption was now studied by measuring the influxes of Glycyl-L-Proline, L-Phenylalanine, L-Lysine and L-Glutamic acid across the brush border of jejunum and ileum in rats treated with phenobarbital for two or four days. No significant changes of these influxes were observed in the treated animals as compared to the controls, hence suggesting that the effect of phenobarbital on plasma levels of free amino acids is not mediated by an effect on intestinal absorption. The rate of Glycyl-Proline influx as compared to those of amino acid influxes suggests the occurrence of a carrier-mediated transport process for this dipeptide in the rat intestine as previously shown in the rabbit.

Amino Acids↗

PubMed1979

[Phenobarbital determination using direct densitometry of thin-layer chromatography].

A report on the determination of phenobarbital in model specimens of plasma and blood using direct densitometry of thin-layer chromatograms, namely by measurements of fluorescence quenching using remission technique following previous conversion of phenobarbital to sodium salt. Phenobarbital is extracted by three fundamentally different techniques, the results of estimation are given statistical evaluation, and the yield of each of the techniques is compared. Since the processing of 1 ml serum still allows the estimation of quantities as low as 1 microgram per stain the proposed method can be recommended for the determination of toxic levels of phenobarbital in plasma or in blood.

Chromatography, Thin Layer↗

PubMed1979

Effect of phenobarbital on induction of liver and lung tumors by dimethylnitrosamine in newborn mice.

The effect of phenobarbital on simultaneous induction of liver and lung tumors was examined in inbred DDD mice. Group 1 of newborn mice received a single intraperitoneal (ip) injection of dimethylnitrosamine (DMN) and after weaning they were given 0.05% phenobarbital solution to drink. Group 2 received an injection of DMN like Group 1 but were then given normal water. Group 3 were injected ip with 0.9% NaCl solution and then given phenobarbital solution to drink as in Group 1, and Group 4 were injected with 0.9% NaCl solution like Group 3, and then given tap water to drink. The animals were examined 16 weeks after birth. In Group 1, 27 of 35 mice (77%) had liver tumor and 15 (43%) had lung tumor. In Group 2, 8 of 24 mice (33%) had liver tumor and 16 (67%) had lung tumor. Animals in Groups 3 and 4 did not develop tumors. The difference in the incidences of liver tumor, but not lung tumor, in Groups 1 and 2 was statistically significant (P less than 0.01); that is, a promoting effect of phenobarbital was observed in induction of liver tumor, but not lung tumor.

Adenoma↗

PubMed1979

In vitro and in vivo characteristics of some commercial phenobarbital tablets.

Using an incompletely randomized crossover study design, the oral bioavailability characteristics of 7 different brands of phenobarbital tablets, USP, 100 mg was investigated in 5 adult, male volunteers. From plasma drug concentration-time data, best estimates for the bioavailability parameters of peak plasma phenobarbital concentration (Cmax) and time to peak concentration (tmax) were obtained by curve fitting and area under the plasma drug concentration-time curve (AUC) computed with the trapezoid rule. No significant difference in Cmax or normalized AUC was seen for the 7 products investigated. Additionally, a difference in tmax was observed between 2 preparations (A and E) only (p less than or equal to 0.05). All drug products met USP requirements for weight variation and tablet disintegration and all but one product (D) exhibited reasonably good and similar dissolution characteristics in simulated gastric fluid. No correlation between various in vitro dissolution parameters and in vivo bioavailability of phenobarbital could be found for the 7 phenobarbital products studied.

Adult↗

PubMed1976

Prophylactic effects of phenytoin, phenobarbital, and carbamazepine examined in kindling cat preparations.

Prophylactic effects of phenobarbital, phenytoin (diphenylhydantoin), and carbamazepine were examined in amygdaloid kindling preparations in cats. Daily electrical stimulation was delivered at the time of peak plasma levels. Comparative examination of the chronological pattern of the clinical seizure development, after discharge growth, and formation of distant independent spike foci was made between periods of kindling with chronic drug administration and of rekindling without drugs. Both phenobarbital and carbamazepine were effective, but phenytoin was totally ineffective. Prophylactic action of phenobarbital and carbamazepine was mainly through the suppression of the development of motor seizures manifestations in the former and the same with the development of sustained after discharge in the latter. The kindling preparation appears to possess many desirable features as an ideal model of human epilepsy for the purpose of assessment and recruitment of potential antiepileptic drugs and development of a rational pharmacotherapeutic approach for the management and prevention of seizure disorder.

Animals↗

PubMed1979

Plasma renin concentration and phenobarbital levels in patients with epilepsy.

Plasma renin activity, renin concentration, and renin substrate were measured in patients on long-term anticonvulsant medication. An inverse correlation was observed between phenobarbital levels and renin activity or concentration. There was a positive correlation between phenobarbital and renin substrate. Since elevation of renin substrate should have resulted in increased renin activity, it is possible that phenobarbital exerts 2 effects on the renin system: induction of renin substrate synthesis and suppression of renin release.

Adolescent↗