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Aminoglutethimide: Difference between revisions

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{{Short description|Group of stereoisomers}}
{{Use dmy dates|date=May 2013}}
{{Use dmy dates|date=December 2022}}
{{Drugbox
{{Drugbox
| Verifiedfields = verified
| Verifiedfields = verified
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| image = Aminoglutethimide.svg
| image = Aminoglutethimide.svg
| width = 185px
| width = 185px
| image2 = Aminoglutethimide molecule ball.png
| width2 = 185px


<!--Clinical data-->
<!--Clinical data-->
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<!--Chemical data-->
<!--Chemical data-->
| C=13 | H=16 | N=2 | O=2
| C=13 | H=16 | N=2 | O=2
| chirality = [[Racemic mixture]]
| molecular_weight = 232.278 g/mol
| SMILES = O=C1NC(=O)CCC1(c2ccc(N)cc2)CC
| SMILES = O=C1NC(=O)CCC1(c2ccc(N)cc2)CC
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
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}}
}}


'''Aminoglutethimide''' ('''AG'''), sold under the brand names '''Elipten''', '''Cytadren''', and '''Orimeten''' among others, is a medication which has been used in the treatment of [[seizure]]s, [[Cushing's syndrome]], [[breast cancer]], and [[prostate cancer]], among other indications.<ref name="MortonHall2012">{{cite book|author1=I.K. Morton|author2=Judith M. Hall|title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA14|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-011-4439-1|pages=14–}}</ref><ref name="FiggChau2010">{{cite book|author1=William D. Figg|author2=Cindy H. Chau|author3=Eric J. Small|title=Drug Management of Prostate Cancer|url=https://books.google.com/books?id=4KDrjeWA5-UC&pg=PA93|date=14 September 2010|publisher=Springer Science & Business Media|isbn=978-1-60327-829-4|pages=91–96}}</ref><ref name="pmid17961023">{{cite journal |vauthors =Gross BA, Mindea SA, Pick AJ, Chandler JP, Batjer HH |title=Medical management of Cushing disease |journal=Neurosurgical Focus |volume=23 |issue=3 |pages=E10 |year=2007 |pmid=17961023 |doi=10.3171/foc.2007.23.3.12 |url=http://thejns.org/doi/abs/10.3171/foc.2007.23.3.12?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dncbi.nlm.nih.gov}}</ref><ref name="Osborne2012" /><ref name="Llewellyn2011" /> It has also been used by [[bodybuilder]]s, [[athlete]]s, and other men for [[anabolic|muscle-building]] and [[performance-enhancing drug|performance- and physique-enhancing purpose]]s.<ref name="Llewellyn2011">{{cite book|author=William Llewellyn|title=Anabolics|url=https://books.google.com/books?id=afKLA-6wW0oC&pg=PT770|year=2011|publisher=Molecular Nutrition Llc|isbn=978-0-9828280-1-4|pages=770–}}</ref><ref name="TindallSedrak2013" /> AG is taken [[oral administration|by mouth]] three or four times per day.<ref name="WilkesBarton-Burke2013" /><ref name="FiggChau2010" />
'''Aminoglutethimide''' ('''AG'''), sold under the brand names '''Elipten''', '''Cytadren''', and '''Orimeten''' among others, is a medication which has been used in the treatment of [[seizure]]s, [[Cushing's syndrome]], [[breast cancer]], and [[prostate cancer]], among other indications.<ref name="Milne2018">{{cite book| vauthors = Milne GW |title=Drugs: Synonyms and Properties: Synonyms and Properties|url=https://books.google.com/books?id=xUlaDwAAQBAJ&pg=PT1182|year=2018|publisher=Taylor & Francis|isbn=978-1-351-78989-9|pages=1182–}}</ref><ref name="MortonHall2012">{{cite book| vauthors = Morton IK, Hall JM |title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA14|year=2012|publisher=Springer Science & Business Media|isbn=978-94-011-4439-1|pages=14–}}</ref><ref name="FiggChau2010">{{cite book| vauthors = Friedlander TW, Ryan CJ | chapter = Adrenal Androgen Synthesis Inhibitor Therapies in Castrate-Resistant Prostate Cancer | veditors = Figg WD, Chau CH, Small EJ |title=Drug Management of Prostate Cancer| chapter-url=https://books.google.com/books?id=4KDrjeWA5-UC&pg=PA93|year=2010|publisher=Springer Science & Business Media|isbn=978-1-60327-829-4|pages=91–96}}</ref><ref name="pmid17961023">{{cite journal |vauthors =Gross BA, Mindea SA, Pick AJ, Chandler JP, Batjer HH |title=Medical management of Cushing disease |journal=Neurosurgical Focus |volume=23 |issue=3 |pages=1–6 |year=2007 |pmid=17961023 |doi=10.3171/foc.2007.23.3.12 |doi-access=free }}</ref><ref name="Osborne2012" /><ref name="Llewellyn2011" /> It has also been used by [[bodybuilder]]s, [[athlete]]s, and other men for [[anabolic|muscle-building]] and [[performance-enhancing drug|performance- and physique-enhancing purpose]]s.<ref name="Llewellyn2011">{{cite book|author=William Llewellyn|title=Anabolics|url=https://books.google.com/books?id=afKLA-6wW0oC&pg=PT770|year=2011|publisher=Molecular Nutrition Llc|isbn=978-0-9828280-1-4|pages=770–}}</ref><ref name="TindallSedrak2013" /> AG is taken [[oral administration|by mouth]] three or four times per day.<ref name="WilkesBarton-Burke2013" /><ref name="FiggChau2010" />


[[Side effect]]s of AG include [[lethargy]], [[somnolence]], [[dizziness]], [[headache]], [[appetite loss]], [[skin rash]], [[hypertension]], [[hepatotoxicity|liver damage]], and [[adrenal insufficiency]], among others.<ref name="FiggChau2010" /> AG is both an [[anticonvulsant]] and a [[steroidogenesis inhibitor]].<ref name="MortonHall2012" /><ref name="FiggChau2010" /> In terms of the latter property, it [[enzyme inhibitor|inhibit]]s [[enzyme]]s such as [[cholesterol side-chain cleavage enzyme]] (CYP11A1, P450scc) and [[aromatase]] (CYP19A1), thereby inhibiting the conversion of [[cholesterol]] into [[steroid hormone]]s and blocking the [[biosynthesis|production]] of [[androgen]]s, [[estrogen]]s, and [[glucocorticoid]]s, among other [[endogenous]] [[steroid]]s.<ref name="FiggChau2010" />
[[Side effect]]s of AG include [[lethargy]], [[somnolence]], [[dizziness]], [[headache]], [[appetite loss]], [[skin rash]], [[hypertension]], [[hepatotoxicity|liver damage]], and [[adrenal insufficiency]], among others.<ref name="FiggChau2010" /> AG is both an [[anticonvulsant]] and a [[steroidogenesis inhibitor]].<ref name="MortonHall2012" /><ref name="FiggChau2010" /> In terms of the latter property, it [[enzyme inhibitor|inhibit]]s [[enzyme]]s such as [[cholesterol side-chain cleavage enzyme]] (CYP11A1, P450scc) and [[aromatase]] (CYP19A1), thereby inhibiting the conversion of [[cholesterol]] into [[steroid hormone]]s and blocking the [[biosynthesis|production]] of [[androgen]]s, [[estrogen]]s, and [[glucocorticoid]]s, among other [[endogenous]] [[steroid]]s.<ref name="FiggChau2010" /> As such, AG is an [[aromatase inhibitor]] and [[adrenal steroidogenesis inhibitor]], including both an [[androgen synthesis inhibitor]] and a [[corticosteroid synthesis inhibitor]].<ref name="Patrick2013" /><ref name="SmithWilliams2005" /><ref name="Ebadi2007" /><ref name="Osborne2012" /><ref name="Llewellyn2011" />


AG was introduced for medical use, as an anticonvulsant, in 1960.<ref name="Sneader2005" /><ref name="HarrapDavis2012" /> It was withdrawn in 1966 due to [[toxicity]].<ref name="Sneader2005" /><ref name="HarrapDavis2012" /> Its steroidogenesis-inhibiting properties were discovered serendipitously and it was subsequently repurposed for use in the treatment of Cushing's syndrome, breast cancer, and prostate cancer from 1969 and thereafter.<ref name="Patrick2013" /><ref name="HarrapDavis2012" /><ref name="Osborne2012" /> However, although used in the past, it has mostly been superseded by newer agents with better efficacy and lower toxicity such as [[ketoconazole]], [[abiraterone acetate]], and [[aromatase inhibitor]]s.<ref name="FiggChau2010" /><ref name="Patrick2013" /> It remains marketed only in a few countries.<ref name="Drugs.com">https://www.drugs.com/international/aminoglutethimide.html</ref><ref name="Llewellyn2011" />
AG was introduced for medical use, as an anticonvulsant, in 1960.<ref name="Sneader2005" /><ref name="HarrapDavis2012" /> It was withdrawn in 1966 due to [[toxicity]].<ref name="Sneader2005" /><ref name="HarrapDavis2012" /> Its steroidogenesis-inhibiting properties were discovered serendipitously and it was subsequently repurposed for use in the treatment of Cushing's syndrome, breast cancer, and prostate cancer from 1969 and thereafter.<ref name="Patrick2013" /><ref name="HarrapDavis2012" /><ref name="Osborne2012" /> However, although used in the past, it has mostly been superseded by newer agents with better [[efficacy]] and lower toxicity such as [[ketoconazole]], [[abiraterone acetate]], and other aromatase inhibitors.<ref name="FiggChau2010" /><ref name="Patrick2013" /> It remains marketed only in a few countries.<ref name="Drugs.com">{{Cite web|url=https://www.drugs.com/drug-class/aromatase-inhibitors.html|title=List of Aromatase inhibitors|website=Drugs.com}}</ref><ref name="Llewellyn2011" />


