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At least 19 recordsLinked to original sources
PubMed1978

A selected ion monitoring method for glutethimide and six metabolites: application to blood and urine from humans intoxicated with glutethimide.

A method employing selected ion monitoring for the analysis of glutethimide and six of its metabolites has been developed. Hydroxylated metabolites analyzed as trifluoroacetates, included 4-hydroxyglutethimide, (1-hydroxyethyl)glutethimide and p-hydroxyglutethimide. The unchanged drug, 3-dehydroglutethimide, desethylglutethimide and the internal standard, [2H5]glutethimide, were chromatographed underivatized on OV-225. The assay was used to measure drug and metabolites in the plasma and urine of patients intoxicated with glutethimide. High levels (e.g. 20--35 microgram ml-1) of unconjugated 4-hydroxyglutethimide, an active metabolite, were found in all patients at a time when levels of unchanged drug were lower and declining. Other unconjugated and conjugated metabolites were found in relatively low concentrations in the plasma (i.e. less than 4 microgram ml-1). The major urinary metabolites were conjugates of 4-hydroxyglutethimide and (1-hydroxyethyl)glutethimide. The unchanged drug and other conjugated and unconjugated metabolites were found in lower amounts in the urine. Normal plasma half-lives of glutethimide and the relatively small amounts in urine of unchanged drug and unconjugated metabolites indicated that drug elimination was not markedly impaired in the intoxicated patients.

Adult↗
PubMed1977

Glutethimide and 4-OH glutethimide: pharmacokinetics and effect on performance in man.

The relationship between the plasma concentration of glutethimide (G) and the change from baseline of the standard error of the mean (deltaSDE) of a tracking test was determined in 7 volunteers. There was excellent positive correlation (r = 0.91) between log G and log deltaSDE and good correlation between log G and deltaSDE (r = 0.77). The metabolite, 4 hydroxyglutethimide, did not contribute significantly to the effect of G administered in therapeutic doses. No trend in performance versus level was found with 5 other tests (finger tapping, card sorting, digit substitution, subtraction, and subjective perception of drowsiness). Although the numbers were small, when the volunteers were divided into smokers (3) and nonsmokers (4) G decreased tracking ability to a greater extent in smokers than in nonsmokers.

Adult↗
PubMed1989

Comparison of the form(s) of cytochrome P-450 induced by ethanol and glutethimide in cultured chick hepatocytes.

In this study, using a combination of immunological and enzymatic characterizations, we compared the forms of cytochrome P-450 induced by ethanol and glutethimide in primary cultures of chicken embryo hepatocytes. Recently we purified a cytochrome P-450 of 50K molecular weight from chicken embryo liver using glutethimide as a prototypic inducer. Antibodies to both this chicken cytochrome P-450 and to rabbit cytochrome P-450 form 3a from the IIE subfamily detected microsomal proteins of 50K induced by either ethanol or glutethimide in cultured chick embryo hepatocytes, indicating the antigenic homology of these subfamilies of cytochromes P-450 among different animal species. However, the antibody to glutethimide-induced chick cytochrome P-450 of 50K inhibited p-nitrophenol hydroxylase and benzphetamine demethylase activities 85-90% in microsomes from both ethanol- and glutethimide-treated cells, indicating similar epitopes whose integrity is required for catalytic activity. In contrast, antibodies to rabbit cytochrome P-450 form 3a had little to no effect on these same microsomal activities. Both ethanol and glutethimide induced microsomal p-nitrophenol and aniline hydroxylase activities in cultured chick embryo hepatocytes. In microsomes from ethanol-treated cells, the turnover of p-nitrophenol per cytochrome P-450 was 2-fold greater than that induced by glutethimide treatment, suggesting that ethanol is inducing a form of cytochrome P-450 that has greater catalytic activity with this substrate than glutethimide-induced forms. Thus, in cultured chick embryo hepatocytes, ethanol may induce cytochromes P-450 from both the IIB and IIE subfamilies.

Animals↗
PubMedDate not supplied

Lack of correlation between plasma 4-hydroxyglutethimide and severity of coma in acute glutethimide poisoning. A case report and brief review of the literature.

