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PubMed1998

Mechanism of the synergistic induction of CYP2H by isopentanol plus ethanol: comparison to glutethimide and relation to induction of 5-aminolevulinate synthase.

We had previously found that combined treatment with isopentanol and ethanol synergistically induced CYP2H protein and activity in cultured chick nepatoytes. Here we investigated the mechanism of induction of CYP2H by the alcohols and whether they caused a coordinate induction of 5-aminolevulinate synthase (ALAS) mRNA. Treatment with isopentanol alone or in combination with ethanol resulted in coordinate increases in CYP2H1 and ALAS mRNAs. With isopentanol alone, the amounts of CYP2H1 and ALAS mRNAs at 4 to 6 h were similar to those observed after treatment with the alcohol combination, but declined by 11 h. Readdition of isopentanol at 11 h again increased the expression of both mRNAs, indicating that the decreases at 11 h were due to limiting amounts of inducer. Similar results were observed in cells exposed to low concentrations of glutethimide. In the combined alcohol treatment, increases in CYP2H1 and ALAS mRNAs were sustained from 4 h to 11 h after addition of the alcohols, but decreased to control levels by 24 h. Using pulse labeling to measure de novo synthesis of CYP2H1/2 protein, we found that the increases in CYP2H1/2 protein reflected the increases in CYP2H1 mRNA. The half-life of CYP2H1/2 protein, measured from pulse-chase experiments, was approximately twofold greater than the half-life of CYP2H1 mRNA. Our results indicate that the alcohols and glutethimide coordinately increase ALAS and CYP2H1 mRNA, and that increases in CYP2H1/2 protein arise from increases in its mRNA.

5-Aminolevulinate Synthetase↗

PubMed1990

Mechanism of synergistic induction of hepatic heme oxygenase by glutethimide and iron: studies in cultured chick embryo liver cells.

Heme oxygenase, the rate controlling enzyme for heme catabolism, is inducible by a variety of treatments, some of which induce by a heme-dependent mechanism and others by a heme-independent mechanism. This work shows that, in cultured chick embryo liver cells, synergistic induction of heme oxygenase by iron, added with the phenobarbital-like drug, glutethimide was heme-dependent. Addition of an inhibitor of heme biosynthesis abolished the synergistic induction of heme oxygenase providing evidence for the heme-dependent mechanism of induction. Glutethimide and iron appeared to induce at the transcriptional level since both heme oxygenase mRNA and protein levels correlate with changes in heme oxygenase activity.

Animals↗

PubMed1975

Synthesis of an active hydroxylated glutethimide metabolite and some related analogs with sedative-hypnotic and anticonvulsant properties.

Two synthetic pathways are described for the preparation of 4-hydroxy-2-ethyl-2-phenylglutarimide (2), an active hydroxylated metabolite of glutethimide (1). Fourteen other glutethimide analogs were also synthesized and tested for biological activity. Most of the analogs exhibited sedative-hypnotic properties and compound 2 possessed the greatest activity compared to the parent drug. 4-Amino-2-ethyl-2-phenylglutarimide and 4-hydroxy-2-ethyl-2-phenylglutaconimide (13) exhibited the greatest potential as anticonvulsant agents. The structure-activity relationships of the series are discussed.

Animals↗

PubMed1977

Changes in reaction time and drug plasma concentrations after nitrazepam and glutethimide.

1 The effects of nitrazepam, glutethimide and placebo were assessed in a double-blind cross-over study with five healthy human subjects, using reaction time, and relating changes to drug concentrations in the plasma. 2 After glutethimide in all five subjects, and after nitrazepam in four subjects, larger doses led to higher concentrations in plasma and to greater changes in reaction time; one subject displayed the higher nitrazepam concentrations and the greater effect following the smaller dose. 3 The relationship between change in reaction time and concentration appeared to be mainly a within-subject dose-effect relationship, with the peak concentration in plasma as the 'dose' and the area under the reaction time curve as the effect.

Adult↗

PubMed1978

The features of hepatic enzyme induction with glutethimide in man.

1 Sequential measurements of D-glucaric acid excretion were made in six healthy volunteers before, during and after 3 weeks' daily medication with glutethimide 500 mg. 2 There was a rapid rise in D-glucaric acid excretion within 2 days of starting medication and a rapid decline when it was stopped. 3 Antipyrine clearance and indocyanine green clearance were measured before and at the end of the 3 weeks' medication. 4 There was a 55% increase in antipyrine clearance but no change in indocyanine green clearance. 5 There was no correlation between antipyrine clearance and D-glucaric acid excretion. 6 Glutethimide causes rapid enzyme induction in man without concomitant rise in hepatic blood flow.

Antipyrine↗

PubMedDate not supplied

Influence of glutethimide on rat brain mononucleotides by sub-chronic codeine treatment.