==Medical uses==
==Medical uses==
AG is used as an anticonvulsant in the treatment of [[petit mal epilepsy]] and as a steroidogenesis inhibitor in the treatment of Cushing's syndrome, [[postmenopausal|postmenopausal]] breast cancer, and prostate cancer.<ref name="Castro2013">{{cite book|author=J.E. Castro|title=The Treatment of Prostatic Hypertrophy and Neoplasia|url=https://books.google.com/books?id=Nc8hBQAAQBAJ&pg=PA179|date=9 March 2013|publisher=Springer Science & Business Media|isbn=978-94-015-7190-6|pages=179–}}</ref><ref name="Osborne2012" /><ref name="Sneader2005" /><ref name="Llewellyn2011" /> It is also used to treat [[secondary hyperaldosteronism]], [[edema]], [[adrenocortical carcinoma]], and [[ectopia (medicine)|ectopic]] [[adrenocorticotropic hormone]] (ACTH) producing [[tumor]]s.<ref name="MortonHall2012" /><ref name="TindallSedrak2013" /><ref name="Krieger2012">{{cite book|author=D. T. Krieger|title=Cushing’s Syndrome|url=https://books.google.com/books?id=b663BgAAQBAJ&pg=PT200|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-81659-8|pages=200–201}}</ref> When used as a steroidogenesis inhibitor to treat breast cancer and prostate cancer, AG is given in combination with [[hydrocortisone]], [[prednisone]], or an equivalent [[corticosteroid]] to prevent [[adrenal insufficiency]].<ref name="FiggChau2010" /><ref name="Osborne2012" /> AG is a second- or third-line choice in the treatment of [[hormone-sensitive cancer|hormone-sensitive]] [[metastatic]] breast cancer. While effective in the treatment of breast cancer in postmenopausal women, it is not effective in [[premenopause|premenopausal]] women and is not an effective [[ovary|ovarian]] steroidogenesis inhibitor, probably because it is not a [[potency (pharmacology)|potent]] enough [[aromatase inhibitor]].<ref name="Osborne2012" /><ref name="Priestman2012" /> The medication is effective in the treatment of prostate cancer, but its effectiveness is low and inconsistent, likely due to its relatively weak steroidogenesis inhibition and poor [[pharmacokinetics]].<ref name="Osborne2012" /> Nonetheless, AG was found to be non-significantly different in effectiveness from [[surgical adrenalectomy]] in terms of prostate cancer [[tumor]] regression.<ref name="Osborne2012" /> In any case, AG is not recommended as a first-line therapy in prostate cancer, but instead only as a second-line therapy.<ref name="Osborne2012" /><ref name="Priestman2012" /> It has only rarely been used in the treatment of prostate cancer.<ref name="FiggChau2010" />
AG is used as an anticonvulsant in the treatment of [[petit mal epilepsy]] and as a steroidogenesis inhibitor in the treatment of Cushing's syndrome, [[postmenopausal]] breast cancer, and prostate cancer.<ref name="Castro2013">{{cite book| vauthors = Hendy WF | chapter = Adrenalectomy and hypophysectomy in disseminated prostate cancer | veditors = Castro JE |title=The Treatment of Prostatic Hypertrophy and Neoplasia| chapter-url=https://books.google.com/books?id=Nc8hBQAAQBAJ&pg=PA179|year=2013|publisher=Springer Science & Business Media|isbn=978-94-015-7190-6|pages=179–}}</ref><ref name="Osborne2012" /><ref name="Sneader2005" /><ref name="Llewellyn2011" /> It is also used to treat [[secondary hyperaldosteronism]], [[edema]], [[adrenocortical carcinoma]], and [[ectopia (medicine)|ectopic]] [[adrenocorticotropic hormone]] (ACTH) producing [[tumor]]s.<ref name="MortonHall2012" /><ref name="TindallSedrak2013" /><ref name="Krieger2012">{{cite book| vauthors = Krieger DT | chapter = Chapter 8: Treatment of Cushing's Disease and Syndrome: Adrenocortical Carcinoma: Aminoglutethimide |title=Cushing's Syndrome| chapter-url = https://books.google.com/books?id=b663BgAAQBAJ&pg=PT200|year=1982|publisher=Springer Science & Business Media|isbn=978-3-642-81659-8|pages=120}}</ref> When used as a steroidogenesis inhibitor to treat breast cancer and prostate cancer, AG is given in combination with [[hydrocortisone]], [[prednisone]], or an equivalent [[corticosteroid]] to prevent [[adrenal insufficiency]].<ref name="FiggChau2010" /><ref name="Osborne2012" /> AG is a second- or third-line choice in the treatment of [[hormone-sensitive cancer|hormone-sensitive]] [[metastatic]] breast cancer. While effective in the treatment of breast cancer in postmenopausal women, it is not effective in [[premenopause|premenopausal]] women and is not an effective [[ovary|ovarian]] steroidogenesis inhibitor, probably because it is not a [[potency (pharmacology)|potent]] enough [[aromatase inhibitor]].<ref name="Osborne2012" /><ref name="Priestman2012" /> The medication is effective in the treatment of prostate cancer, but its effectiveness is low and inconsistent, likely due to its relatively weak steroidogenesis inhibition and poor [[pharmacokinetics]].<ref name="Osborne2012" /> Nonetheless, AG was found to be non-significantly different in effectiveness from [[surgical adrenalectomy]] in terms of prostate cancer [[tumor]] regression.<ref name="Osborne2012" /> In any case, AG is not recommended as a first-line therapy in prostate cancer, but instead only as a second-line therapy.<ref name="Osborne2012" /><ref name="Priestman2012" /> It has only rarely been used in the treatment of prostate cancer.<ref name="FiggChau2010" />


AG is used for adrenal steroidogenesis inhibition [[oral administration|by mouth]] at a dosage of 250&nbsp;mg three times per day (750&nbsp;mg/day total) for the first 3&nbsp;weeks of therapy and then increased to 250&nbsp;mg four times per day (1,000&nbsp;mg/day total) thereafter.<ref name="FiggChau2010" /> It can be used at a dosage of up to 500&nbsp;mg four times per day (2,000&nbsp;mg/day).<ref name="TindallSedrak2013" /><ref name="WilkesBarton-Burke2013" /> It is used as an [[aromatase inhibitor]] to inhibit [[:wikt:periphery|peripheral]] estrogen production by mouth at a dosage of 125&nbsp;mg twice per day (250&nbsp;mg/day total), without significant suppression of adrenal steroidogenesis at this dosage.<ref name="Priestman2012" /> Maximal aromatase inhibition is said to occur between dosages of 250 to 500&nbsp;mg per day.<ref name="Llewellyn2011" /> The side effects of AG are less frequent and severe at this dosage.<ref name="Priestman2012" /> However, they are still less when AG is combined with hydrocortisone, and so AG is generally combined with a corticosteroid even at this lower dosage.<ref name="Priestman2012" /> AG should only be used under close [[medical supervision]] and with [[laboratory test]]s including [[thyroid function]], [[baseline hematological]], [[serum glutamic-oxaloacetic transaminase]], [[alkaline phosphatase]], and [[bilirubin]].<ref name="TindallSedrak2013" /><ref name="WilkesBarton-Burke2013" />
AG is used for adrenal steroidogenesis inhibition [[oral administration|by mouth]] at a dosage of 250&nbsp;mg three times per day (750&nbsp;mg/day total) for the first 3&nbsp;weeks of therapy and then increased to 250&nbsp;mg four times per day (1,000&nbsp;mg/day total) thereafter.<ref name="FiggChau2010" /> It can be used at a dosage of up to 500&nbsp;mg four times per day (2,000&nbsp;mg/day).<ref name="TindallSedrak2013" /><ref name="WilkesBarton-Burke2013" /> It is used as an [[aromatase inhibitor]] to inhibit [[:wikt:periphery|peripheral]] estrogen production by mouth at a dosage of 125&nbsp;mg twice per day (250&nbsp;mg/day total), without significant suppression of adrenal steroidogenesis at this dosage.<ref name="Priestman2012" /> Maximal aromatase inhibition is said to occur between dosages of 250 to 500&nbsp;mg per day.<ref name="Llewellyn2011" /> The side effects of AG are less frequent and severe at this dosage.<ref name="Priestman2012" /> However, they are still less when AG is combined with hydrocortisone, and so AG is generally combined with a corticosteroid even at this lower dosage.<ref name="Priestman2012" /> AG should only be used under close [[medical supervision]] and with [[laboratory test]]s including [[thyroid function]], [[baseline hematological]], [[serum glutamic-oxaloacetic transaminase]], [[alkaline phosphatase]], and [[bilirubin]].<ref name="TindallSedrak2013" /><ref name="WilkesBarton-Burke2013" />


[[Ketoconazole]] can achieve similar decreases in steroid hormone levels as AG but is more effective in promoting [[tumor]] regression and is moderately less toxic in comparison.<ref name="FiggChau2010" /> AG remains useful in those who have failed or are unable to [[tolerability|tolerate]] ketoconazole and other therapies however.<ref name="FiggChau2010" />
[[Ketoconazole]] can achieve similar decreases in steroid hormone levels as AG but is more effective in promoting [[tumor]] regression and is moderately less toxic in comparison.<ref name="FiggChau2010" /> AG can still be a useful alternative in those who have failed or are unable to [[tolerability|tolerate]] ketoconazole and other therapies however.<ref name="FiggChau2010" />


===Available forms===
===Available forms===
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==Non-medical uses==
==Non-medical uses==
AG is used by [[bodybuilder]]s, [[athlete]]s, and other men to lower circulating levels of [[cortisol]] in the body and thereby prevent [[muscle atrophy|muscle loss]].<ref name="Llewellyn2011" /><ref name="TindallSedrak2013" /> Cortisol is [[catabolic]] to [[protein]] in [[muscle]] and effective suppression of cortisol by AG at high doses can prevent muscle loss.<ref name="Llewellyn2011" /> It is usually used in combination with an [[anabolic steroid]] to avoid [[androgen deficiency]].<ref name="Llewellyn2011" /> However, the usefulness of AG for such purposes has been questioned, with few users reportedly having positive comments about it, and the risks of AG are said to be severe.<ref name="Llewellyn2011" /><ref name="TindallSedrak2013" /> In any case, AG is also used by bodybuilders and other men for its actions as an aromatase inhibitor in order to decrease estrogen levels.<ref name="Llewellyn2011" /> It is said to be useful for inhibiting the estrogenic side effects of certain anabolic steroids such as [[gynecomastia]], increased [[water retention (medicine)|water retention]], and [[weight gain|fat gain]].<ref name="Llewellyn2011" />
AG is used by [[bodybuilder]]s, [[athlete]]s, and other men to lower circulating levels of [[cortisol]] in the body and thereby prevent [[muscle atrophy|muscle loss]].<ref name="Llewellyn2011" /><ref name="TindallSedrak2013" /> Cortisol is [[catabolic]] to [[protein]] in [[muscle]] and effective suppression of cortisol by AG at high doses can prevent muscle loss.<ref name="Llewellyn2011" /> It is usually used in combination with an [[anabolic steroid]] to avoid [[androgen deficiency]].<ref name="Llewellyn2011" /> However, the usefulness of AG for such purposes has been questioned, with few users reportedly having positive comments about it, and the risks of AG are said to be high.<ref name="Llewellyn2011" /><ref name="TindallSedrak2013" /> In any case, AG is also used by bodybuilders and other men for its actions as an aromatase inhibitor in order to decrease estrogen levels.<ref name="Llewellyn2011" /> It is said to be useful for inhibiting the estrogenic side effects of certain anabolic steroids such as [[gynecomastia]], increased [[water retention (medicine)|water retention]], and [[weight gain|fat gain]].<ref name="Llewellyn2011" />


