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At least 325 records · Page 18Linked to original sources
PubMed1995

Preferential effects of the chemotherapeutic DNA crosslinking agent mitomycin C on inducible gene expression in vivo.

The immediate effects of a single dose of the chemotherapeutic DNA crosslinking agent, mitomycin C (MMC), on the expression of several constitutive and drug-inducible genes were examined in a simple in vivo system, the 14 day chick embryo. We observed no effect of MMC on the steady-state mRNA expression of the constitutively expressed beta-actin, transferrin, or albumin genes. In contrast, MMC treatment significantly altered both the basal and drug-inducible mRNA expression of two glutethimide-inducible genes, 5-aminolevulinic acid (ALA) synthase and cytochrome P450 CYP2H1. The basal expression of these genes was transiently but significantly increased over a 24 hr period following a single dose of MMC. Conversely, MMC significantly suppressed the glutethimide-inducible expression of these genes when administered 1 to 24 hr prior to the inducing drug. The effects of MMC on both basal and drug-inducible ALA synthase and CYP2H1 mRNA expression were principally a result of changes in the transcription rates of these genes. In contrast, MMC treatment had little or no effect on glutethimide-induced expression of ALA synthase or CYP2H1 when administered 1 hr after the inducing drug, suggesting that a very early event in the induction process represents the target for these MMC effects. Covalent binding studies demonstrated that the effects of MMC on gene expression were closely correlated temporally with formation of [3H]-porfiromycin-DNA adducts. These results support the hypothesis that genotoxic chemicals specifically target their effects to inducible genes in vivo.

5-Aminolevulinate Synthetase↗
PubMed1979

Double-blind evaluation of the efficacy and safety of temazepam in outpatients with insomnia.

1 The efficacy and safety of temazepam 30 mg, compared with glutethimide 500 mg and placebo, were evaluated in double-blind conditions in a 4-day study in 75 outpatients with a history of insomnia. 2 Temazepam and glutethimide were rated by the patients as effective and significantly superior to placebo for general quality of sleep, time required to fall asleep, frequency of nocturnal and early morning awakenings, and duration of sleep. 3 Residual effects reported for temazepam and glutethimide immediately after awakening and during the day were similar to or less than those reported for placebo.

Adolescent↗
PubMed1981

Dialysability of benzodiazepines by haemodialysis and controlled sequential ultrafiltration (CSU) in vitro.

The efficacy of haemodialysis and controlled sequential ultrafiltration (CSU) for the elimination of three hypnotic and 6 benzodiazepine drugs was compared in vitro. In comparison to haemodialysis the efficacy of ultrafiltration by CSU was poor, as the mean per cent of CSU/haemodialysis (mg/hr) for 5 benzodiazepines was only 0.6-4.0% and for three hypnotics, phenobarbital 3.4%, pyrithyldione 8.2% and glutethimide 2.5% of the haemodialysis values. In haemodialysis in vitro phenobarbital, pyrithyldione, glutethimide and chlordiazepoxide were significantly and markedly more dialysable than 5 other benzodiazepines. The mean clearance of six benzodiazepine derivatives was about 2 to 3 times higher at blood flow rates of 200 ml/min. than 100 ml/min. In CSU experiments in vitro it was possible to remove approximately (as the mean percent of the initial dose) only the amount of five benzodiazepines corresponding to the per cent of the protein unbound fraction in the plasma (correlation r = 0.975, P less than 0.01). Only low amounts of three hypnotics, especially glutethimide, were removed by CSU in vitro.

Benzodiazepines↗
PubMed1962

Comparative clinical study of two hypnotic drugs.

The comparative sleep-inducing and sleep-sustaining effects of glutethimide, 0.5 g., and ethchlorvynol, 0.5 g., were studied in 20 patients hospitalized for a considerable time (average: 21 years; minimum nine years and maximum 32 years) and not receiving psychotropic agents. Assessment of sleep and para-sleep parameters (pre-sleep tension; frequency of awakening at night; post-sleep activity) revealed that patients fell asleep faster (P>.001) and slept for a longer time with ethchlorvynol than with glutethimide.

