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PubMed1986

Androgen priming and response to chemotherapy in advanced prostatic cancer.

A total of 67 patients with progressive stage D2 prostatic cancer refractory to orchiectomy was entered in a controlled clinical trial to test whether androgen priming enhances the efficacy of cytotoxic drugs. All patients were treated continuously with aminoglutethimide and hydrocortisone to lower adrenal androgen secretion and were given cyclic intravenous chemotherapy. In addition, the 34 patients randomized to the stimulation arm received fluoxymesterone for 3 days before and on the day of chemotherapy. There was 33 controls. The median duration of followup was 24 months. A modestly higher response rate (objective remission plus disease stabilization) was observed in the stimulation arm (85 versus 72 per cent, p less than 0.05) when the analysis was restricted to the evaluable patients. However, a larger fraction of unevaluable patients was present in the stimulation group (41 versus 16 per cent), mostly as a result of toxicity from fluoxymesterone, which prompted early discontinuation of treatment. Thus, when data analysis included all patients the response rate actually was slightly higher in the control than in the stimulation arm (60 versus 50 per cent, p not significant). No difference was observed in median duration of response (9 months in both groups) or over-all survival. Our data suggest that at least in those patients with advanced disease androgen priming does not seem to enhance significantly the antitumor effect of the combination of amino-glutethimide and chemotherapy, and is associated with significant toxicity. These largely negative results may be explained by the large number of hormone-resistant cells present in tumors that have become refractory to orchiectomy.

Aged↗
PubMed1981

Value of toxicological investigation in the diagnosis of acute drug poisoning in children.

In the 2 years 1978 and 1979 specimens from 287 children aged between 10 days and 14 years were received for general toxicological investigations. Of the 95 (33%) cases of confirmed poisoning, the diagnosis was established as a direct result of the analyses in 48 patients. No diagnosis was made in at least 85 (30%) of the remaining cases. Benzodiazepines were the drugs most commonly encountered (33%), followed by barbiturates, glutethimide, and meprobamate (15%), salicylate and paracetamol (15%), tricyclic antidepressants (12%), and ethanol (11%). 36 patients were severely poisoned (grade 3 or 4 coma, or convulsions), although only 1 patent died. There was evidence that drug(s) had been administered without authorisation in at least 7 instances, and in 51 (54%) of the poisoned patients there was sufficient concern about the safety of the child or the mode of administration of the drug(s) to institute legal proceedings (8 cases), involve the social services (25 cases), or arrange further medical appointments (18 cases). Drugs are readily available in most households and offer a means of inflicting injury that is less easily detectable than physical assault. For this reason, comprehensive toxicological investigations should be considered in children not only when they may assist in management but also in the presence of unusual or unexplained symptoms which could be drug-induced.

Adolescent↗
PubMed1990

Identification and differentiation of barbiturates, other sedative-hypnotics and their metabolites in urine integrated in a general screening procedure using computerized gas chromatography-mass spectrometry.

A gas chromatographic-mass spectrometric procedure is described for the identification and differentiation of sedative-hypnotics and their metabolites in urine. The following 24 barbiturates and thirteen other hypnotics could be detected: acecarbromal, allobarbital, amobarbital, aprobarbital, barbital, brallobarbital, bromisoval, (sec)butabarbital, butalbital, butobarbital, carbromal, clomethiazole, crotylbarbital, cyclobarbital, cyclopentobarbital, diethylallylacetamide, dipropylbarbital, glutethimide, guaifenesin, ethinamate, heptabarbital, hexobarbital, meprobamate, methaqualone, metharbital, methohexital, methylphenobarbital, methyprylone, pentobarbital, phenobarbital, propallylonal, pyrithyldione, secobarbital, thiobutabarbital, thiopental, vinbarbital and vinylbital. The procedure presented is integrated in a general screening procedure (general unknown analysis) for several groups of drugs detecting over 300 drugs and over 1000 of their metabolites. It includes cleavage of conjugates by acid hydrolysis, isolation by liquid-liquid extraction, derivatization by acetylation, separation by capillary gas chromatography, and identification by computerized mass spectrometry. Using mass chromatography with the selected ions m/z 83, 117, 141, 167, 169, 207, 221 and 235, the presence of barbiturates, other hypnotics and/or their metabolites was indicated. The identity of positive signals in the reconstructed mass chromatograms was confirmed by a visual or computerized comparison of the stored full mass spectra with the reference spectra. The sample preparation, mass chromatograms, reference mass spectra and gas chromatographic retention indices are documented.