==Contraindications==
==Contraindications==
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==Side effects==
==Side effects==
AG has many [[side effect]]s and is a relatively [[toxicity|toxic]] medication, although its side effects are described as usually relatively mild.<ref name="FiggChau2010" /><ref name="Osborne2012" /> The side effects of AG include [[lethargy]], [[fatigue (medical)|fatigue]], [[weakness]], [[malaise]], [[drowsiness]], [[somnolence]], [[depression (mood)|depression]], [[apathy]], [[sleep disturbance]]s, [[stomach discomfort]], [[nausea]], [[vomiting]] [[ataxia]], [[joint pain|joint aches and pains]], [[fever]], [[skin rash]], [[hypotension]] or [[hypertension]], [[high cholesterol levels]], [[virilization]], [[hypothyroidism]], [[thyroid abnormalities]], [[elevated liver enzymes]], [[jaundice]], [[hepatotoxicity]], [[weight gain]], [[leg cramp]]s, [[personality changes]], [[blood dyscrasia]]s, and [[adrenal insufficiency]] (e.g., [[hyponatremia]], [[hypoglycemia]], others).<ref name="FiggChau2010" /><ref name="Osborne2012" /><ref name="Priestman2012" /><ref name="Llewellyn2011" /><ref name="TindallSedrak2013" /><ref name="WilkesBarton-Burke2013" /> Lethargy is the most common side effect and has been found to occur in 31 to 70% of people treated with AG.<ref name="Osborne2012" /> It is the most common reason for discontinuation of AG.<ref name="Osborne2012" /> Skin rash and hypotension have both been observed in about 15% of people.<ref name="Osborne2012" /> At least one side effect will occur in 45 to 85% of people.<ref name="Osborne2012" /> Severe toxicity is seen in 10% of people, including [[circulatory collapse]] thought to be due to adrenal insufficiency.<ref name="Osborne2012" /> [[Hematological toxicity|Hematological]] and [[bone marrow toxicity]], including marked depression of [[white blood cell count]], [[platelet]]s, or both, occurs rarely, with an incidence of about 0.9%.<ref name="Osborne2012" /><ref name="PonderWaring2012">{{cite book|author1=B.A. Ponder|author2=M.J. Waring|title=The Science of Cancer Treatment|url=https://books.google.com/books?id=EbGvBQAAQBAJ&pg=PA48|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-009-0709-6|pages=48–}}</ref> It is usually seen within the first 7&nbsp;weeks of treatment and resolves within 3&nbsp;weeks following discontinuation.<ref name="Osborne2012" /> AG is discontinued in 5 to 10% of people due to intolerable side effects.<ref name="Osborne2012" /> The [[central nervous system]] side effects of AG are due to its nature as an anticonvulsant and relation to [[glutethimide]].<ref name="Priestman2012" />
AG has many [[side effect]]s and is a relatively [[toxicity|toxic]] medication, although its side effects are described as usually relatively mild.<ref name="FiggChau2010" /><ref name="Osborne2012" /> The side effects of AG include [[lethargy]], [[fatigue (medical)|fatigue]], [[weakness]], [[malaise]], [[drowsiness]], [[somnolence]], [[depression (mood)|depression]], [[apathy]], [[sleep disturbance]]s, [[stomach discomfort]], [[nausea]], [[vomiting]], [[ataxia]], [[joint pain|joint aches and pains]], [[fever]], [[skin rash]], [[hypotension]] or [[hypertension]], [[high cholesterol levels]], [[virilization]], [[hypothyroidism]], [[thyroid abnormalities]], [[elevated liver enzymes]], [[jaundice]], [[hepatotoxicity]], [[weight gain]], [[leg cramp]]s, [[personality changes]], [[blood dyscrasia]]s, and [[adrenal insufficiency]] (e.g., [[hyponatremia]], [[hypoglycemia]], others).<ref name="FiggChau2010" /><ref name="Osborne2012" /><ref name="Priestman2012" /><ref name="Llewellyn2011" /><ref name="TindallSedrak2013" /><ref name="WilkesBarton-Burke2013" /> Lethargy is the most common side effect and has been found to occur in 31 to 70% of people treated with AG.<ref name="Osborne2012" /> It is the most common reason for discontinuation of AG.<ref name="Osborne2012" /> Skin rash and hypotension have both been observed in about 15% of people.<ref name="Osborne2012" /> At least one side effect will occur in 45 to 85% of people.<ref name="Osborne2012" /> Severe toxicity is seen in 10% of people, including [[circulatory collapse]] thought to be due to adrenal insufficiency.<ref name="Osborne2012" /> [[Hematological toxicity|Hematological]] and [[bone marrow toxicity]], including marked depression of [[white blood cell count]], [[platelet]]s, or both, occurs rarely, with an incidence of about 0.9%.<ref name="Osborne2012" /><ref name="PonderWaring2012">{{cite book| vauthors = Waxman J, Jane N | chapter = New endocrine therapies for cancer | veditors = Ponder BA, Waring MJ |title=The Science of Cancer Treatment| chapter-url = https://books.google.com/books?id=EbGvBQAAQBAJ&pg=PA48|year=2012|publisher=Springer Science & Business Media|isbn=978-94-009-0709-6|pages=48–}}</ref> It is usually seen within the first 7&nbsp;weeks of treatment and resolves within 3&nbsp;weeks following discontinuation.<ref name="Osborne2012" /> AG is discontinued in 5 to 10% of people due to intolerable side effects.<ref name="Osborne2012" /> The [[central nervous system]] side effects of AG are due to its nature as an anticonvulsant and relation to [[glutethimide]].<ref name="Priestman2012" />


==Overdose==
==Overdose==
In the event of [[overdose]] of AG, [[drowsiness]], [[nausea]], [[vomiting]], [[hypotension]], and [[respiratory depression]] may occur.<ref name="Upfal2006">{{cite book|author=Jonathan Upfal|title=The Australian Drug Guide: Every Person's Guide to Prescription and Over-the-counter Medicines, Street Drugs, Vaccines, Vitamins and Minerals...|url=https://books.google.com/books?id=7O9kiqN2q2YC&pg=PA45|year=2006|publisher=Black Inc.|isbn=978-1-86395-174-6|pages=45–}}</ref><ref name="Springhouse2000">{{cite book|title=Nurse Practitioner's Drug Handbook|url=https://books.google.com/books?id=I6Jt1THMB_4C|year=2000|publisher=Springhouse Corp.|pages=40–41}}</ref> Medical attention should be sought urgently.<ref name="Upfal2006" /> Treatment of AG overdose can include [[gastric lavage]] to decrease [[absorption (pharmacokinetics)|absorption]] and [[dialysis]] to enhance [[elimination (pharmacology)|elimination]].<ref name="Convention2006">{{cite book|author=United States Pharmacopeial Convention|title=USP DI: United States Pharmacopeia Dispensing Information|url=https://books.google.com/books?id=hMpKAQAAIAAJ|year=2006|publisher=United States Pharmacopeial Convention|isbn=978-1-56363-429-1|pages=75–76}}</ref>
In the event of [[overdose]] of AG, [[drowsiness]], [[nausea]], [[vomiting]], [[hypotension]], and [[respiratory depression]] may occur.<ref name="Upfal2006">{{cite book| vauthors = Upfal J |title=The Australian Drug Guide: Every Person's Guide to Prescription and Over-the-counter Medicines, Street Drugs, Vaccines, Vitamins and Minerals...|url=https://books.google.com/books?id=7O9kiqN2q2YC&pg=PA45|year=2006|publisher=Black Inc.|isbn=978-1-86395-174-6|pages=45–}}</ref><ref name="Springhouse2000">{{cite book|title=Nurse Practitioner's Drug Handbook|url=https://books.google.com/books?id=I6Jt1THMB_4C|year=2000|publisher=Springhouse Corp.|pages=40–41|isbn = 9780874349979}}</ref> Medical attention should be sought urgently.<ref name="Upfal2006" /> Treatment of AG overdose can include [[gastric lavage]] to decrease [[absorption (pharmacokinetics)|absorption]] and [[Kidney dialysis|dialysis]] to enhance [[elimination (pharmacology)|elimination]].<ref name="Convention2006">{{cite book|author=United States Pharmacopeial Convention|title=USP DI: United States Pharmacopeia Dispensing Information|url=https://books.google.com/books?id=hMpKAQAAIAAJ|year=2006|publisher=United States Pharmacopeial Convention|isbn=978-1-56363-429-1|pages=75–76}}</ref>