It was investigated the in vivo effect of glutethimide on the intracellular neuroadaptation characteristic for m-opioid receptor tolerance induced by chronic codeine treatment and reflected by increased levels of adenylyl cyclase (AC) and cAMP-dependent protein kinase (PKA). AC activity was appreciated by cyclic-AMP (cAMP) formation, the levels of adenine and guanine nucleotides in brain extracts being assayed using a high performance liquid chromatographic method. The concomitant chronic administration of codeine and glutethimide resulted in a pronounced and long-lasting energetic depletion of the neurons, consistent with the high risk of overdose, and increase of cAMP's stable metabolite, 5'-AMP. This increase is persistent even after withdrawal and suggests an interference with the adenylyl cyclase system involved in the development of tolerance of opioid receptor and in relapse and provides a possible explanation of addiction and fast increase of doses observed in humans abusing this combination.

Adenylyl Cyclases↗

PubMed1973

Osteomalacia after prolonged glutethimide administration.

Vitamin D deficiency is a previously unreported complication of therapy with hypnotics, and we here report a case of osteomalacia associated with long-term glutethimide administration. There was evidence of pronounced hepatic enzyme induction, and the plasma half-time of (3)H vitamin D(3) was decreased by this drug. In addition, raised levels of serum gamma-glutamyl transpeptidase, 5-nucleotidase, and leucine aminopeptidase were observed and the patient excreted large amounts of xylulose. These changes were reversed by stopping the glutethimide.

Cholecalciferol↗

PubMed1975

Metabolism of glutethimide in the human.

Gas chromatographic and gas chromatographic-mass spectrometric techniques were used to identify metabolites of glutethimide excreted in human urine. In this study three monohydroxy metabolites, a dihydrodiol and three dihydroxy metabolites were detected after ingestion of the drug. The results indicate that the phenyl ring of glutethimide is metabolized by the epoxide-dihydrodiol pathway in the human following chronic administration of the drug.

Adolescent↗

PubMed1975

Definitive characterization of the para-hydroxyphenyl metabolite of glutethimide in human urine.

The compound, 2-ethyl-2-(4-hydroxyphenyl)-glutarimide was prepared synthetically. Spectral data is presented which identifies this compound to be a metabolite of glutethimide isolated from enzymatically hydrolyzed human urine, following an overdose of the parent drug. New data supporting the structure of a minor metabolite, 2-ethyl-2-(3-methoxy-4-hydroxy)-glutarimide, is considered. Finally, gas chromatographic techniques have been perfected and are presented which yield complete purification of new metabolites of glutethimide.

Chromatography, Gas↗

PubMed1990

[Extraction of glutethimide and methyprylon from blood using thin layer chromatography].

Glutethimide and methyprylone were extracted from blood and plasma at pH ca. 4 (acetate buffer) thrice with chloroform, using 2.5 solvent volume ratio to that of aqueous phase. Phenobarbital was used as an internal standard in thin-layer chromatography experiments on silica gel--to obtain of comparable ratios of Rf values of glutethimide and/or methyprylone to that of phenobarbital. Suitable conditions of the separation of three substances were established using one of following mobile phases: benzene-dioxane-aq.ammonia (15:4:1), chloroform-acetone-aq.ammonia (25:25:1), chloroform-acetone-diaethylamine (5:4:1) and chloroform-diethyl ether-acetone (5:3:2); on 7.5 x 2.5 cm plates; development time (at 5 cm distance) was up to 10 minutes. The concentrations as small as 0.1 microg of examined substances in 1 cm3 of plasma may be identified on chromatograms using 20% Na2CO3 solution.

Buffers↗

PubMed1985

Deaths as a result of a combination of codeine and glutethimide.

Toxicological findings are described in 16 medical examiner cases directly related to the combination of codeine and glutethimide. The cases described represent a six-month period, July through December 1982, showing the epidemic rate of abuse of this drug combination, most prominent in the Newark, NJ area since the late 1970s. Concentrations of codeine and glutethimide, measured by gas liquid chromatography (GLC), in the blood averaged 0.62 and 4.07 mg/L, respectively. Similarly determined urine concentrations averaged 38.06 and 12.68 mg/L, respectively. Specific concentrations of each drug in most cases were in the high therapeutic range, suggesting a possible toxic synergistic effect.

Adult↗

PubMed1970

A comparative study of three hypnotics: methyprylon, glutethimide and chloral hydrate.

