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At least 37 records · Page 2Linked to original sources
PubMed1985

Induction of a cytochrome P-450-dependent fatty acid monooxygenase in Bacillus megaterium by a barbiturate analog, 1-[2-phenylbutyryl]-3-methylurea.

In previous publications from our laboratory, we reported that a soluble, cytochrome P-450-dependent fatty acid monooxygenase from Bacillus megaterium ATCC 14581 can be induced by phenobarbital and a variety of other barbiturates. The tested barbiturates showed an excellent correlation between increasing lipophilicity and increasing inducer potency (Kim BH, Fulco AJ; Biochem Biophys Res Commun 116: 843-850, 1983). The only exception proved to be mephobarbital (N-methylphenobarbital) which, although more lipophilic than phenobarbital, is not an inducer of fatty acid monooxygenase activity. We have now found that 1-[2-phenylbutyryl]-3-methylurea (PBMU), an acylurea that can be derived from mephobarbital by hydrolytic cleavage of the barbiturate ring, is an excellent inducer of this activity. Paradoxically, the addition of mephobarbital to the bacterial growth medium containing PBMU significantly enhances the apparent potency of the acylurea to induce fatty acid monooxygenase activity as measured in cell-free extracts. When cell-free extracts of cells grown separately in PBMU or mephobarbital are mixed no enhancement of activity is seen. This finding suggests that the effect of mephobarbital is to somehow increase the efficiency of PBMU as an inducer of the P-450-dependent fatty acid monooxygenase rather than to induce an activator of this enzyme or a rate-limiting component of the monooxygenase system. Finally, both mephobarbital and PBMU induce the synthesis of total cytochrome P-450 in B. megaterium although PBMU is a much more potent P-450 inducer. For cytochrome P-450 induction, however, there is no synergistic or even additive effect when mephobarbital and PBMU are used together in the bacterial growth medium.

Bacillus megaterium↗
PubMed1994

Computer modeling of adsorption on an activated charcoal surface.

The molecular modeling program SYBYL was used to simulate the adsorption of various barbiturates by an activated charcoal surface. The compounds barbituric acid (BA), barbital (B), phenobarbital (PB), mephobarbital (M), and primidone (Pr) were modeled, and their structures were energetically minimized. These structures agreed with literature reports for the conformations of these molecules in dimethyl sulfoxide-d6, methanol-d4, and chloroform-d. The activated charcoal surface was modeled using graphitic crystallites which had either no oxygen-containing functional group, a C-OH functional group, or a C = O functional group. The presence of the C-O (presumably C-OH) and C = O functional states on activated charcoal surfaces had been previously determined by X-ray photoelectron spectroscopy. It was assumed that the crystallite was locally flat. Upon docking, conformational changes were observed for barbital, phenobarbital, mephobarbital, and primidone. Estimates for the heat of adsorption ranged from -62.3 kJ/mol for barbituric acid to -91.1 kJ/mol for mephobarbital on the hydroxylated surface. Allowance for the heat of desorption of the required number of water molecules from the surface, also determined by SYBYL, gave heat of displacement values of -19.4 kJ/mol for barbituric acid and -32.6 kJ/mol for mephobarbital. These values compared well to the heat of displacement values obtained by isoperibol calorimetry, which were -20.3 kJ/mol for barbituric acid and -31.6 kJ/mol for mephobarbital. Previous laboratory studies had demonstrated the greater importance of the C-O functional state for barbiturate adsorption compared to the C = O functional state. The computer-modeled system predicted the same result.

Adsorption↗
PubMed1981

Pharmacokinetics and bioavailability of methylphenobarbital in man.

The pharmacokinetics and bioavailability of mephobarbital have been studied in 2 volunteers. Plasma levels of mephobarbital and phenobarbital were measured by gas chromatography-mass spectroscopy with selected ion monitoring. Urinary output of phenobarbital and the p-hydroxy derivatives of both mephobarbital and phenobarbital was measured by high pressure liquid chromatography. The time course of these plasma and urinary levels was monitored following single 800-mg oral and 200-mg intravenous doses in the 2 patients. The major conclusions of the study were that mephobarbital is reasonably well absorbed following oral dosing and that some 35% or so of the dose (by either route) is converted to the recently identified metabolite, p-hydroxymephobarbital.