Acetylation↗
PubMed2002

Immobilized halogenophenylcarbamate derivatives of cellulose as novel stationary phases for enantioselective drug analysis.

Three different halogeno-phenylcarbamate derivatives of cellulose have been prepared and coated on silica gel. The coated materials have been immobilized and their chiral recognition ability as chiral stationary phase (CSP) has been evaluated with a set of reference racemates, including several drugs such as lormetazepam, glutethimide, and warfarin, using various mobile phase mixtures. The novel phases were found to exhibit unique enantioselective properties compared with more established polysaccharide-based CSPs. A good resolution of all racemates could be successfully achieved on at least one of the immobilized CSPs. Moreover, it has been pointed out that selectivity may considerably vary with the composition of the mobile phase.

Carbamates↗
PubMed1983

Analogues of aminoglutethimide: selective inhibition of cholesterol side-chain cleavage.

In our probing of the structural features responsible for the inhibitory activity of aminoglutethimide [1, 3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione] toward the cholesterol side-chain cleavage enzyme system desmolase and the estrogen-forming system aromatase, targets in the action of 1 against hormone-dependent mammary tumors, analogues in several categories have been synthesized and evaluated. Of the known monoamino derivatives, the meta derivative [2, 3-(3-aminophenyl)-3-ethylpiperidine-2,6-dione] was as inhibitory toward desmolase as 1, and the N-amino analogue [4, 1-amino-3-ethyl-3-phenylpiperidine-2,6-dione] was three times as inhibitory (respective Ki values of 1, 2, and 4 are 14, 13, and 4.6 microM), but 2 was a weak inhibitor and 4 was a noninhibitor of aromatase. Another amino analogue [5, 5-amino-3-ethyl-3-phenylpiperidine-2,6-dione] inhibited neither enzyme system. Reaction of glutethimide (11) with hydrazine and thermal cyclization of the resulting amide hydrazide (15) afforded an improved synthesis of 4. Analogues having a second amino substituent, either at C-5 (10) or at N-1 (14) of the piperidine-2,6-dione residue, were less inhibitory than was 1 toward desmolase and aromatase. Among analogues having little or no inhibitory activity were hydroxy derivatives of 1 and 2, namely, 3-(4-amino-3-hydroxyphenyl)-3-ethylpiperidine-2,6-dione (20) and the 3-amino-4-hydroxy analogue (21).

Aminoglutethimide↗
PubMedDate not supplied

Hepatic cytochrome P450 2B-type induction by ethyl/phenyl-substituted congeners of phenobarbital in the rat.

As part of an investigation of the structural requirements for the induction, by phenobarbital-type inducers, of a coordinate pleiotropic response consisting of increases in hepatic cytochrome P450 2B (P450 2B) activity, increases in other phase I and II enzyme activities, and liver hypertrophy, we have examined a series of analogues of phenobarbital in which the ethyl/phenyl substitution at the sp3 carbon of the parent molecule was kept constant while the heterocyclic portion of the molecule was modified. The induction of hepatic P450 2B protein and ethoxy-, pentoxy-, and (benzyloxy)resorufin O-dealkylation activities, and epoxide hydration activity and liver/body weight ratio increase were examined in male F344/NCr rats fed the various congeners for 14 days at doses equimolar to 500 ppm phenobarbital. Increases in the measured parameters were maximal in rats fed phenobarbital or 5-ethyl-5-phenylhydantoin. The responses to primidone or 2-ethyl-2-phenylsuccinimide were approximately 65% of maximal, while glutethimide yielded a response approximately 50% of maximal. Induction of this response in rats fed the ring-opened and decarboxylated analogues, (ethylphenylacetyl)urea and 2-ethyl-2-phenylmalonamide, were < 25% of maximal. 5-Ethyl-5-phenyloxazolidinedione caused minimal increases in the measured end points when administered at a dose equimolar to 500 ppm phenobarbital. The profound differences among the congeners in ability to induce P450 2B protein and associated catalytic activities were not due to differences in food consumption by the various groups of rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Rapid method for screening toxic drugs in serum with liquid chromatography.