==Interactions==
==Interactions==
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===Pharmacodynamics===
===Pharmacodynamics===
AG is a [[potency (pharmacology)|potent]] and [[binding selectivity|non-selective]] [[steroidogenesis inhibitor]], acting as a [[reversible inhibitor|reversible]] and [[competitive inhibitor]] of multiple [[steroidogenic enzyme]]s including:<ref name="Patrick2013" /><ref name="SmithWilliams2005">{{cite book|author1=H. John Smith|author2=Hywel Williams|title=Smith and Williams' Introduction to the Principles of Drug Design and Action, Fourth Edition|url=https://books.google.com/books?id=P2W6B9FQRKsC&pg=PA281|date=10 October 2005|publisher=CRC Press|isbn=978-0-203-30415-0|pages=281–}}</ref><ref name="Ebadi2007">{{cite book|author=Manuchair Ebadi|title=Desk Reference of Clinical Pharmacology, Second Edition|url=https://books.google.com/books?id=ihxyHbnj3qYC&pg=PA63|date=31 October 2007|publisher=CRC Press|isbn=978-1-4200-4744-8|pages=63–}}</ref><ref name="Osborne2012">{{cite book|author=C. Kent Osborne|title=Endocrine Therapies in Breast and Prostate Cancer|url=https://books.google.com/books?id=gW0eBAAAQBAJ&pg=PA87|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-1-4613-1731-9|pages=39,73,87–93}}</ref><ref name="Llewellyn2011" />
AG is a [[potency (pharmacology)|potent]] and [[binding selectivity|non-selective]] [[steroidogenesis inhibitor]], acting as a [[reversible inhibitor|reversible]] and [[competitive inhibitor]] of multiple [[steroidogenic enzyme]]s, including:<ref name="Patrick2013" /><ref name="SmithWilliams2005">{{cite book| vauthors = Patel A, Smith HJ, Steinmetzer T | chapter = Design of Enzyme Inhibitors and Drugs | veditors = Smith HJ, Williams W |title=Smith and Williams' Introduction to the Principles of Drug Design and Action | edition = Fourth | chapter-url = https://books.google.com/books?id=P2W6B9FQRKsC&pg=PA281|year=2005|publisher=CRC Press|isbn=978-0-203-30415-0|pages=281–}}</ref><ref name="Ebadi2007">{{cite book| vauthors = Ebadi M | chapter = Aminoglutethimide |title=Desk Reference of Clinical Pharmacology, Second Edition| chapter-url=https://books.google.com/books?id=ihxyHbnj3qYC&pg=PA63|year=2007|publisher=CRC Press|isbn=978-1-4200-4744-8|pages=63–}}</ref><ref name="Osborne2012">{{cite book| vauthors = Havlin KA, Trump DL | title = Aminoglutethimide: theoretical considerations and clinical results in advanced prostate cancer | veditors = Osborne CK | chapter = Endocrine Therapies in Breast and Prostate Cancer|chapter-url=https://books.google.com/books?id=gW0eBAAAQBAJ&pg=PA87|year=2012|publisher=Springer Science & Business Media|isbn=978-1-4613-1731-9|pages=39, 73, 87–93}}</ref><ref name="Llewellyn2011" />


* [[Aromatase]] (CYP19A1) (600&nbsp;nM).<ref name="FiggChau2010" /><ref name="pmid17602675">{{cite journal |vauthors =Siraki AG, Bonini MG, Jiang J, Ehrenshaft M, Mason RP |title=Aminoglutethimide-induced protein free radical formation on myeloperoxidase: a potential mechanism of agranulocytosis |journal=[[Chemical research in toxicology]] |volume=20 |issue=7 |pages=1038–45 |date=July 2007 |pmid=17602675 |pmc=2073000 |doi=10.1021/tx6003562}}</ref> Inhibits the formation of the [[estrogen]]s [[estradiol]] and [[estrone]] from [[testosterone]] and [[androstenedione]], respectively.
* [[Aromatase]] (CYP19A1) (600&nbsp;nM).<ref name="FiggChau2010" /><ref name="pmid17602675">{{cite journal |vauthors =Siraki AG, Bonini MG, Jiang J, Ehrenshaft M, Mason RP |title=Aminoglutethimide-induced protein free radical formation on myeloperoxidase: a potential mechanism of agranulocytosis |journal=[[Chemical Research in Toxicology]] |volume=20 |issue=7 |pages=1038–45 |date=July 2007 |pmid=17602675 |pmc=2073000 |doi=10.1021/tx6003562}}</ref> Inhibits the formation of the [[estrogen]]s [[estradiol]] and [[estrone]] from [[testosterone]] and [[androstenedione]], respectively.
* [[Cholesterol side-chain cleavage enzyme]] (P450scc; CYP11A1) (~20,000&nbsp;nM).<ref name="FiggChau2010" /><ref name="Osborne2012" /> Inhibits the conversion of [[cholesterol]] into [[pregnenolone]] and consequently decreases the synthesis of all [[steroid hormone]]s including the [[progestogen]]s, [[androgen]]s, [[estrogen]]s, [[glucocorticoid]]s, and [[mineralocorticoid]]s, as well as [[neurosteroid]]s.
* [[Cholesterol side-chain cleavage enzyme]] (P450scc; CYP11A1) (~20,000&nbsp;nM).<ref name="FiggChau2010" /><ref name="Osborne2012" /> Inhibits the conversion of [[cholesterol]] into [[pregnenolone]] and consequently decreases the synthesis of all [[steroid hormone]]s including the [[progestogen]]s, [[androgen]]s, [[glucocorticoid]]s, and [[mineralocorticoid]]s, as well as [[neurosteroid]]s.
* [[21-Hydroxylase]] (CYP21A2).<ref name="Llewellyn2011" /> Prevents the conversion of [[progesterone]] and [[17αあるふぁ-hydroxyprogesterone]] into [[11-deoxycorticosterone]] and [[11-deoxycortisol]], respectively.
* [[21-Hydroxylase]] (CYP21A2).<ref name="Llewellyn2011" /> Prevents the conversion of [[progesterone]] and [[17αあるふぁ-hydroxyprogesterone]] into [[11-deoxycorticosterone]] and [[11-deoxycortisol]], respectively.
* [[Steroid 11βべーた-hydroxylase|11βべーた-Hydroxylase|]] (CYP11B1).<ref name="Osborne2012" /><ref name="Llewellyn2011" /><ref name="HaschekBolon2017">{{cite book|author1=Wanda M. Haschek|author2=Brad Bolon|author3=Colin G. Rousseaux|author4=Matthew A. Wallig|title=Fundamentals of Toxicologic Pathology|url=https://books.google.com/books?id=M4yZDgAAQBAJ&pg=PA580|date=25 October 2017|publisher=Elsevier Science|isbn=978-0-12-809842-4|pages=580–}}</ref> Prevents the conversion of [[11-deoxycorticosterone]] and [[11-deoxycortisol]] into [[corticosterone]] and [[cortisol]], respectively.
* [[Steroid 11βべーた-hydroxylase|11βべーた-Hydroxylase]] (CYP11B1).<ref name="Osborne2012" /><ref name="Llewellyn2011" /><ref name="HaschekBolon2017">{{cite book| vauthors = Wallig MA | chapter = Endocrine System | veditors = Haschek WM, Bolon B, Rousseaux CG, Wallig MA |title=Fundamentals of Toxicologic Pathology| chapter-url = https://books.google.com/books?id=M4yZDgAAQBAJ&pg=PA580|year=2017|publisher=Elsevier Science|isbn=978-0-12-809842-4|pages=580–}}</ref> Prevents the conversion of [[11-deoxycorticosterone]] and [[11-deoxycortisol]] into [[corticosterone]] and [[cortisol]], respectively.
⚫
* [[Aldosterone synthase]] (18-hydroxylase; CYP11B2).<ref name="Osborne2012" /><ref name="Llewellyn2011" /> Prevents the conversion of corticosterone into [[aldosterone]].<ref name="ThomasKeenan2012">{{cite book| vauthors = Thomas JA, Keenan EJ | chapter = Effects of Drugs on the Endocrine System |title=Principles of Endocrine Pharmacology| chapter-url=https://books.google.com/books?id=mTagBQAAQBAJ&pg=PA278|year=2012|publisher=Springer Science & Business Media|isbn=978-1-4684-5036-1|pages=278–}}</ref>
* [[Aldosterone synthase]] (18-hydroxylase).<ref name="Osborne2012" /><ref name="Llewellyn2011" />


As such, AG is an [[estrogen synthesis inhibitor]] and [[adrenal steroidogenesis inhibitor]], including both an [[androgen synthesis inhibitor]] and a [[corticosteroid synthesis inhibitor]].<ref name="Patrick2013" /><ref name="SmithWilliams2005" /><ref name="Ebadi2007" /><ref name="Osborne2012" /><ref name="Llewellyn2011" /> For these reasons, AG has functional [[antiestrogen]]ic, [[antiandrogen]]ic, [[antiglucocorticoid]], and [[antimineralocorticoid]] actions.<ref name="Patrick2013" /><ref name="SmithWilliams2005" /><ref name="Ebadi2007" /><ref name="Osborne2012" /><ref name="Llewellyn2011" /> In terms of its actions as an adrenal steroidogenesis inhibitor, it is described as a form of reversible "medical adrenalectomy" or "chemical adrenalectomy".<ref name="FiggChau2010" /><ref name="Osborne2012" /><ref name="WilkesBarton-Burke2013">{{cite book| vauthors = Wilkes GM, Barton-Burke M | chapter = Introduction to Chemotherapy Drugs |title=2014 Oncology Nursing Drug Handbook| chapter-url=https://books.google.com/books?id=sM2FAgAAQBAJ&pg=PA50|year=2013|publisher=Jones & Bartlett Publishers|isbn=978-1-284-05374-6|pages=50–52}}</ref> While AG inhibits all of the enzymes listed above, inhibition of P450scc is primarily responsible for its inhibition of [[adrenal gland|adrenal]] [[steroidogenesis]].<ref name="JonesMohr2012">{{cite book | vauthors = Zak F | chapter = Lipid Hyperplasia, Adrenal Cortex, Rat | series = Monographs on Pathology of Laboratory Animals | veditors = Jones TC, Mohr U, Hunt RD |title=Endocrine System| chapter-url = https://books.google.com/books?id=UTfvCAAAQBAJ&pg=PA83|year=2012|publisher=Springer Science & Business Media|isbn=978-3-642-96720-7|pages=83– | doi = 10.1007/978-3-642-60996-1_65 }}</ref> In terms of [[adrenal androgen]]s, AG has been shown to significantly suppress [[dehydroepiandrosterone sulfate]], [[androstenedione]], testosterone, and [[dihydrotestosterone]] levels in men.<ref name="Osborne2012" /> Although it is most potent in inhibiting aromatase among the enzymes it targets, AG is described nonetheless as a relatively weak [[aromatase inhibitor]].<ref name="Ebadi2007" /><ref name="FiggChau2010" /> In addition, it is described as a much more potent aromatase inhibitor than adrenal steroidogenesis inhibitor.<ref name="Priestman2012">{{cite book| vauthors = Priestman TJ |title=Cancer Chemotherapy: an Introduction|url=https://books.google.com/books?id=wGlyBgAAQBAJ&pg=PT178|year=2012|publisher=Springer Science & Business Media|isbn=978-1-4471-1686-8|pages=178–}}</ref> AG can inhibit aromatase by 74 to 92% and decrease circulating estradiol levels by 58 to 76% in men and postmenopausal women.<ref name="TindallSedrak2013" /><ref name="Llewellyn2011" /> AG is not an effective [[ovary|ovarian]] steroidogenesis inhibitor in premenopausal women.<ref name="Priestman2012" /> However, interference with ovarian steroidogenesis by AG may in any case result in [[hyperandrogenism]] and [[virilization]] in premenopausal women.<ref name="WilkesBarton-Burke2013" /><ref name="Llewellyn2011" />
⚫
The production of steroid hormones downstream of 11-deoxycorticosterone and corticosterone such as [[aldosterone]] is also inhibited.<ref name="ThomasKeenan2012">{{cite book|author1=John A. Thomas|author2=Edward J. Keenan|title=Principles of Endocrine Pharmacology|url=https://books.google.com/books?id=mTagBQAAQBAJ&pg=PA278|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-1-4684-5036-1|pages=278–}}</ref>