Ethchlorvynol↗
PubMed1976

Correlation of dielectric constant and solubilizing properties of tetramethyldicarboxamides.

The dielectric constants of aqueous solutions of four tetramethyldicarboxamides (tetramethylpimelamide, tetramethylsuberamide, tetramethylazelamide, and tetramethylsebacamide) were measured at 25 degrees. The values obtained were utilized in assessing the solubility behavior patterns of glutethimide, a semipolar, water-insoluble drug in these amide-water systems. At equimolar concentrations of water-rich amide solutions, the solubilizing power paralleled the chain length of the amides. The higher homologs appeared to favor more extensive solvation, as shown by the lower dielectric constants of their resulting solutions. Deviation in solubilizing action between the odd-carbon amides and the even-carbon amides, however, was exhibited at higher amide concentrations. The two odd-carbon amides, tetramethylpimelamide and tetramethylazelamide, showed consistently greater solubilizing action. This phenomenon was attributed to the greater association tendencies of the odd-carbon amides with water, which effectively reduced self-associations of glutethimide.

Amides↗
PubMed1993

Preferential alteration of inducible gene expression in vivo by carcinogens that induce bulky DNA lesions.

Our laboratory is interested in whether chemical carcinogen-induced DNA damage is nonrandomly distributed in the genome, i.e., "targeted," at the level of individual genes. To examine this, we have been investigating whether carcinogen treatment in vivo differentially alters the expression of specific genes. In this study, we examined the effects of four model carcinogens that induce bulky lesions in DNA--benzo[a]pyrene (B[a]P), aflatoxin B1 (AFB1), 7,12-dimethylbenz[a]anthracene (DMBA), and 2-acetylaminofluorene (AAF)--on the steady-state mRNA expression of several constitutive and drug-inducible genes in vivo. We specifically tested the hypothesis that carcinogen-induced DNA damage is preferentially targeted to inducible genes relative to constitutively expressed genes using the chick embryo as a simple in vivo test system. In summary, the four carcinogens had no effect on the steady-state mRNA expression of constitutively expressed beta-actin, transferrin, or albumin genes over a 24-h period after a single dose of each carcinogen. In contrast, each of these same treatments significantly altered the mRNA expression of two glutethimide-inducible genes, ALA synthase and CYP2H1. Both the basal expression of these genes and their drug-inducible expression was altered. B[a]P and AFB1 had similar effects on expression of the two inducible genes and caused similar levels of covalent adducts in total DNA, even though the administered doses differed by 30-fold. B[a]P binding to DNA, and the basal expression of CYP2H1 were similar in liver and lung. However, B[a]P significantly altered basal CYP2H1 mRNA expression in liver, a tissue in which this gene is highly inducible by glutethimide, and had no effect on basal CYP2H1 mRNA expression in lung, a tissue in which this gene is not drug-inducible. These data support the hypothesis that inducible gene expression is a target for carcinogen-induced DNA damage in vivo.

5-Aminolevulinate Synthetase↗
PubMed1995

Inactivation of chick embryo hepatic cytochrome P450 1A, 2H and 3A following in ovo administration of 3,5-diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-ethylpyridine and 3-[2-(2,4,6-trimethylphenyl)thioethyl]-4-methylsydnone.