A controlled study designed to evaluate the hypnotic potentiality of methyprylon (300 mg.), glutethimide (500 mg.) and chloral hydrate (1000 mg.) was carried out on 50 in-patients experiencing long-standing insomina. The patients ranged in age from 21 to 60 years, the sexes were equally represented and the clinical diagnoses were psychoneurosis, reactive depression, or anxiety reaction. An interesting feature of the experimental design allowed for the exclusion of placebo reactors before the initiation of the main trials. No difference in effectiveness of maintaining sleep could be established among the three hypnotic agents, indicating that at the usual levels of statistical significance, all three agents were equally effective as hypnotics. However, a significant trend (P = .05) was found for methyprylon (Noludar) to be the most effective and chloral hydrate to be the least effective of the three drugs in maintaining sleep. Methyprylon was found statistically (P = .05) to be the fastest sleep-inducing agent, whereas glutethimide (Doriden) proved to be the slowest of the three hypnotics with respect to sleep induction time.

Adjustment Disorders↗

PubMedDate not supplied

[Changes in rat behavior after glutethimide exposure in various stages of antenatal neurogenesis].

After administration to rats in a dose of 200-400 mg/kg on days 14 and 15 of the pregnancy the hypnotic drug glutethimide induces in the rat progeny variations in the orienting-motor activity, latent period of runnings and raises the frequency of urinations upon training in a maze. The effect of glutethimide on the orienting-motor behavior was seen only in the first generation of the animals and was absent from the second generation animals.

Animals↗

PubMed1980

Inhibition of steroidogenesis in isolated rat adrenal cells by glutethimide congeners.

A series of glutethimide congeners produce concentration-dependent inhibition of corticosterone production by a suspension of isolated rat adrenal cells. The dextro-rotatory antipode of aminoglutethimide is more potent than its levo enantiomer in inhibiting corticosterone production in this system. Glutethimide, its metabolite glutaconimide, and congeners including those with anti-convulsant activity, 4-hydroxyglutaconimide and 4-aminoglutethimide, have all demonstrated concentration-dependent inhibition of corticosterone production by isolated rat adrenal cells.

Adrenal Glands↗

PubMed1977

Toxicity of alpha-phenyl-gamma-butyrolactone, a metabolite of glutethimide in human urine.

A novel metabolite, alpha-phenyl-gamma-butyrolactone, isolated from the urine of a glutethimide overdose victim, was synthesized and tested for biological activity in mice. Interperitoneal injections of this lactone caused severe toxicity at moderate dose levels. These results point to another metabolite of glutethimide contributing toxicity to patients severely intoxicated by the parent drug. An improved synthesis as well as complete spectral data of this lactone are also presented.

4-Butyrolactone↗

PubMed1976

Synthesis and characterization of a catechol metabolite of glutethimide (Doriden) in human urine.

A metabolite of glutethimide, 2-ethyl-2-(3,4-dihydroxyphenyl)-glutarimide, previously identified in enzymatically hydrolyzed human urine of overdosed victims was prepared synthetically and its chemical and spectral data compared to the proposed material. Results of these comparisons confirm the presence of a catechol metabolite of glutethimide in the urine of patients severely intoxicated by the parent drug.

Catechols↗

PubMed2002

Enantioseparation of glutethimide and its 5-OH-metabolite in capillary electrophoresis and study of selector-selectand interactions using one-dimensional rotating frame nuclear Overhauser and exchange spectroscopy.

Enantioseparation of glutethimide (GT) and its 5-hydroxy metabolite (5-OH-GT) has been studied with several charged cyclodextrin (CD) derivatives. The emphasis was made on the enantiomer migration order of GT and simultaneous enantioseparation of GT and 5-OH-GT. The possible structural differences of GT complexes with three different single isomer charged CD derivatives were studied using one-dimensional rotating frame nuclear Overhauser and exchange spectroscopy (1-D ROESY).

Cyclodextrins↗

PubMed1993

Synthesis and evaluation of sulfur-containing glutethimide derivatives for aromatase and desmolase inhibitory activity.

Novel sulfur-containing glutethimide derivatives, substituted with either thiol or methylsulfide groups in the ortho/para positions of the aromatic ring, were synthesized and tested for both human placental aromatase and bovine adrenocortical desmolase inhibitory activities. The synthesis was achieved by the chlorosulfonation of gluthethimide, which yielded a 3:1 mixture of the para to ortho sulfonyl chlorides 2a/b. The sulfonyl chlorides of gluthethimide were reduced with Zn/H2SO4 to give the thioglutethimides 3a/b, which in turn were methylated with MeI/EtOH to give the corresponding methylsulfides 4a/b. In comparison to aminoglutethimide (AG), 3a/b and 4a/b were weak inhibitors of aromatase, with 3a/b being more potent than 4a/b. Aromatase inhibition by the thiol compound was pH-dependent; 3a/b was most potent at higher pH (7.4) than at lower (6.6). This suggested that the thiolate form of 4 coordinates with the ferric heme of aromatase. Likewise, both 3a/b were less potent at inhibiting bovine adrenal desmolase than AG. Possible reasons for the surprisingly poor aromatase inhibitor activity of these compounds are discussed.

Adrenal Cortex↗