glutethimide

アミノグルテチミド 　

WordNet

1. sedative (trade name Doriden) used to treat some sleep disorders (同)Doriden

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/05/06 22:25:22」(JST)

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Glutethimide

Systematic (IUPAC) name
3-ethyl-3-phenyl-piperidine-2,6-dione
Clinical data
Pregnancy category	C: (United States)
Legal status	AU: Prescription Only (S4) US: Schedule II Schedule III international
Routes of administration	oral
Pharmacokinetic data
Bioavailability	Variable
Metabolism	Hepatic
Half-life	10-12 hours
Excretion	Renal:2% Fecal:2%
Identifiers
CAS Registry Number	77-21-4 Y
ATC code	N05CE01
PubChem	CID 3487
DrugBank	DB01437 Y
ChemSpider	3367 Y
UNII	C8I4BVN78E Y
KEGG	D00532 Y
ChEMBL	CHEMBL1102 Y
Chemical data
Formula	C13H15NO2
Molecular mass	217.264 g/mol
SMILES O=C1NC(CCC1(CC)C2=CC=CC=C2)=O
InChI InChI=1S/C13H15NO2/c1-2-13(10-6-4-3-5-7-10)9-8-11(15)14-12(13)16/h3-7H,2,8-9H2,1H3,(H,14,15,16)  Y Key:JMBQKKAJIKAWKF-UHFFFAOYSA-N  Y
Y (what is this?)  (verify)

Glutethimide is a hypnotic sedative that was introduced by Ciba in 1954 as a safe alternative to barbiturates to treat insomnia. Before long, however, it had become clear that glutethimide was just as likely to cause addiction and caused similarly severe withdrawal symptoms. Doriden was the brand-name version of the drug; it was also available under the brand names Elrodorm, Noxyron, Glimid and others. Both the generic and brand-name forms are very rarely prescribed today. Current production levels in the United States (the annual quota for manufacturing imposed by the DEA has been three grams, enough for six Doriden tablets, for a number of years) point to it only being used in small scale research.

Long term use

Long term use rebound effects, which resembled those seen in withdrawal, have anecdotally been described in patients who were still taking a stable dose of the drug. The symptoms included delirium, hallucinosis, convulsions and fever.

Recreational use

Glutethimide is a CYP2D6 enzyme inducer. When taken with codeine, it enables the body to convert higher amounts of the codeine (higher than the average 5 - 10%) to morphine. The general sedative effect also adds to the effect of the combination. The effect was also used clinically, including some research in the 1970s in various countries of using it under carefully monitored circumstances as a form of oral opioid agonist substitution therapy, e.g. as a Substitutionmittel that may be a useful alternative to methadone The combination was known as Dors & Fours, a Six Pack, Loads, etc. as two Doriden tablets and four Tylenol (or Emprin, Emprazil or other drugs) With Codeine No. 4, or plain 60 mg codeine tablets were sold as a set. The demand for this combination, in western Pennsylvania and surrounding areas of other states and perhaps elsewhere, has led to small-scale clandestine synthesis of glutethimide since 1984, a process that is, like methaqualone synthesis, somewhat difficult and fraught with potential bad outcomes when less-than-gifted chemists are doing the deed with industrial-grade precursors without adequate quality control. The fact that the simpler clandestine synthesis of other extinct pharmaceutical depressants like ethchlorvynol, methyprylon, or the oldest barbiturates is not reported would seem to point to a high level of motivation surrounding a unique drug, again much like methaqualone. Analysis of confiscated glutethimide seems to invariably show the drug or the results of attempted synthesis, whereas purported methaqualone is in a significant minority of cases found to be inert, or contain diphenhydramine or benzodiazepines

The enzyme induction is apparently several times stronger than that induced by promethazine (Phenergan, Atosil), a phenothiazine antihistamine used clinically as an opioid potentiator (Phenergan VC With Codeine, Mepergan (pethidine + promethazine), mixing the antihistamine with alphaprodine and other such drugs in an IV)

Legal status

Glutethimide is a Schedule II drug under the Convention on Psychotropic Substances. It was originally a Schedule III drug in the United States under the Controlled Substances Act, but in 1991 it was upgraded to Schedule II, after it was discovered that misuse combined with codeine increased the effect of the codeine and deaths had resulted from the combination. It has a DEA ACSCN of 2550 and a 2013 production quota of 3 g.