{{Pharmacodynamics of aromatase inhibitors}}
AG is described as an [[adrenal gland|adrenal]] steroidogenesis inhibitor, including of [[adrenal androgen]]s and [[corticosteroid]]s, and as a form of "medical adrenalectomy" or "chemical adrenalectomy".<ref name="FiggChau2010" /><ref name="Osborne2012" /><ref name="WilkesBarton-Burke2013">{{cite book|author1=Gail M. Wilkes|author2=Margaret Barton-Burke|title=2014 Oncology Nursing Drug Handbook|url=https://books.google.com/books?id=sM2FAgAAQBAJ&pg=PA50|date=27 November 2013|publisher=Jones & Bartlett Publishers|isbn=978-1-284-05374-6|pages=50–52}}</ref> While AG inhibits all of the above-listed enzymes, inhibition of P450scc is primarily responsible for its inhibition of adrenal steroidogenesis.<ref name="JonesMohr2012">{{cite book|author1=T.C. Jones|author2=U. Mohr|author3=R.D. Hunt|title=Endocrine System|url=https://books.google.com/books?id=UTfvCAAAQBAJ&pg=PA83|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-96720-7|pages=83–}}</ref> In terms of androgens, AG has been shown to significantly suppress [[dehydroepiandrosterone sulfate]], [[androstenedione]], testosterone, and [[dihydrotestosterone]] levels in men.<ref name="Osborne2012" />

Although it is most potent in inhibiting aromatase among the enzymes it targets, AG is described nonetheless as a relatively weak [[aromatase inhibitor]].<ref name="Ebadi2007" /><ref name="FiggChau2010" /> In addition, it is said to be a "much more powerful" aromatase inhibitor than adrenal steroidogenesis inhibitor.<ref name="Priestman2012">{{cite book|author=Terry J. Priestman|title=Cancer Chemotherapy: an Introduction|url=https://books.google.com/books?id=wGlyBgAAQBAJ&pg=PT178|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-1-4471-1686-8|pages=178–}}</ref> AG can inhibit aromatase by 74 to 92% and decrease circulating estradiol levels by 58 to 76% in men and postmenopausal women.<ref name="TindallSedrak2013" /><ref name="Llewellyn2011" /> AG is not an effective [[ovary|ovarian]] steroidogenesis inhibitor in premenopausal women.<ref name="Priestman2012" /> However, interference with ovarian steroidogenesis may result in [[hyperandrogenism]] and [[virilization]] in premenopausal women.<ref name="WilkesBarton-Burke2013" /><ref name="Llewellyn2011" />


===Pharmacokinetics===
===Pharmacokinetics===
With [[oral administration]], the [[absorption (pharmacokinetics)|absorption]] of AG is rapid and complete.<ref name="TindallSedrak2013">{{cite book|author1=William N Tindall|author2=Mona Sedrak|author3=John Boltri|title=Patient-Centered Pharmacology: Learning System for the Conscientious Prescribe|url=https://books.google.com/books?id=-Q_TAQAAQBAJ&pg=PA218|date=6 August 2013|publisher=F.A. Davis|isbn=978-0-8036-4070-2|pages=218–}}</ref> It is [[distribution (pharmacology)|well-distributed]] throughout the body.<ref name="TindallSedrak2013" /> In terms of [[metabolism]], a portion of AG is [[acetylation|acetylated]] in the [[liver]].<ref name="TindallSedrak2013" /> The [[biological half-life]] of AG is 12.5&nbsp;hours.<ref name="TindallSedrak2013" /> It is [[excretion|excreted]] in [[urine]] 34 to 54% unchanged.<ref name="TindallSedrak2013" />
With [[oral administration]], the [[absorption (pharmacokinetics)|absorption]] of AG is rapid and complete.<ref name="TindallSedrak2013">{{cite book| vauthors = House AA, Tindall WN, Sedrak MM | chapter = Drugs Used to Treat Endocrine Gland Disorders | veditors = Tindall WN, Sedrak M, Boltri J |title=Patient-Centered Pharmacology: Learning System for the Conscientious Prescribe| chapter-url = https://books.google.com/books?id=-Q_TAQAAQBAJ&pg=PA218|year=2013|publisher=F.A. Davis|isbn=978-0-8036-4070-2|pages=218–}}</ref> It is [[distribution (pharmacology)|well-distributed]] throughout the body.<ref name="TindallSedrak2013" /> In terms of [[metabolism]], a portion of AG is [[acetylation|acetylated]] in the [[liver]].<ref name="TindallSedrak2013" /> The [[biological half-life]] of AG is 12.5&nbsp;hours.<ref name="TindallSedrak2013" /> It is [[excretion|excreted]] in [[urine]] 34 to 54% unchanged.<ref name="TindallSedrak2013" />


==Chemistry==
==Chemistry==
AG is a [[nonsteroidal]] [[chemical compound|compound]], specifically a [[glutarimide]], and is a [[chemical derivative|derivative]] of [[glutethimide]].<ref name="MortonHall2012" /><ref name="Sneader2005" /><ref name="Llewellyn2011" /> It is also known by its chemical names 2-(4-aminophenyl)-2-ethylglutarimide and 2-(aminophenyl)-3-ethylpiperidine-2,6-dione.<ref name="Elks2014" /><ref name="Llewellyn2011" /> Aside from glutethimide, AG is structurally related to [[rogletimide]] (pyridoglutethimide) and [[thalidomide]], as well as [[amphenone B]], [[metyrapone]], and [[mitotane]].<ref name="SmithWilliams2005">{{cite book|author1=H. John Smith|author2=Hywel Williams|title=Smith and Williams' Introduction to the Principles of Drug Design and Action, Fourth Edition|url=https://books.google.com/books?id=P2W6B9FQRKsC&pg=PA281|date=10 October 2005|publisher=CRC Press|isbn=978-0-203-30415-0|pages=281–}}</ref><ref name="Wiley-VCH2005">{{cite book|author=Wiley-VCH|title=Ullmann's Industrial Toxicology|url=https://books.google.com/books?id=r-4JAQAAMAAJ|date=28 October 2005|publisher=Wiley|isbn=978-3-527-31247-4|page=876}}</ref><ref name="Bentley1980">{{cite book|author=P. J. Bentley|title=Endocrine Pharmacology: Physiological Basis and Therapeutic Applications|url=https://books.google.com/books?id=W6M9AAAAIAAJ&pg=PA143|year=1980|publisher=CUP Archive|isbn=978-0-521-22673-8|pages=143,162–163}}</ref><ref name="Selye2013">{{cite book|author=Hans Selye|title=Stress in Health and Disease|url=https://books.google.com/books?id=wrfYBAAAQBAJ&pg=PA57|date=22 October 2013|publisher=Elsevier Science|isbn=978-1-4831-9221-5|pages=57–}}</ref><ref name="Sneader2005" />
AG is a [[nonsteroidal]] [[chemical compound|compound]], specifically a [[glutarimide]], and is a [[chemical derivative|derivative]] of [[glutethimide]].<ref name="MortonHall2012" /><ref name="Sneader2005" /><ref name="Llewellyn2011" /> It is also known by its chemical names 2-(4-aminophenyl)-2-ethylglutarimide and 2-(aminophenyl)-3-ethylpiperidine-2,6-dione.<ref name="Elks2014" /><ref name="Llewellyn2011" /> Aside from glutethimide, AG is structurally related to [[rogletimide]] (pyridoglutethimide) and [[thalidomide]], as well as [[amphenone B]], [[metyrapone]], and [[mitotane]].<ref name="SmithWilliams2005"/><ref name="Wiley-VCH2005">{{cite book |title=Ullmann's Industrial Toxicology|url=https://books.google.com/books?id=r-4JAQAAMAAJ|year=2005|publisher=Wiley|isbn=978-3-527-31247-4|page=876}}</ref><ref name="Bentley1980">{{cite book| vauthors = Bentley PJ | chapter = Steroid Hormones |title=Endocrine Pharmacology: Physiological Basis and Therapeutic Applications| chapter-url = https://books.google.com/books?id=W6M9AAAAIAAJ&pg=PA143|year=1980|publisher=CUP Archive|isbn=978-0-521-22673-8|pages=143, 162–163}}</ref><ref name="Selye2013">{{cite book | vauthors = Selye H | chapter = Stressors and Conditioning Agents |title=Stress in Health and Disease| chapter-url = https://books.google.com/books?id=wrfYBAAAQBAJ&pg=PA57 |year=2013|publisher=Elsevier Science|isbn=978-1-4831-9221-5|pages=57–}}</ref><ref name="Sneader2005" />