We present a method for the simultaneous analysis of a variety of commonly abused drugs (acetaminophen, theophylline, salicylate, primidone, methyprylon, phenobarbital, butabarbital, ethchlorvynol, butalbital, chlordiazepoxide, pentobarbital, amobarbital, phenytoin, glutethimide, secobarbital, flurazepam, nitrazepam, methaqualone, N-desmethyldiazepam, and diazepam) in serum or plasma. Serum proteins are precipitated with an acetonitrile solution containing hexobarbital, the internal standard. The drugs are eluted from a reversed-phase column with a mobile phase consisting of acetonitrile/phosphate buffer (pH 3.2), using a two-step linear gradient, at a flow rate of 3.0 mL/min. The eluted drugs are detected by their absorption at 210 nm; their quantities are estimated from their peak heights. A complete analysis requires no longer than 45 minutes at the optimum column temperature of 50 degree C. A sensitivity of 2 mg/L of serum is attained routinely for most of the hypnotic and analgesic drugs; while methaqualone, chlordiazepoxide, diazepam, and N-desmethyldiazepam can be detected at a concentration of 0.2 mg/L. Analytical recoveries for the twenty drugs varied from 93-112%, with good reproducibility. Of more than forty drugs tested for possible interference, desmethyldoxepin, procainamide, phenylpropanolamine, mesantoin, and phenacetin interfere with the analysis of flurazepam, acetaminophen, ethchlorvynol, and phenobarbital, respectively.

Chromatography, Liquid↗
PubMedDate not supplied

Analysis of post mortem brain tissue using EMIT.

EMIT, normally used on urine or serum for the detection of drugs of abuse, has been utilized for the analysis of drugs in aqueous brain extracts. A modified Stas-Otto procedure performed on the brain tissue produced a liquid containing no interfering substances. The detection limits proved to be at least as sensitive as the chromatographic screening techniques normally applied to larger portions of the final aqueous filtrate. Out of 166 cases, 50 positive findings were determined. Two glutethimide cases gave positives for the barbiturate assay and a fatal overdose of amitriptyline appeared positive when tested with the benzodiazepine reagents. All other positive findings correlated well with the chromatographic findings.

Brain Chemistry↗
PubMed1999

Synthesis of steroids in pancreas: evidence of cytochrome P-450scc activity.

In pancreas, the activities of several sex steroid-transforming enzymes have been reported. Data have been obtained in perfused organs, total tissue homogenates, and subcellular organelles. These data, concurrent with the description of the presence of ligand-regulated steroid receptors, as well as the sexually dimorphic behavior of some pancreatic tumors, are clear evidence in support of the participation of steroid hormones in the pancreatic function. In this study, the steroidogenic ability of the pancreas was demonstrated by two different methods: (a) in tissue homogenates, by the identification of cytochrome P-450scc gene (CYP11A) transcripts after reverse transcription-polymerase chain reaction amplification (RT-PCR); and (b) in isolated mitochondria by the glutethimide-dependent inhibition of cholesterol-pregnenolone biotransformation. The results obtained in a series of independent experiments showed that (a) the pancreatic tissue possessed transcriptional activity of the CYP11A gene, although to a lesser extent than the typical steroidogenic tissues, and (b) isolated mitochondria obtained from the pancreas were able consistently to synthesize pregnenolone; furthermore, the addition of the specific inhibitor aminoglutethimide (AMG) blocked its synthesis. On the whole, these findings are interpreted as clear evidences of the activity of the cytochrome P-450scc enzymatic complex (P450scc), responsible for the transformation of cholesterol into pregnenolone and considered the first and limiting step in steroid biosynthesis.

Aminoglutethimide↗
PubMed1962

Increase of pentobarbitone metabolism induced in rats pretreated with some centrally acting compounds.

Rats treated with phenobarbitone, phenaglycodol, glutethimide, nikethamide, meprobamate, chlorbutol and chlorpromazine showed an increased metabolism of pentobarbitone and, at the same time, a diminished sleeping-time after pentobarbitone. This effect developed 24 hr after treatment, the maximum increase in metabolism occurring after about 48 hr. The increased pentobarbitone metabolism was inhibited by ethionine injected shortly before treatment. Using a liver slice preparation, increased pentobarbitone metabolism was also observed in vitro. These results are in accord with the view that the capacity of compounds to increase pentobarbitone metabolism may be related to their ability to act directly on microsomal enzyme systems.

Animals↗
PubMed2001

The antiglucocorticoid RU486 inhibits phenobarbital induction of the chicken CYP2H1 gene in primary hepatocytes.