Chemistry

Glutethimide (2-ethyl-2-phenylgutarimide) is synthesized by addition of 2-phenylbutyronitrile to the methylacrylate (Michael reaction), and the subsequent alkaline hydrolysis of the nitrile group in the obtained compound into an amide group, and the subsequent acidic cyclization of the product into the desired glutethimide. The (R) isomer has a faster onset and more potent anticonvulsant activity in animal models than the (S) isomer.

See also

• Aminoglutethimide
• Piperidione
• Methyprylone
• Pyrithyldione

References

UpToDate Contents

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• 1. 本態性振戦の薬理学的治療 pharmacologic treatment of essential tremor
• 2. 血液灌流 hemoperfusion
• 3. 小児における急性中毒性代謝性脳症 acute toxic metabolic encephalopathy in children
• 4. 成人における急性中毒性代謝性脳症 acute toxic metabolic encephalopathy in adults
• 5. 抗てんかん剤と骨疾患 antiepileptic drugs and bone disease

English Journal

• Effect of aminoglutethimide on neutrophils in rats: implications for idiosyncratic drug-induced blood dyscrasias.

• Ng W1, Uetrecht J.Author information 1Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada M5S 3M2.AbstractAminoglutethimide (AMG) is an aromatic amine aromatase inhibitor associated with a high incidence of idiosyncratic blood dyscrasias, especially agranulocytosis. Animal models of idiosyncratic drug reactions (IDRs) represent essential tools to study these reactions; however, there is currently no valid model of idiosyncratic drug-induced agranulocytosis. Although AMG does not cause agranulocytosis in most animals or humans, drugs associated with serious IDRs generally cause a higher incidence of mild reactions that resolve despite continued treatment. Therefore, the effects of AMG on neutrophils and bone marrow in rats were studied to understand the mechanisms of more serious IDRs. An increase in peripheral blood neutrophils occurred as early as 24 h after AMG treatment with minimal changes to the total leukocyte count. Further investigation using 5-bromo-2'-deoxyuridine (BrdU) found an increased release of neutrophils from the bone marrow. Histologically, this corresponded to an increase in myeloid cells in the bone marrow, which was confirmed by differential staining with CD45 and CD71. AMG treatment stimulated an increase in colony forming unit granulocyte-macrophage and colony forming unit granulocyte ex vivo. There was also a marked increase in the number of activated neutrophils in the circulation expressing the extravasation marker CD62L. These findings indicate that AMG affects neutrophil production, release, and function. Similar effects on neutrophil kinetics in clozapine-treated rats have previously been found, and transient neutrophilia has been observed in patients taking other drugs associated with idiosyncratic agranulocytosis; therefore, the changes observed with AMG may be biomarkers to predict the risk that a drug will cause agranulocytosis.
• Chemical research in toxicology.Chem Res Toxicol.2013 Aug 19;26(8):1272-81. doi: 10.1021/tx400224j. Epub 2013 Aug 9.
• Aminoglutethimide (AMG) is an aromatic amine aromatase inhibitor associated with a high incidence of idiosyncratic blood dyscrasias, especially agranulocytosis. Animal models of idiosyncratic drug reactions (IDRs) represent essential tools to study these reactions; however, there is currently no val
• PMID 23889370

• Efficacy of tamoxifen ± aminoglutethimide in normal weight and overweight postmenopausal patients with hormone receptor-positive breast cancer: an analysis of 1509 patients of the ABCSG-06 trial.