Glutethimide poisoning is characterised by coma, anticholinergic poisoning syndrome, hypotension, and other complications. Previous studies have shown that the severity of intoxication does not correlate with plasma glutethimide concentrations in individual patients. Glutethimide is partly converted to 4-hydroxyglutethimide, a metabolite which accumulates in the plasma of humans, and which has been thought to contribute to coma after plasma glutethimide concentrations have fallen. We followed plasma concentrations of glutethimide and 4-hydroxyglutethimide in a man who overdosed with glutethimide. Plasma 4-hydroxyglutethimide concentrations did not correlate with the degree of coma in our patient, and actually rose as the patient awakened. Other studies also indicate that 4-hydroxyglutethimide may not play an important role in glutethimide poisoning.

Coma↗
PubMedDate not supplied

Blood concentrations and clinical findings in nonfatal and fatal intoxications involving glutethimide and codeine.

Blood concentrations and clinical findings were evaluated in twenty-six nonfatal and twelve fatal intoxications involving the combination of glutethimide and codeine ("loads"). The mean glutethimide concentration was 10 +/- 5 mg/L for nonfatal cases (range 2-18 mg/L) and 13.9 +/- 6.6 mg/L for fatal cases (range 4.6-26.4 mg/L). The mean codeine concentration for fatal intoxications was 1.21 +/- 1.17 mg/L (range 0.13-4.32 mg/L). Codeine concentrations were not measured in cases of nonfatal intoxication. Nine nonfatal cases required hospitalization on a medical ward (mean length of stay 3 +/- 3 days). Depressed level of consciousness was the most common abnormal physical finding (24 cases); 18 patients were lethargic but arousable with nonpainful stimulation and 6 patients with serum glutethimide concentrations of 10 mg/L or greater were comatose. The level of consciousness showed statistically significant correlation with the glutethimide concentration (P less than 0.01). Twenty-four nonfatal intoxications involved at least one other drug in addition to glutethimide and codeine (salicylates in 12 and acetaminophen in 4), while only 7 fatal cases involved at least one additional drug (acetaminophen and diazepam in 3 each). The finding of glutethimide should prompt a search for codeine and vice versa, especially when the presence of either does not in and of itself explain the clinical condition of the patient.

Adult↗
PubMed1979

Correlates of outcome following acute glutethimide overdosage.

Potential predictors of outcome following acute glutethimide overdosage were assessed in 63 patients hospitalized with this diagnosis at a large urban medical center between 1962 and 1975. Their mean age was 34 years (range, 15 to 84 years) and 62% were female. Assisted ventilation was required in 59% of cases, and 32% developed hypotension. Six patients died, including all three aged 60 years or older. Multiple regression analysis confirmed that age was the major identifiable determinant of survival, regardless of other factors. Among identifiable determinants of coma grade, glutethimide dose, glutethimide plasma concentration, and coingestion of barbiturates were the most important. An ingested dose of 10 g or more, or a plasma concentration exceeding 30 microgram/ml, was almost always associated with deep coma. However, a relatively small ingested dose or a low plasma level by no means ruled out development of serious intoxication, particularly in those patients who also ingested barbiturates. Thus elderly individuals are at high risk for fatal outcome following glutethimide overdosage and should receive priority for intensive care and monitoring. Glutethimide dose, plasma concentration, and history of coingestion of barbiturates are of value in predicting development of deep coma. These items of information should be obtained on admission whenever possible.

Adolescent↗
PubMed1975

Neurologic and electroencephalographic correlates in glutethimide intoxication.

Neurologic and electroencephalographic (EEG) examinations were performed every two hours during a case of severe glutethimide intoxication resulting from the acute ingestion of at least 15 grams of glutethimide. Neurologic data were reduced to 10 measurements of brainstem function and plotted as an index that varied cyclically in amplitude during the clinical course. Electroencephalographic data were computer-processed by power spectral methods and related to the brainstem function index. Good positive correlation existed between the frequency and reactivity of EEG activity and the level of brainstem function as reflected in the index. The cyclic and, sometimes, unilateral nature of the clinical findings previously reported in glutethimide coma was confirmed and seen to be reflected in the EEG. The present case also indicates that, in the absence of cerebral ischemia or hypoxemia secondary to cardiopulmonary depression, complete clinical recovery from glutethimide-induced coma is possible no matter how severe the presenting neurologic and EEG signs.

Brain Stem↗
PubMed1991

Synergistic induction of delta-aminolevulinate synthase by glutethimide and iron: relationship to the synergistic induction of heme oxygenase.