Rat hepatic cytochrome P450 (P450) isozymes 1A1, 2C6, 2C11, 3A1 and 3A2 are targets for mechanism-based inactivation by the porphyrinogenic compound 3,5-diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-ethylpyridine (4-ethyl DDC). It is of interest to determine whether similar P450 isozymes are targets of porphyrinogenic drugs in the chick embryo liver. The chick embryo expresses P450 2H1/2 isozymes, which are similar to the rat P450 2B1/2 isozymes, a polycyclic aromatic hydrocarbon-inducible P450 1A isozyme, and a pregnenolone 16 alpha-carbonitrile-inducible P450 3A isozyme. We have found previously that chick embryo hepatic P450 1A and 3A isozymes are targeted for in vitro mechanism-based inactivation by 4-ethyl DDC and by the sydnone 3-[2-(2,4,6-trimethylphenyl)thioethyl]-4-methylsydnone (TTMS). Marked differences have been observed between the in vitro and in vivo effects of porphyrinogenic drugs on P450 isozymes. Thus, the first objective of this study was to determine whether chick embryo hepatic P450 1A and 3A isozymes are subject to in ovo inactivation by these porphyrinogenic compounds. Our second objective was to determine whether the chick embryo hepatic P450 2H isozyme(s) was subject to in ovo and in vitro inactivation by 4-ethyl DDC and TTMS. Using hepatic microsomes prepared from beta-naphthoflavone-, dexamethasone-, phenobarbital-, and glutethimide-induced 19-day-old chick embryos, we found that total P450 content was decreased significantly in microsomes prepared from all treatment groups following in ovo administration of 4-ethyl DDC and TTMS. Moreover, in ovo administration of both 4-ethyl DDC and TTMS caused a significant decrease of 7-ethoxyresorufin O-deethylase, erythromycin N-demethylase, and benzphetamine N-demethylase activities, which are selective catalytic markers for chick embryo hepatic P450 1A, 3A and 2H isozymes, respectively. In addition, in vitro administration of 4-ethyl DDC and TTMS caused mechanism-based inactivation of benzphetamine N-demethylase activity in microsomes from phenobarbital- and glutethimide-treated chick embryos, showing that the chick embryo hepatic P450 2H isozyme is a target for mechanism-based inactivation. Therefore, it was concluded that the chick embryo hepatic P450 1A, 2H and 3A isozymes serve as targets for both in ovo and in vitro mechanism-based inactivation by 4-ethyl DDC and TTMS.

Alkylation↗
PubMedDate not supplied

Assessment of thyrotoxicity using in vitro cell culture systems.

The potential thyrotoxic effect of SK&F 93479 (an H2-receptor antagonist), aminoglutethimide (AG) and glutethimide were studied by examining their effects on 125iodide uptake and organification (incorporation into thyroglobulin) in cultured thyroid cells from the pig and rat. These effects were compared with those of positive controls (3-isobutyl-1-methylxanthine (IBMX), methimazole (MTI), propylthiouracil (PTU) and NaClO4). SK&F 93479 had no effect on 125I uptake in rat FRTL-5 cells or on 125I uptake and organification in porcine thyroid cells. In contrast, MTI, PTU and NaClO4 all depressed 125I uptake and organification and IBMX potentiated 125I uptake. It is concluded, therefore, that SK&F 93479 does not increase 125I uptake in rats in vivo by a direct action on the thyroidal iodide trapping mechanism. AG, but not glutethimide, depressed 125I organification by cultured porcine thyrocytes without affecting uptake. These results suggest that AG is thyrotoxic in rats and man probably as a result of its ability to inhibit iodide organification in thyroid cells.

Aminoglutethimide↗
PubMed1984

Thalidomide in severe orogenital ulceration.

Thalidomide was given to 15 patients with severe orogenital ulceration (OGU). 4 patients underwent a double-blind controlled trial with glutethimide as placebo and 11 were treated openly. Treatment with thalidomide produced complete resolution of ulcers in 14 and significant improvement in the remaining patient. No peripheral neuropathies developed. Patients did not respond to glutethimide. Thalidomide is an effective treatment for severe OGU. Adequate contraceptive measures should be taken during treatment.

Adolescent↗
PubMed1984

Drug induction of hepatic enzymes in the elderly.

Previous workers have suggested that hepatic enzyme induction by drugs does not occur in the elderly. We have studied the effect of a potent enzyme inducer--glutethimide--on a group of nine patients over the age of 70 years, using antipyrine clearance as a measure of hepatic drug metabolism. After six days treatment with glutethimide, antipyrine clearance rose from 22.8 +/- 4.5 ml/min to 38.3 +/- 7.6 ml/min (P less than 0.001). The results suggest that the elderly are at risk for the full range of drug interactions due to hepatic microsomal enzyme induction.