• Pfeiler G1, Stöger H, Dubsky P, Mlineritsch B, Singer C, Balic M, Fitzal F, Moik M, Kwasny W, Selim U, Renner K, Ploner F, Steger GG, Seifert M, Hofbauer F, Sandbichler P, Samonigg H, Jakesz R, Greil R, Fesl C, Gnant M; ABCSG.Author information 1Division of Gynecology and Gynecological Oncology, Department of Obstetrics and Gynecology, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.AbstractBACKGROUND: There exists evidence that body mass index (BMI) impacts on the efficacy of aromatase inhibitors in patients with breast cancer. The relationship between BMI and the efficacy of tamoxifen is conflicting. We investigated the impact of BMI on the efficacy of single tamoxifen and tamoxifen plus an aromatase inhibitor in the well-defined prospective study population of the ABCSG-06 trial.
• British journal of cancer.Br J Cancer.2013 Apr 16;108(7):1408-14. doi: 10.1038/bjc.2013.114. Epub 2013 Mar 19.
• BACKGROUND: There exists evidence that body mass index (BMI) impacts on the efficacy of aromatase inhibitors in patients with breast cancer. The relationship between BMI and the efficacy of tamoxifen is conflicting. We investigated the impact of BMI on the efficacy of single tamoxifen and tamoxifen
• PMID 23511562

• Changes in gene expression induced by aromatic amine drugs: testing the danger hypothesis.

• Ng W1, Uetrecht J.Author information 1Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Ontario, Canada.AbstractVirtually all drugs that contain a primary aromatic amine are associated with a high incidence of idiosyncratic drug reactions (IDRs), suggesting that this functional group has biological effects that may be used as biomarkers to predict IDR risk. Most IDRs exhibit evidence of immune involvement and the ability of aromatic amines to form reactive metabolites and redox cycle may be responsible for initiation of an immune response through induction of cell stress, as postulated by the Danger Hypothesis. If true, danger signals could be biomarkers of IDR risk. A previous attempt to test the Danger Hypothesis found that sulfamethoxazole (SMX), the only aromatic amine tested, was also the only drug not associated with an increase of cell stress genes in mice. To ensure that these observations were not species-specific, and to determine biomarkers of IDR risk common to aromatic amines, rats were treated with SMX and two other aromatic amine drugs, dapsone (DDS) and aminoglutethimide (AMG), and hepatic gene expression was determined using microarrays. As in mice, SMX induced minimal gene changes in the rat, and none indicated cell stress, whereas DDS and AMG induced several changes including up-regulation of enzymes such as aldo-keto reductase, glutathione-S-transferase, and aldehyde dehydrogenase, which may represent danger signals. Early insulin-induced hepatic gene (Eiih) was up-regulated by all three drugs. Some mRNA changes were observed in the Keap-1-Nrf2-ARE pathway; however, the pattern was significantly different for each drug. Overall, the most salient finding was that the changes in the liver were minimal, even though aromatic amines cause a high incidence of IDRs. The liver generates a large number of reactive species; however, the ability of aromatic amines to be bioactivated by cells of the immune system may be why they cause a high incidence of IDRs.
• Journal of immunotoxicology.J Immunotoxicol.2013 Apr-Jun;10(2):178-91. doi: 10.3109/1547691X.2012.707699. Epub 2012 Sep 12.
• Virtually all drugs that contain a primary aromatic amine are associated with a high incidence of idiosyncratic drug reactions (IDRs), suggesting that this functional group has biological effects that may be used as biomarkers to predict IDR risk. Most IDRs exhibit evidence of immune involvement and
• PMID 22970684

Japanese Journal

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

• WEINZ Corinna,BLASCHKE Gottfried,SCHIEBEL Hans-Martin
• Journal of chromatography. B, Biomedical sciences and applications 690(1), 233-242, 1997-03-07
• NAID 10024512363

• 原子吸光分析法によるバルビツール酸類の間接定量

• 南 幸男,三井 利幸,藤村 義和
• 分析化学 31(10), 604-607, 1982-10-05
• … No detectable interference for determination of barbiturates occured with any of the other compounds, such as sulfonal, bromovalerylurea, bromodiethylacetylurea, ethinamate, and glutethimide. …
• NAID 110002908407

Related Links

• Glutethimide | Define Glutethimide at Dictionary.com

glutethimide glu·teth·i·mide (glōō-těth'ə-mīd') n. A nonbarbiturate sedative and hypnotic drug.

• glutethimide - definition of glutethimide by Medical dictionary

glutethimide /glu·teth·i·mide/ (gloo-teth´ĭ-mīd) a nonbarbiturate used as a hypnotic and sedative. glu·teth·i·mide (glōō-tĕth′ə-mīd′) n. A nonbarbiturate sedative and hypnotic drug. glutethimide [gloo-teth´ĭ-mīd] a nonbarbiturate sedative and ...

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