Administration, Oral↗
PubMed1977

Urinary excretion of phenobarbital in a neonate having withdrawal symptoms.

Utilizing methods of gas chromatography-mass spectrometry-computer systems operated in a chemical ionization mode, metabolites of mephobarbital were demostrated in urines collected from two infants whose mother was treated with mephobarbital during pregnancy. Identification of the major metabolite in one infant was possibe for 22 days after delivery. The urinary half-life of mephobartial was 30 hours and the half-life of phenobarbital was 48 hours. Both infants demonstrated withdrawal symptoms for four to six months and manifested the physical phenotype of infants exposed in utero to anticonvulsant agents.

Adult↗
PubMed1990

Stereochemical characterization of the diastereomers of the phenobarbital N-beta-D-glucose conjugate excreted in human urine.

The absolute configuration of the N-beta-D-glucoside metabolites of phenobarbital was determined by methylation of the diastereomers to make mephobarbital N-beta-D-glucosides, followed by oxidative removal of glucose to give the optical isomers of mephobarbital. Following a single oral dose of phenobarbital to two male subjects, both phenobarbital N-beta-D-glucosides were excreted in the urine. The absolute configuration (C-5 position) of the major phenobarbital N-beta-D-glucoside excreted in the urine was the S form. A pronounced stereoselective formation and/or urinary excretion occurs for the N-glucoside conjugates of phenobarbital in humans.

Chromatography, High Pressure Liquid↗
PubMed1997

Barbiturate anticonvulsants: a neuropsychological and quantitative electroencephalographic study.

We studied 11 epileptic children aged 7 to 14 years with quantitative electroencephalographic (EEG) and neuropsychological tests, both on and off the barbiturate anticonvulsants phenobarbital and mephobarbital, comparing them to 13 controls matched for age and IQ who received testing at similar intervals. Neuropsychological tests employed were the Wechsler Intelligence Scale for Children-Revised (WISC-R), Bender-Gestalt, controlled oral word association test (COWAT), selected subtests of the Wechsler Memory Scale-Revised, Purdue Peg Board, Stroop Test, Trail Making Test, Wide Range Achievement Test-Revised, and Achenbach Behavior Rating Scale. There was no difference between on- and off-drug quantitative EEG in percentage power of any frequency band between 0.6 and 32 Hz. Neuropsychological data from all 11 subjects were analyzed with a two-factor analysis of variance with repeated measures on the time factor. The only difference from controls was on the Stroop Test. Parents reported clear behavioral changes in 6 of 11 subjects, but in 4 of these children the behavioral changes were sufficiently mild that parents chose to continue the barbiturate anticonvulsants: irritability, oppositional attitude, and overactivity were described. Mephobarbital was reported by parents to cause less severe problems than phenobarbital in subjects who had taken both barbiturate anticonvulsants. Barbiturate anticonvulsants have no effect on quantitative EEG and limited effects on neuropsychological tests in school-aged children.

Adolescent↗
PubMed1993

Barbiturate anticonvulsants in refractory affective disorders.

Despite an increasing literature demonstrating both acute and long-term positive psychopharmacological effects of both valproate and carbamazepine, phenytoin has remained a controversial intervention, and barbiturate anticonvulsants have generally received poor press with regard to psychotropic effects. In the present investigation, 27 seizure-free, affectively ill patients who received therapeutic trials of primidone and/or mephobarbital after failing on antidepressants, lithium, carbamazepine, valproate, and phenytoin were analyzed with regard to effects on illness severity and affective cycle rate over a period of as long as four years. Nine (33%) of the patients had a sustained positive therapeutic effect on affective state and/or psychotic symptoms to primidone and three (11%) had positive effects on mephobarbital after primidone failure. Four (15%) had brief positive effects that were not sustained, and the remaining 11 (41%) had no effects or negative effects to these agents. The theoretical and practical implications of this new and unexpected finding are discussed.

Adult↗