Aged↗
PubMed1975

Use of charcoal haemoperfusion in the management of severely poisoned patients.

The clinical use of uncoated charcoal haemoperfusion systems, despite their efficacy, has hitherto been prevented by the occurrence of a number of adverse effects including charcoal embolism and marked thrombocytopenia. Charcoal coated with a synthetic hydrogel overcomes many of the disadvantages associated with the use of uncoated material in that there is a much reduced thrombocytopenia and no evidence of charcoal embolism. Six patients, severely poisoned as a result of overdoses of either a barbiturate or glutethimide, were haemoperfused using such a system. Four made complete recoveries, and the two patients who died had both suffered cardiorespiratory arrests before perfusion. In contrast to haemodialysis charcoal haemoperfusion is simple to initiate, less expensive in terms of manpower and equipment, and gives superior clearance data for all barbiturates and glutethimide. We believe that this technique may have a significant role to play in the management of the severely poisoned patient.

Adult↗
PubMed1976

Catatonialike symptomatology and withdrawal dyskinesias.

The authors describes a patient who presented catatonialike symptoms and dyskinesias associated with glutethimide discontinuance and antihistamine use. He hypothesizes that altered dopamine metabolism may produce some of the unusual neuropsychiatric characteristics of glutethimide withdrawal. Drug-withdrawal catatonia may be an additional entity in the differential diagnosis of catatonialike states of organic etiology.

Adult↗
PubMed2002

[Suicidal attempts with old (currently unused) drug].

Suicidal attempt with old (currently unused) drug is described. The suicidal attempts are usually performed with the use of contemporary pharmacotherapeutics. In the report a case of suicidal attempt with old drug Tardyl is presented. Tardyl (Glutethimid) was prescribed to the patient and has been stored for 20 years. The patient was previously treated for depression and many suicidal attempts. In the course of intoxication: balance disturbances, psychomotor retardation, changes in consciousness with temporary excitation were observed. The concentration of glutethimid in the urine was 1.1 mg% and 0.5 mg% in the blood. Patient was treated according to the general rules of intensive care. After 4 days of therapy the patient improved and was transferred to psychiatric unit in Kościan.

Amobarbital↗
PubMed1992

Porphyrogenic properties of the terpenes camphor, pinene, and thujone (with a note on historic implications for absinthe and the illness of Vincent van Gogh).

Camphor, alpha-pinene (the major component of turpentine), and thujone (a constituent in the liqueur called absinthe) produced an increase in porphyrin production in primary cultures of chick embryo liver cells. In the presence of desferrioxamine (an iron chelator which inhibits heme synthesis and thereby mimics the effect of the block associated with acute porphyria), the terpenes enhanced porphyrin accumulation 5- to 20-fold. They also induced synthesis of the rate-controlling enzyme for the pathway, 5-aminolevulinic acid synthase, which was monitored both spectrophotometrically and immunochemically. These effects are shared by well-known porphyrogenic chemicals such as phenobarbital and glutethimide. Camphor and glutethimide alone led to the accumulation of mostly uro- and heptacarboxylporphyrins, whereas alpha-pinene and thujone resulted in lesser accumulations of porphyrins which were predominantly copro- and protoporphyrins. In the presence of desferrioxamine, plus any of the three terpenes, the major product that accumulated was protoporphyrin. The present results indicate that the terpenes tested are porphyrogenic and hazardous to patients with underlying defects in hepatic heme synthesis. There are also implications for the illness of Vincent van Gogh and the once popular, but now banned liqueur, called absinthe.

5-Aminolevulinate Synthetase↗
PubMed1991

Indices of drug misuse for prescription drugs.