==History==
==History==
AG was introduced for medical use, as an [[anticonvulsant]], in 1960.<ref name="Sneader2005">{{cite book|author=Walter Sneader|title=Drug Discovery: A History|url=https://books.google.com/books?id=Cb6BOkj9fK4C&pg=PA367|date=23 June 2005|publisher=John Wiley & Sons|isbn=978-0-471-89979-2|pages=367–}}</ref><ref name="HarrapDavis2012">{{cite book|author1=K.R. Harrap|author2=W. Davis|author3=A.H. Calvert|title=Cancer Chemotherapy and Selective Drug Development: Proceedings of the 10th Anniversary Meeting of the Coordinating Committee for Human Tumour Investigations, Brighton, England, October 24–28, 1983|url=https://books.google.com/books?id=y3bjBwAAQBAJ&pg=PA481|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-1-4613-3837-6|pages=481–}}</ref> In 1963, it was reported that AG had induced symptoms of [[Addison's disease]] ([[adrenal insufficiency]]) in a young girl.<ref name="Sneader2005" /> Following additional reports, it was determined that AG acts as a steroidogenesis inhibitor.<ref name="Sneader2005" /> As such, the discovery of AG as a steroidogenesis inhibitor was serendipitous.<ref name="Patrick2013">{{cite book|author=Graham L. Patrick|title=An Introduction to Medicinal Chemistry|url=https://books.google.com/books?id=Pj7xJRuhZxUC&pg=PA208|date=10 January 2013|publisher=OUP Oxford|isbn=978-0-19-969739-7|pages=208–,539}}</ref> The medication was withdrawn from the market in 1966 due to its adverse effects.<ref name="Sneader2005" /><ref name="HarrapDavis2012" /> The first report of AG in the treatment of [[breast cancer]] was published in 1969, and the first report of AG in the treatment of [[prostate cancer]] was published in 1974.<ref name="HarrapDavis2012" /><ref name="Osborne2012" /> The medication was one of the first adrenal steroidogenesis inhibitors as well as the first aromatase inhibitor to be discovered and used clinically, and led to the development of other aromatase inhibitors.<ref name="PonderWaring2012" /><ref name="FiggChau2010" /><ref name="Furr2008">{{cite book|author=B.J.A. Furr|title=Aromatase Inhibitors|url=https://books.google.com/books?id=dyg9Ab3FsVgC&pg=PA4|date=28 March 2008|publisher=Springer Science & Business Media|isbn=978-3-7643-8693-1|pages=4,101,127}}</ref><ref name="Patrick2013" /> Along with [[testolactone]], it is described as a "first-generation" aromatase inhibitor.<ref name="Llewellyn2011" /> AG has largely been superseded by medications with better effectiveness and [[tolerability]] and reduced toxicity, such as [[ketoconazole]], [[abiraterone acetate]], and [[aromatase inhibitor]]s.<ref name="FiggChau2010" /><ref name="Osborne2012" /><ref name="Patrick2013" />
AG was introduced for medical use, as an [[anticonvulsant]], in 1960.<ref name="Sneader2005">{{cite book| vauthors = Sneader W | chapter = The First Synthetic Drugs and Their Analogues |title=Drug Discovery: A History| chapter-url=https://books.google.com/books?id=Cb6BOkj9fK4C&pg=PA367|year=2005|publisher=John Wiley & Sons|isbn=978-0-471-89979-2 | doi = 10.1002/0470015535.ch26 |pages=367–}}</ref><ref name="HarrapDavis2012">{{cite book| vauthors = Jackson IM | chapter = Aminoglutethimide (Orimeten): The Present and the Future | veditors = Harrap LR, Davis W, Calvert AH |title=Cancer Chemotherapy and Selective Drug Development: Proceedings of the 10th Anniversary Meeting of the Coordinating Committee for Human Tumour Investigations, Brighton, England, October 24–28, 1983| chapter-url=https://books.google.com/books?id=y3bjBwAAQBAJ&pg=PA481|year=2012|publisher=Springer Science & Business Media|isbn=978-1-4613-3837-6|pages=481– | doi = 10.1007/978-1-4613-3837-6_73 }}</ref> In 1963, it was reported that AG had induced symptoms of [[Addison's disease]] ([[adrenal insufficiency]]) in a young girl.<ref name="Sneader2005" /> Following additional reports, it was determined that AG acts as a steroidogenesis inhibitor.<ref name="Sneader2005" /> As such, the discovery of AG as a steroidogenesis inhibitor was serendipitous.<ref name="Patrick2013">{{cite book| vauthors = Patrick G | chapter = Drug Discovery: Finding a Lead |title=An Introduction to Medicinal Chemistry| chapter-url = https://books.google.com/books?id=Pj7xJRuhZxUC&pg=PA208|year=2013|publisher=OUP Oxford|isbn=978-0-19-969739-7|pages=208–,539}}</ref> The medication was withdrawn from the market in 1966 due to its adverse effects.<ref name="Sneader2005" /><ref name="HarrapDavis2012" /> The first report of AG in the treatment of [[breast cancer]] was published in 1969, and the first report of AG in the treatment of [[prostate cancer]] was published in 1974.<ref name="HarrapDavis2012" /><ref name="Osborne2012" /> The medication was one of the first adrenal steroidogenesis inhibitors as well as the first aromatase inhibitor to be discovered and used clinically, and led to the development of other aromatase inhibitors.<ref name="PonderWaring2012" /><ref name="FiggChau2010" /><ref name="Furr2008">{{cite book| vauthors = Miller WR | chapter = Background and development of aromatase inhibitors | veditors = Furr BJ |title=Aromatase Inhibitors| chapter-url = https://books.google.com/books?id=dyg9Ab3FsVgC&pg=PA4|year=2008|publisher=Springer Science & Business Media|isbn=978-3-7643-8693-1|pages=4,101,127}}</ref><ref name="Patrick2013" /> Along with [[testolactone]], it is described as a "first-generation" aromatase inhibitor.<ref name="Llewellyn2011" /> AG has largely been superseded by medications with better effectiveness and [[tolerability]] and reduced toxicity, such as [[ketoconazole]], [[abiraterone acetate]], and other aromatase inhibitors.<ref name="FiggChau2010" /><ref name="Osborne2012" /><ref name="Patrick2013" />


==Society and culture==
==Society and culture==


===Generic names===
===Generic names===
''Aminoglutethimide'' is the [[generic term|generic name]] of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}, and {{abbrlink|BAN|British Approved Name}}, while ''aminoglutéthimide'' is its {{abbrlink|DCF|Dénomination Commune Française}} and ''aminoglutetimide'' is its {{abbrlink|DCIT|Denominazione Comune Italiana}}.<ref name="Drugs.com" /><ref name="Elks2014">{{cite book|author=J. Elks|title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA70|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=70–}}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA43|year=2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=43–}}</ref><ref name="MortonHall2012" /> It is also known by its developmental code names ''Ba 16038'', ''Ciba 16038'', and ''ND-1966''.<ref name="Drugs.com" /><ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="MortonHall2012" />
''Aminoglutethimide'' is the [[generic term|generic name]] of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}, and {{abbrlink|BAN|British Approved Name}}, while ''aminoglutéthimide'' is its {{abbrlink|DCF|Dénomination Commune Française}} and ''aminoglutetimide'' is its {{abbrlink|DCIT|Denominazione Comune Italiana}}.<ref name="Drugs.com" /><ref name="Elks2014">{{cite book| vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA70|year=2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=70–}}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA43|year=2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=43–}}</ref><ref name="MortonHall2012" /> It is also known by its developmental code names ''Ba 16038'', ''Ciba 16038'', and ''ND-1966''.<ref name="Drugs.com" /><ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="MortonHall2012" />


===Brand names===
===Brand names===
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==References==
==References==
{{Reflist}}
{{Reflist}}



{{Anticonvulsants}}
{{Anticonvulsants}}
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[[Category:Hormonal antineoplastic drugs]]
[[Category:Hormonal antineoplastic drugs]]
[[Category:Withdrawn drugs]]
[[Category:Withdrawn drugs]]
[[Category:World Anti-Doping Agency prohibited substances]]

Latest revision as of 01:55, 30 November 2023

Aminoglutethimide
Clinical data
Trade namesElipten, Cytadren, Orimeten, numerous others
Other namesAG; AGI; Ba 16038; Ciba 16038; ND-1966; 2-(p-Aminophenyl)-2-ethylglutarimide
AHFS/Drugs.comConsumer Drug Information
MedlinePlusa604039
Pregnancy
category
  • AUえーゆー: D
Routes of
administration		By mouth
Drug classAromatase inhibitor; Antiestrogen; Steroidogenesis inhibitor; Antiglucocorticoid
ATC code
Pharmacokinetic data
BioavailabilityRapid, complete[1]
MetabolismLiver (minimal; acetylation)[1]
Elimination half-life12.5 hours[1]
ExcretionUrine (34–54%, unchanged)[1]
Identifiers
  • (RS)-3-(4-aminophenyl)-3-ethyl-piperidine-2,6-dione
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.004.325 Edit this at Wikidata
Chemical and physical data
FormulaC13H16N2O2
Molar mass232.283 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
  • O=C1NC(=O)CCC1(c2ccc(N)cc2)CC
  • InChI=1S/C13H16N2O2/c1-2-13(8-7-11(16)15-12(13)17)9-3-5-10(14)6-4-9/h3-6H,2,7-8,14H2,1H3,(H,15,16,17) checkY
  • Key:ROBVIMPUHSLWNV-UHFFFAOYSA-N checkY
  (verify)

Aminoglutethimide (AG), sold under the brand names Elipten, Cytadren, and Orimeten among others, is a medication which has been used in the treatment of seizures, Cushing's syndrome, breast cancer, and prostate cancer, among other indications.[2][3][4][5][6][7] It has also been used by bodybuilders, athletes, and other men for muscle-building and performance- and physique-enhancing purposes.[7][1] AG is taken by mouth three or four times per day.[8][4]

Side effects of AG include lethargy, somnolence, dizziness, headache, appetite loss, skin rash, hypertension, liver damage, and adrenal insufficiency, among others.[4] AG is both an anticonvulsant and a steroidogenesis inhibitor.[3][4] In terms of the latter property, it inhibits enzymes such as cholesterol side-chain cleavage enzyme (CYP11A1, P450scc) and aromatase (CYP19A1), thereby inhibiting the conversion of cholesterol into steroid hormones and blocking the production of androgens, estrogens, and glucocorticoids, among other endogenous steroids.[4] As such, AG is an aromatase inhibitor and adrenal steroidogenesis inhibitor, including both an androgen synthesis inhibitor and a corticosteroid synthesis inhibitor.[9][10][11][6][7]