Relationships between activities of delta-aminolevulinate synthase and heme oxygenase, respectively the rate-limiting enzymes of heme biosynthesis and degradation, have been studied in chick embryo liver cell cultures following exposure of the cultures to glutethimide and iron, a combination known to produce a synergistic induction of both enzymes. In time-course experiments, synergistic induction of heme oxygenase activity by glutethimide and iron preceded that of delta-aminolevulinate synthase by 4 h. Effects of selective inhibitors of both heme synthesis and degradation have also been studied with respect to effects on delta-aminolevulinate synthase and heme oxygenase activities. The synergistic induction of heme oxygenase by glutethimide and iron appears to be dependent upon cellular heme synthesis because addition of inhibitors of heme biosynthesis, 4,6-dioxoheptanoic acid or N-methyl-mesoporphyrin abolishes this synergistic induction. Exposure of cultures to tin-mesoporphyrin, a potent inhibitor of heme oxygenase, prevented the synergistic induction of delta-aminolevulinate synthase produced by glutethimide and iron, or, when added after induction was already established, promptly halted any further induction. These results suggest that the level of activity of heme oxygenase can reciprocally modulate intracellular heme levels and thus activity of delta-aminolevulinate synthase.

5-Aminolevulinate Synthetase↗
PubMed1991

Glutethimide treatment of disabling action tremor in patients with multiple sclerosis and traumatic brain injury.

Glutethimide has been used to control essential tremor. Its efficacy in the treatment of disabling cerebellar and rubral tremor was assessed in an open study of six patients with multiple sclerosis and two patients with traumatic brain injury. Functional and quantitative tremor severity was assessed before treatment and 7 to 14 days after a stable dose was achieved. Six of eight patients exhibited visible functional benefit from treatment with glutethimide; abstract testing results correlated well with functional status in most cases. Four patients chose to continue to receive medication. Controlled trials of glutethimide to compare its efficacy with that of other medications used in the treatment of action tremor are indicated.

Brain Injuries↗
PubMed1979

Identification and synthesis of a methylated catechol metabolite of glutethimide isolated from biological fluids of overdose victims.

Urine samples from victims severely intoxicated by glutethimide were hydrolyzed enzymatically. TLC, GLC, and mass spectral analyses revealed a methylated catechol metabolite of the parent drug. Two synthetic pathways are described for the preparation of 2-ethyl-2-(3-methoxy-4-hydroxyphenyl)glutarimide and 2-ethyl-2-(3-hydroxy-4-methoxyphenyl)glutarimde. Comparisons of GLC and mass spectral data to a compound isolated from the body fluids of glutethimide overdose victims conclusively identified a new 3-methoxy-4-hydroxyphenyl metabolite of glutethimide in humans.

Catechols↗
PubMed1979

Enhancement of hepatic drug metabolism by glutethimide in patients with liver disease.

A controlled study of the effects of glutethimide on antipyrine metabolism was performed to ascertain how patients with varying degrees of liver damage responded to microsomal enzyme inducing agents. The administration of 250mg glutethimide daily for one week resulted in significant enhancement of antipyrine metabolism in 4 patients with compensated cirrhosis and 5 patients with features of hepatic failure as well as 7 control subjects without liver disease. Even patients with very severe liver disease did undergo microsomal enzyme induction. Changes in antipyrine half-life after glutethimide were directly proportional to the original antipyrine half-life so that the greatest absolute alterations due to enzyme induction occurred in patients with the most severely impaired hepatic function. These results indicate that not only is antipyrine metabolism severely impaired in patients with liver failure, but elimination rates are markedly altered by enzyme inducing agents. Thus, although these results cannot be extrapolated to all inducers of hepatic microsomal enzymes nor to all drugs metabolized by microsomal oxidases, it is suggested that safe and effective management of drug therapy in these patients requires measurement of plasma levels.

Adult↗
PubMed1997

Investigation of the stereoselective in vitro biotransformation of glutethimide by high-performance liquid chromatography and capillary electrophoresis.

Due to our interest in drugs with a glutarimide structure, we reinvestigated the stereoselectivity of the in vitro biotransformation of the chiral hypnotic-sedative drug glutethimide. Glutethimide enantiomers were separated on a preparative scale by HPLC on cellulose tris(4-methylbenzoate) as chiral stationary phase. The enantiomeric purity was higher than 99%. A reversed-phase HPLC method was developed to determine the metabolites of glutethimide. After incubations with rat liver microsomes both enantiomers formed 5-hydroxyglutethimide as the main metabolite, as well as additional metabolites, of which some were formed stereoselectively. Mass spectrometry of the unknown metabolites indicated a hydroxylation in the ethyl side chain for two of the metabolites. A third metabolite was tentatively identified as desethylglutethimide.