The cytochrome P450 gene CYP2H1 is highly induced by phenobarbital in chick embryo hepatocytes. Recent studies have established that the orphan nuclear receptor CAR plays a critical role in the induction mechanism. Here, we show that a high concentration of the potent glucocorticoid and progesterone receptor antagonist RU486 almost completely blocks phenobarbital-induced accumulation of CYP2H1 mRNA in hepatocytes yet has no effect on basal expression. In marked contrast, CYP2H1 mRNA induced by the phenobarbital-type inducers glutethimide and 2-allylisopropylacetamide is not affected by RU486. RU486 inhibition is not mediated through the glucocorticoid or progesterone receptors. Transient transfection studies showed that RU486 does not repress through activation of the orphan receptor PXR and subsequent competition with CAR for binding to the upstream drug-responsive 556-base-pair enhancer. Additionally, none of the known functional transcription factor binding sites found in the enhancer region was a target of RU486 inhibition. Using an artificial construct containing multiple CAR binding sites, we also established that RU486 has no direct effect on the activity of exogenously expressed CAR. There is no evidence that phenobarbital binds to CAR; we propose that RU486 inhibits phenobarbital induction, either by interfering with a phenobarbital-dependent mechanism responsible for nuclear import of CAR or with the metabolism of phenobarbital to the true inducer. Whether a novel nuclear receptor that binds RU486 at high concentrations plays a role in the inhibitory action of RU486 is an interesting possibility.

Animals↗
PubMed1977

Haemoperfusion with R-004 Amberlite resin for treating acute poisoning.

Eleven patients who had taken overdoses of barbiturates, glutethimide, tricyclic antidepressants, and chloroquine were treated by resin haemoperfusion using an R-004 haemoperfusion cartridge containing XAD-4 resin. All but one patient showed rapid clinical recovery and the drugs were cleared rapidly from the plasma. There were few complications. Resin haemoperfusion is more effective than dialysis and other perfusion methods, especially in poisoning with tricyclic antidepressants. Although haemoperfusion is expensive, it greatly reduces the length of the patient's stay in an intensive care unit and hence is cost-effective.

Acute Disease↗
PubMed1980

Baclofen overdose.

A 57-year-old woman suffering from multiple sclerosis took an estimated 1500 mg of baclofen. She became deeply unconscious with generalized flaccid muscle paralysis and absent tendon reflexes. Toxicological analysis confirmed the presence of baclofen together with small amounts of paracetamol and glutethimide. Supportive therapy, including assisted ventilation for 3 days, led to complete recovery; anticonvulsant drugs were necessary for the treatment of grand mal fits. The clinical features and treatment of baclofen overdose are discussed.

Baclofen↗
PubMed1982

Temazepam (Restoril, Sandoz Pharmaceuticals).

Temazepam is a benzodiazepine derivative indicated for the treatment of insomnia. Pharmacokinetic studies of the hard capsule formulation indicate that the mean time to peak is 2.99 hours and the mean elimination half-life is 14.7 hours. Sleep laboratory studies have demonstrated improvements in all sleep parameters except sleep onset latency. Clinically, patients report improvements in all sleep parameters including sleep onset latency. The efficacy of temazepam compares favorably with barbiturates, glutethimide, nitrazepam, lorazepam, oxazepam, and flurazepam. It has not been compared with diazepam in the clinical setting. Side effects include drowsiness, dizziness, and lethargy. The incidence of hangover effects from 15- and 30-mg doses is relatively low. Temazepam has no proven advantages over other benzodiazepine hypnotics. The major issues that need further clarification include temazepam's sleep induction properties and the relative incidence of hangover and rebound insomnia when compared with longer-acting benzodiazepines.

Animals↗
PubMed1986

Adenosine 3',5'-monophosphate-mediated induction of 17 alpha-hydroxylase and C 17-20 lyase activities in cultured mouse Leydig cells is enhanced by inhibition of steroid biosynthesis.

We recently reported that treatment of mouse Leydig cell cultures for 5 days with LH or cAMP caused an induction of the microsomal cytochrome P-450 activities 17 alpha-hydroxylase and C17-20 lyase. We also have shown that the microsomal P-450s are very sensitive to oxygen-mediated loss of these activities and that this decrease is enhanced by steroids produced during acute cAMP stimulation of Leydig cells. In the present study, we investigated whether steroids produced during chronic cAMP treatment of Leydig cells limit the extent of induction of 17 alpha-hydroxylase and C17-20 lyase. Treatment of Leydig cell cultures with 8-bromo-cAMP in the presence of aminoglutethimide, an inhibitor of cholesterol side-chain cleavage, resulted in a 4- to 7-fold enhancement of cAMP-mediated induction of the 17 alpha-hydroxylase and C17-20 lyase activities and, after 11 days of treatment, completely restored the activities to those found in freshly isolated Leydig cells. Treatment with aminoglutethimide in the absence of cAMP had no effect on these enzyme activities. Addition of the steroid products androstenedione and/or testosterone (5 microM) to cAMP-plus amino-glutethimide-treated cultures caused a significant reduction in cAMP-mediated induction of microsomal P-450, while addition of estradiol (50 nM) had no significant effect. 3 beta-Hydroxysteroid dehydrogenase-isomerase, another microsomal enzyme that is not a P-450 enzyme, was not induced by cAMP in either the presence or absence of aminoglutethimide. The data suggest that Leydig cell microsomal P-450 activities are maintained in vivo by a balance between two processes: cAMP-mediated induction and steroid product-induced degradation.