AG was introduced for medical use, as an anticonvulsant, in 1960.[12][13] It was withdrawn in 1966 due to toxicity.[12][13] Its steroidogenesis-inhibiting properties were discovered serendipitously and it was subsequently repurposed for use in the treatment of Cushing's syndrome, breast cancer, and prostate cancer from 1969 and thereafter.[9][13][6] However, although used in the past, it has mostly been superseded by newer agents with better efficacy and lower toxicity such as ketoconazole, abiraterone acetate, and other aromatase inhibitors.[4][9] It remains marketed only in a few countries.[14][7]

Medical uses[edit]

AG is used as an anticonvulsant in the treatment of petit mal epilepsy and as a steroidogenesis inhibitor in the treatment of Cushing's syndrome, postmenopausal breast cancer, and prostate cancer.[15][6][12][7] It is also used to treat secondary hyperaldosteronism, edema, adrenocortical carcinoma, and ectopic adrenocorticotropic hormone (ACTH) producing tumors.[3][1][16] When used as a steroidogenesis inhibitor to treat breast cancer and prostate cancer, AG is given in combination with hydrocortisone, prednisone, or an equivalent corticosteroid to prevent adrenal insufficiency.[4][6] AG is a second- or third-line choice in the treatment of hormone-sensitive metastatic breast cancer. While effective in the treatment of breast cancer in postmenopausal women, it is not effective in premenopausal women and is not an effective ovarian steroidogenesis inhibitor, probably because it is not a potent enough aromatase inhibitor.[6][17] The medication is effective in the treatment of prostate cancer, but its effectiveness is low and inconsistent, likely due to its relatively weak steroidogenesis inhibition and poor pharmacokinetics.[6] Nonetheless, AG was found to be non-significantly different in effectiveness from surgical adrenalectomy in terms of prostate cancer tumor regression.[6] In any case, AG is not recommended as a first-line therapy in prostate cancer, but instead only as a second-line therapy.[6][17] It has only rarely been used in the treatment of prostate cancer.[4]

AG is used for adrenal steroidogenesis inhibition by mouth at a dosage of 250 mg three times per day (750 mg/day total) for the first 3 weeks of therapy and then increased to 250 mg four times per day (1,000 mg/day total) thereafter.[4] It can be used at a dosage of up to 500 mg four times per day (2,000 mg/day).[1][8] It is used as an aromatase inhibitor to inhibit peripheral estrogen production by mouth at a dosage of 125 mg twice per day (250 mg/day total), without significant suppression of adrenal steroidogenesis at this dosage.[17] Maximal aromatase inhibition is said to occur between dosages of 250 to 500 mg per day.[7] The side effects of AG are less frequent and severe at this dosage.[17] However, they are still less when AG is combined with hydrocortisone, and so AG is generally combined with a corticosteroid even at this lower dosage.[17] AG should only be used under close medical supervision and with laboratory tests including thyroid function, baseline hematological, serum glutamic-oxaloacetic transaminase, alkaline phosphatase, and bilirubin.[1][8]

Ketoconazole can achieve similar decreases in steroid hormone levels as AG but is more effective in promoting tumor regression and is moderately less toxic in comparison.[4] AG can still be a useful alternative in those who have failed or are unable to tolerate ketoconazole and other therapies however.[4]

Available forms[edit]

AG is provided most commonly in the form of 250 mg tablets.[7][8]

Non-medical uses[edit]

AG is used by bodybuilders, athletes, and other men to lower circulating levels of cortisol in the body and thereby prevent muscle loss.[7][1] Cortisol is catabolic to protein in muscle and effective suppression of cortisol by AG at high doses can prevent muscle loss.[7] It is usually used in combination with an anabolic steroid to avoid androgen deficiency.[7] However, the usefulness of AG for such purposes has been questioned, with few users reportedly having positive comments about it, and the risks of AG are said to be high.[7][1] In any case, AG is also used by bodybuilders and other men for its actions as an aromatase inhibitor in order to decrease estrogen levels.[7] It is said to be useful for inhibiting the estrogenic side effects of certain anabolic steroids such as gynecomastia, increased water retention, and fat gain.[7]

Contraindications[edit]

AG should not be used in people with known hypersensitivity to AG.[1] It should not be used in women who are pregnant or breastfeeding.[1] Other potential contraindications include chicken pox, shingles (herpes zoster), infection, kidney disease, liver disease, and hypothyroidism.[1]

Side effects[edit]

AG has many side effects and is a relatively toxic medication, although its side effects are described as usually relatively mild.[4][6] The side effects of AG include lethargy, fatigue, weakness, malaise, drowsiness, somnolence, depression, apathy, sleep disturbances, stomach discomfort, nausea, vomiting, ataxia, joint aches and pains, fever, skin rash, hypotension or hypertension, high cholesterol levels, virilization, hypothyroidism, thyroid abnormalities, elevated liver enzymes, jaundice, hepatotoxicity, weight gain, leg cramps, personality changes, blood dyscrasias, and adrenal insufficiency (e.g., hyponatremia, hypoglycemia, others).[4][6][17][7][1][8] Lethargy is the most common side effect and has been found to occur in 31 to 70% of people treated with AG.[6] It is the most common reason for discontinuation of AG.[6] Skin rash and hypotension have both been observed in about 15% of people.[6] At least one side effect will occur in 45 to 85% of people.[6] Severe toxicity is seen in 10% of people, including circulatory collapse thought to be due to adrenal insufficiency.[6] Hematological and bone marrow toxicity, including marked depression of white blood cell count, platelets, or both, occurs rarely, with an incidence of about 0.9%.[6][18] It is usually seen within the first 7 weeks of treatment and resolves within 3 weeks following discontinuation.[6] AG is discontinued in 5 to 10% of people due to intolerable side effects.[6] The central nervous system side effects of AG are due to its nature as an anticonvulsant and relation to glutethimide.[17]

Overdose[edit]

In the event of overdose of AG, drowsiness, nausea, vomiting, hypotension, and respiratory depression may occur.[19][20] Medical attention should be sought urgently.[19] Treatment of AG overdose can include gastric lavage to decrease absorption and dialysis to enhance elimination.[21]

Interactions[edit]

AG has an interaction with all corticosteroids.[1] It enhances the metabolism of dexamethasone, so hydrocortisone should be used instead.[8] If the person is taking warfarin, the dosage of warfarin may need to be increased.[8] Alcohol potentiates the central nervous system side effects of AG.[8] Dosages of theophylline, digitoxin, and medroxyprogesterone acetate may need to be increased.[8]

Pharmacology[edit]

Pharmacodynamics[edit]

AG is a potent and non-selective steroidogenesis inhibitor, acting as a reversible and competitive inhibitor of multiple steroidogenic enzymes, including:[9][10][11][6][7]

As such, AG is an estrogen synthesis inhibitor and adrenal steroidogenesis inhibitor, including both an androgen synthesis inhibitor and a corticosteroid synthesis inhibitor.[9][10][11][6][7] For these reasons, AG has functional antiestrogenic, antiandrogenic, antiglucocorticoid, and antimineralocorticoid actions.[9][10][11][6][7] In terms of its actions as an adrenal steroidogenesis inhibitor, it is described as a form of reversible "medical adrenalectomy" or "chemical adrenalectomy".[4][6][8] While AG inhibits all of the enzymes listed above, inhibition of P450scc is primarily responsible for its inhibition of adrenal steroidogenesis.[25] In terms of adrenal androgens, AG has been shown to significantly suppress dehydroepiandrosterone sulfate, androstenedione, testosterone, and dihydrotestosterone levels in men.[6] Although it is most potent in inhibiting aromatase among the enzymes it targets, AG is described nonetheless as a relatively weak aromatase inhibitor.[11][4] In addition, it is described as a much more potent aromatase inhibitor than adrenal steroidogenesis inhibitor.[17] AG can inhibit aromatase by 74 to 92% and decrease circulating estradiol levels by 58 to 76% in men and postmenopausal women.[1][7] AG is not an effective ovarian steroidogenesis inhibitor in premenopausal women.[17] However, interference with ovarian steroidogenesis by AG may in any case result in hyperandrogenism and virilization in premenopausal women.[8][7]

Pharmacodynamics of aromatase inhibitors
Generation Medication Dosage % inhibitiona Classb IC50c
First Testolactone 250 mg 4x/day p.o. ? Type I ?
100 mg 3x/week i.m. ?
Rogletimide 200 mg 2x/day p.o.
400 mg 2x/day p.o.
800 mg 2x/day p.o.		 50.6%
63.5%
73.8%		 Type II ?
Aminoglutethimide 250 mg mg 4x/day p.o. 90.6% Type II 4,500 nM
Second Formestane 125 mg 1x/day p.o.
125 mg 2x/day p.o.
250 mg 1x/day p.o.		 72.3%
70.0%
57.3%		 Type I 30 nM
250 mg 1x/2 weeks i.m.
500 mg 1x/2 weeks i.m.
500 mg 1x/1 week i.m.		 84.8%
91.9%
92.5%
Fadrozole 1 mg 1x/day p.o.
2 mg 2x/day p.o.		 82.4%
92.6%		 Type II ?
Third Exemestane 25 mg 1x/day p.o. 97.9% Type I 15 nM
Anastrozole 1 mg 1x/day p.o.
10 mg 1x/day p.o.		 96.7–97.3%
98.1%		 Type II 10 nM
Letrozole 0.5 mg 1x/day p.o.
2.5 mg 1x/day p.o.		 98.4%
98.9%–>99.1%		 Type II 2.5 nM
Footnotes: a = In postmenopausal women. b = Type I: Steroidal, irreversible (substrate-binding site). Type II: Nonsteroidal, reversible (binding to and interference with the cytochrome P450 heme moiety). c = In breast cancer homogenates. Sources: See template.