Few studies of prescription-drug misuse have taken into account the numbers of prescriptions dispensed for specific drugs. Using data from the Drug Abuse Warning Network (DAWN) and the National Prescription Audit, we calculated indices of drug misuse for specific prescription drugs that are used mainly in outpatient settings and are either benzodiazepines, barbiturates, other sedative-hypnotics, analgesics, or CNS stimulants. In 1983-1985 the drugs associated with the highest numbers of DAWN medical examiner-reported drug-misuse deaths were codeine, diazepam, propoxyphene, phenobarbital, and secobarbital. However, the drugs with the highest indices of DAWN medical examiner-reported drug-misuse deaths/100,000 dispensed prescriptions were methamphetamine, methaqualone, amobarbital, secobarbital, and glutethimide. An index of fatality risk, calculated as 100 x DAWN medical examiner-reported drug-misuse deaths/DAWN emergency room-reported drug-misuse episodes, suggested that the risk of death from a glutethimide-associated drug-misuse episode had increased 92% from 1975-1979 to 1983-1983 and in 1983-1985 was the highest for the drugs studied. These indices might assist public health authorities attempting to design effective strategies to efficiently address the problem of prescription-drug misuse.

Cause of Death↗
PubMed1984

[Simultaneous high performance liquid chromatographic determination of 8 anti-epileptics and sedatives in plasma. Use of a radial compression column system].

The authors describe a method of assaying anti-epileptic and sedative drugs by high performance liquid chromatography. This method allows for simultaneous separation and quantification of these drugs (Ethosuximide, Primidone, Phenobarbital, Beclamide, Prominal, Diphenylhydantoin, Glutethimide, Carbamazepine) in a relatively short analysis time, by means of a system of radial compression of the column. The serum is acidified and extracted by ethyl acetate. After evaporation, the residue is taken up in the mobile phase. The various drugs are eluted in a 10 micron Rad-Pak C 18 column with a mobile phase consisting of a mixture of methanol and water with a flow rate of 4 ml/min. The chromatograph is read at 200 nm and the separation is effective in about 16 minutes. The yield is between 75 and 100 per cent and the repeatability of the method is good (C. V. less than 9 per cent). The originality of the method resides in the assay of drugs such as beclamide, methylphenobarbital and glutethimide at the same time as the major anti-epileptics.

Anticonvulsants↗
PubMed1963

Clinical and statistical evaluation of six hypnotic agents.

Six hypnotic drugs and a placebo were coded and administered at random, one dose at 8 p.m., to 20 patients in a Toronto hospital. A special evaluation scale was used, studying average duration of sleep, time of onset of sleep, quality of sleep and side effects. Secobarbital sodium and methyprylon were statistically significantly more effective than the placebo. The other drugs, glutethimide and three quinozolinone derivatives, were not statistically different from the placebo in their effects. The placebo effect itself was studied. A particular feature of this report is the detailed statistical treatment of the data collected.

Glutethimide↗
PubMed1993

Separation of the enantiomers of some racemic nonsteroidal aromatase inhibitors and barbiturates by capillary electrophoresis.

High-performance capillary electrophoresis (HPCE) and micellar electrokinetic capillary chromatography (MECC) were applied to the resolution of racemic nonsteroidal antiaromatase drugs and intermediates. Successful results were obtained in both modes using alpha-cyclodextrin (alpha-CD), beta-cyclodextrin (beta-CD), gamma-cyclodextrin (gamma-CD), or 2,6-di-O-methyl-beta-cyclodextrin (DM-beta-CD) as chiral selectors. Depending on the structure of the solute, one of the cyclodextrins was generally better suited for resolution of the racemate. The basic solutes were analyzed under HPCE conditions, whereas the nonionizable compounds such as glutethimide (Doriden) were analyzed in MECC mode. For the azole-type antiaromatase Fadrozole, both HPCE and MECC modes could be used to achieve the separation of the enantiomers. The influence of experimental factors such as pH, the presence of organic modifier, temperature, the micelle concentration, and the concentration of the chiral selector is also discussed on the basis of the results obtained with some chiral barbiturates. The possibility of analyzing the enantiomers directly in plasma samples was also demonstrated.

Aminoglutethimide↗