Aldehyde-Lyases↗
PubMed1990

Identification and characterization of an abundant phosphoprotein specific to the large luteal cell.

An abundant protein with a relative mol wt of 32K present specifically in the large cells of the pregnant rat corpus luteum has been identified. Separation of large and small luteal cells by elutriation, followed by protein analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), have revealed that the 32K protein was present as a major protein in the large luteal cells but was practically absent in the small cell population. This protein appears to be highly tissue and cell specific and resolves into three protein species by two-dimensional SDS-PAGE with the major protein having an isoelectric point (pI) greater than or equal to 8.5. It was not detected in preantral follicles or placentas of the same pregnant rats, or in any other tissue examined. After subcellular fractionation, the 32K protein(s) was found in the particulate fraction and was localized principally in the microsomal compartment. Autoradiographic analysis of 35S-amino acid-labeled tissue demonstrated that the 32K protein(s) is synthesized in the corpus luteum. When particulate fractions from small and large cells were incubated in the presence of [gamma-32P]ATP followed by SDS-PAGE, phosphorylation of the 32K protein was apparent. Phosphorylation of this protein was not enhanced by the addition of cofactors for cAMP, Ca2(+)-calmodulin- or Ca2(+)-phospholipid-dependent kinases. Experimental inhibition of steroidogenesis with amino-glutethimide caused a remarkable reduction in the luteal content of this 32K protein whereas estradiol and human CG treatment increased its content. In summary, we have discovered and partially characterized a unique 32K protein(s) which is expressed and phosphorylated only in large luteal cells of the corpus luteum. This protein(s), which is regulated by estradiol formed locally, may serve as a powerful marker for both the large luteal cell and estrogen action in the corpus luteum.

Animals↗
PubMed1991

Evidence that hydrogen peroxide blocks hormone-sensitive cholesterol transport into mitochondria of rat luteal cells.

In luteal and granulosa cells, hydrogen peroxide abruptly inhibits activation of adenylate cyclase by receptor-bound gonadotropin and blocks steroidogenesis. In the present studies a post-cAMP site of peroxide action on inhibition of steroidogenesis was investigated. Steroidogenesis, stimulated by dibutyryl or 8-bromo-cAMP, was inhibited by hydrogen peroxide. Yet, cAMP-dependent protein kinase activation in cytosol or intact cells was unaffected by peroxide treatment. Hydrogen peroxide also did not inhibit the activity of cholesterol esterase and acyl coenzyme-A:acyltransferase. Progesterone synthesis was maximally increased 5- to 50-fold with 25- and 22-hydroxycholesterol, respectively. Unlike that seen with cAMP analogs and LH, however, progestin synthesis stimulated by these cell- and mitochondria-permeant cholesterol analogs was not inhibited by hydrogen peroxide. Treatment of animals with amino-glutethimide produces a marked accumulation of steroidogenic cholesterol substrate and a large increase in hormone-independent steroidogenesis in subsequently isolated and washed luteal tissue. In this paradigm, hydrogen peroxide did not inhibit elevated basal progesterone synthesis in luteal cells produced by in vivo aminoglutethimide treatment, yet LH-stimulated steroidogenesis was blocked. However, treatment of luteal cells with hydrogen peroxide inhibited pregnenolone synthesis in isolated mitochondria, an effect partially reversed by the addition of luteal cell cytosol. In summary, while peroxide inhibited cAMP-dependent steroidogenesis, it did not appear to inhibit protein kinase activation or mobilization of cholesterol from intracellular esterified stores. Although peroxide inhibited pregnenolone synthesis, it had no effect on steroidogenesis when substrate was made available by either addition of cholesterol analogs or prior treatment with aminoglutethimide in vivo. We conclude, therefore, that hydrogen peroxide inhibits steroidogenesis by blocking intracellular transport of cholesterol to mitochondria or translocation of cholesterol across the outer mitochondrial membrane.

Animals↗