Animals↗
PubMed1990

Isocratic high-performance liquid chromatographic resolution of glutethimide enantiomers and their 4-hydroxyglutethimide metabolites using cellulose tribenzoate chiral stationary phase.

Glutethimide (2-ethyl-2-phenylglutarimide) enantiomers and their corresponding 4-hydroxyglutethimide metabolites (RS and RR) are separated using newly developed commercially available cellulose tris(4-methylphenyl benzoate) ester (Chiralcel OJ) chiral stationary phase and hexane-ethanol or hexane-2-propanol as the mobile phase. The effects of ethanol or 2-propanol concentration in the mobile phase and of column temperature on retention and enantioselectivity of glutethimide enantiomers are also demonstrated. Maximum resolutions of 14.23 and 7.09 are obtained for glutethimide and their 4-hydroxyglutethimide metabolites, respectively, with hexane-ethanol (60:40) at 23 degrees C and a flow rate of 1 mL/min.

Chromatography, High Pressure Liquid↗
PubMed1975

Aminoglutethimide and glutethimide: effects on 18-hydroxycorticosterone biosynthesis by human and sheep adrenals in vitro.

The conversion of [1,2-3H]corticosterone to 18-hydroxycorticosterone in vitro was studied on human and animal adrenal tissue homogenates. Human adrenals were surgically resected from a patient with Cushing's disease. Sheep adrenal homogenates were prepared from the pooled glands of 20 animals. Incubations supplemented with a NADPH generating system were performed in order to evaluate the effect of aminoglutethimide and its closely related compound glutethimide on corticosterone 18-hydroxylation in vitro. Increasing concentrations of the two drugs were assayed on both human and animal adrenal homogenates. Aminoglutethimide was clearly found to inhibit corticosterone 18-hydroxylation in sheep adrenal homogenates as a 72.6% inhibition occurred in the presence of only 0.2 mumole of the drug. Inhibition reached 91.1% in the presence of 0.5 mumole aminoglutethimide. When added to the human incubated adrenal, a 59.4% inhibition occurred in the presence of 0.5 mumole aminoglutethimide. Glutethimide, a sedative of wide clinical usage, was also found to inhibit corticosterone 18-hydroxylation but the inhibitory effect occurred only in the presence of much higher concentrations. In fact, 5.0 mumoles were necessary to obtain a 43.9% inhibition of 18-hydroxycorticosterone synthesis. This study clearly demonstrates the marked inhibitory effect of aminoglutethimide on corticosterone 18-hydroxylation. Glutethimide, to a lesser extent, also inhibits 18-hydroxycorticosterone synthesis.

18-Hydroxycorticosterone↗
PubMed1983

Interpretation of blood glutethimide, meprobamate, and methyprylon concentrations in nonfatal and fatal intoxications involving a single drug.

We evaluated blood concentrations of three nonbarbiturate sedative-hypnotics in 19 nonfatal (NF) and five fatal (F) intoxications which were "pure" (i.e. which involved only one drug each): glutethimide, 4 (NF), 3 (F); meprobamate, 9 (NF), 1 (F); and methyprylon, 6 (NF), 1 (F). For each of the 24 cases, both a comprehensive toxicology panel (including blood and urine) and the clinical history established that only a single drug had been ingested. Blood drug concentrations showed statistically significant correlation with the level of consciousness for nonfatal meprobamate intoxication (p less than 0.01) and nonfatal methyprylon intoxication (p less than 0.05). Blood glutethimide concentrations did not show such correlation. Death was associated with a mean blood glutethimide concentration in excess of 4.0 mg/dL, a blood meprobamate concentration of 20.5 mg/dL, and a blood methyprylon concentration of 11.7 mg/dL. Interpretation of blood concentrations of these compounds is discussed, and physical findings and demographic data are presented.

Adult↗
PubMed1989

The use of glutethimide for treatment of essential tremor.

Two patients with long-standing intention tremor that was interfering with their ability to maintain employment were treated with glutethimide. In both patients, this agent successfully suppressed tremor at doses of 1,000 mg and 4,000 mg per day. Glutethimide has been taken for as long as 14 years in one patient without evidence of side effects.

Functional Laterality↗