Pharmacokinetics[edit]

With oral administration, the absorption of AG is rapid and complete.[1] It is well-distributed throughout the body.[1] In terms of metabolism, a portion of AG is acetylated in the liver.[1] The biological half-life of AG is 12.5 hours.[1] It is excreted in urine 34 to 54% unchanged.[1]

Chemistry[edit]

AG is a nonsteroidal compound, specifically a glutarimide, and is a derivative of glutethimide.[3][12][7] It is also known by its chemical names 2-(4-aminophenyl)-2-ethylglutarimide and 2-(aminophenyl)-3-ethylpiperidine-2,6-dione.[26][7] Aside from glutethimide, AG is structurally related to rogletimide (pyridoglutethimide) and thalidomide, as well as amphenone B, metyrapone, and mitotane.[10][27][28][29][12]

History[edit]

AG was introduced for medical use, as an anticonvulsant, in 1960.[12][13] In 1963, it was reported that AG had induced symptoms of Addison's disease (adrenal insufficiency) in a young girl.[12] Following additional reports, it was determined that AG acts as a steroidogenesis inhibitor.[12] As such, the discovery of AG as a steroidogenesis inhibitor was serendipitous.[9] The medication was withdrawn from the market in 1966 due to its adverse effects.[12][13] The first report of AG in the treatment of breast cancer was published in 1969, and the first report of AG in the treatment of prostate cancer was published in 1974.[13][6] The medication was one of the first adrenal steroidogenesis inhibitors as well as the first aromatase inhibitor to be discovered and used clinically, and led to the development of other aromatase inhibitors.[18][4][30][9] Along with testolactone, it is described as a "first-generation" aromatase inhibitor.[7] AG has largely been superseded by medications with better effectiveness and tolerability and reduced toxicity, such as ketoconazole, abiraterone acetate, and other aromatase inhibitors.[4][6][9]

Society and culture[edit]

Generic names[edit]

Aminoglutethimide is the generic name of the drug and its INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, and BANTooltip British Approved Name, while aminoglutéthimide is its DCFTooltip Dénomination Commune Française and aminoglutetimide is its DCITTooltip Denominazione Comune Italiana.[14][26][31][3] It is also known by its developmental code names Ba 16038, Ciba 16038, and ND-1966.[14][26][31][3]

Brand names[edit]

AG has been marketed under brand names including Elipten, Cytandren, and Orimeten.[26][31][7][14][3] It has also been marketed under other brand names such as Aminoblastin, Rodazol, and Mamomit, among numerous others.[31][7]

Availability[edit]

AG appears to remain marketed only in a few countries, which include China, Egypt, and Lithuania.[14] Previously, AG was available very widely throughout the world, including in more than two dozen countries and under numerous brand names.[7] Among other places, it was marketed in the United States, Canada, the United Kingdom, other European countries, Australia, New Zealand, South Africa, South America, Israel, Malaysia, and Hong Kong.[31][7]

References[edit]

  1. ^ a b c d e f g h i j k l m n o p q r s t u House AA, Tindall WN, Sedrak MM (2013). "Drugs Used to Treat Endocrine Gland Disorders". In Tindall WN, Sedrak M, Boltri J (eds.). Patient-Centered Pharmacology: Learning System for the Conscientious Prescribe. F.A. Davis. pp. 218–. ISBN 978-0-8036-4070-2.
  2. ^ Milne GW (2018). Drugs: Synonyms and Properties: Synonyms and Properties. Taylor & Francis. pp. 1182–. ISBN 978-1-351-78989-9.
  3. ^ a b c d e f g Morton IK, Hall JM (2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 14–. ISBN 978-94-011-4439-1.
  4. ^ a b c d e f g h i j k l m n o p q r s Friedlander TW, Ryan CJ (2010). "Adrenal Androgen Synthesis Inhibitor Therapies in Castrate-Resistant Prostate Cancer". In Figg WD, Chau CH, Small EJ (eds.). Drug Management of Prostate Cancer. Springer Science & Business Media. pp. 91–96. ISBN 978-1-60327-829-4.
  5. ^ Gross BA, Mindea SA, Pick AJ, Chandler JP, Batjer HH (2007). "Medical management of Cushing disease". Neurosurgical Focus. 23 (3): 1–6. doi:10.3171/foc.2007.23.3.12. PMID 17961023.
  6. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac Havlin KA, Trump DL (2012). "Endocrine Therapies in Breast and Prostate Cancer". In Osborne CK (ed.). Aminoglutethimide: theoretical considerations and clinical results in advanced prostate cancer. Springer Science & Business Media. pp. 39, 73, 87–93. ISBN 978-1-4613-1731-9.
  7. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac William Llewellyn (2011). Anabolics. Molecular Nutrition Llc. pp. 770–. ISBN 978-0-9828280-1-4.
  8. ^ a b c d e f g h i j k Wilkes GM, Barton-Burke M (2013). "Introduction to Chemotherapy Drugs". 2014 Oncology Nursing Drug Handbook. Jones & Bartlett Publishers. pp. 50–52. ISBN 978-1-284-05374-6.
  9. ^ a b c d e f g h i Patrick G (2013). "Drug Discovery: Finding a Lead". An Introduction to Medicinal Chemistry. OUP Oxford. pp. 208–, 539. ISBN 978-0-19-969739-7.
  10. ^ a b c d e Patel A, Smith HJ, Steinmetzer T (2005). "Design of Enzyme Inhibitors and Drugs". In Smith HJ, Williams W (eds.). Smith and Williams' Introduction to the Principles of Drug Design and Action (Fourth ed.). CRC Press. pp. 281–. ISBN 978-0-203-30415-0.
  11. ^ a b c d e Ebadi M (2007). "Aminoglutethimide". Desk Reference of Clinical Pharmacology, Second Edition. CRC Press. pp. 63–. ISBN 978-1-4200-4744-8.
  12. ^ a b c d e f g h i Sneader W (2005). "The First Synthetic Drugs and Their Analogues". Drug Discovery: A History. John Wiley & Sons. pp. 367–. doi:10.1002/0470015535.ch26. ISBN 978-0-471-89979-2.
  13. ^ a b c d e f Jackson IM (2012). "Aminoglutethimide (Orimeten): The Present and the Future". In Harrap LR, Davis W, Calvert AH (eds.). Cancer Chemotherapy and Selective Drug Development: Proceedings of the 10th Anniversary Meeting of the Coordinating Committee for Human Tumour Investigations, Brighton, England, October 24–28, 1983. Springer Science & Business Media. pp. 481–. doi:10.1007/978-1-4613-3837-6_73. ISBN 978-1-4613-3837-6.
  14. ^ a b c d e "List of Aromatase inhibitors". Drugs.com.
  15. ^ Hendy WF (2013). "Adrenalectomy and hypophysectomy in disseminated prostate cancer". In Castro JE (ed.). The Treatment of Prostatic Hypertrophy and Neoplasia. Springer Science & Business Media. pp. 179–. ISBN 978-94-015-7190-6.
  16. ^ Krieger DT (1982). "Chapter 8: Treatment of Cushing's Disease and Syndrome: Adrenocortical Carcinoma: Aminoglutethimide". Cushing's Syndrome. Springer Science & Business Media. p. 120. ISBN 978-3-642-81659-8.
  17. ^ a b c d e f g h i Priestman TJ (2012). Cancer Chemotherapy: an Introduction. Springer Science & Business Media. pp. 178–. ISBN 978-1-4471-1686-8.
  18. ^ a b Waxman J, Jane N (2012). "New endocrine therapies for cancer". In Ponder BA, Waring MJ (eds.). The Science of Cancer Treatment. Springer Science & Business Media. pp. 48–. ISBN 978-94-009-0709-6.
  19. ^ a b Upfal J (2006). The Australian Drug Guide: Every Person's Guide to Prescription and Over-the-counter Medicines, Street Drugs, Vaccines, Vitamins and Minerals... Black Inc. pp. 45–. ISBN 978-1-86395-174-6.
  20. ^ Nurse Practitioner's Drug Handbook. Springhouse Corp. 2000. pp. 40–41. ISBN 9780874349979.
  21. ^ United States Pharmacopeial Convention (2006). USP DI: United States Pharmacopeia Dispensing Information. United States Pharmacopeial Convention. pp. 75–76. ISBN 978-1-56363-429-1.
  22. ^ Siraki AG, Bonini MG, Jiang J, Ehrenshaft M, Mason RP (July 2007). "Aminoglutethimide-induced protein free radical formation on myeloperoxidase: a potential mechanism of agranulocytosis". Chemical Research in Toxicology. 20 (7): 1038–45. doi:10.1021/tx6003562. PMC 2073000. PMID 17602675.
  23. ^ Wallig MA (2017). "Endocrine System". In Haschek WM, Bolon B, Rousseaux CG, Wallig MA (eds.). Fundamentals of Toxicologic Pathology. Elsevier Science. pp. 580–. ISBN 978-0-12-809842-4.
  24. ^ Thomas JA, Keenan EJ (2012). "Effects of Drugs on the Endocrine System". Principles of Endocrine Pharmacology. Springer Science & Business Media. pp. 278–. ISBN 978-1-4684-5036-1.
  25. ^ Zak F (2012). "Lipid Hyperplasia, Adrenal Cortex, Rat". In Jones TC, Mohr U, Hunt RD (eds.). Endocrine System. Monographs on Pathology of Laboratory Animals. Springer Science & Business Media. pp. 83–. doi:10.1007/978-3-642-60996-1_65. ISBN 978-3-642-96720-7.
  26. ^ a b c d Elks J (2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 70–. ISBN 978-1-4757-2085-3.
  27. ^ Ullmann's Industrial Toxicology. Wiley. 2005. p. 876. ISBN 978-3-527-31247-4.
  28. ^ Bentley PJ (1980). "Steroid Hormones". Endocrine Pharmacology: Physiological Basis and Therapeutic Applications. CUP Archive. pp. 143, 162–163. ISBN 978-0-521-22673-8.
  29. ^ Selye H (2013). "Stressors and Conditioning Agents". Stress in Health and Disease. Elsevier Science. pp. 57–. ISBN 978-1-4831-9221-5.
  30. ^ Miller WR (2008). "Background and development of aromatase inhibitors". In Furr BJ (ed.). Aromatase Inhibitors. Springer Science & Business Media. pp. 4, 101, 127. ISBN 978-3-7643-8693-1.
  31. ^ a b c d e Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 43–. ISBN 978-3-88763-075-1.
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