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Danazol is a derivative of the synthetic steroid ethisterone that suppresses the production of gonadotropins and has some weak androgenic effects.^[1] Before becoming available as a generic drug, danazol was marketed as Danocrine in the United States. It was approved by the US Food and Drug Administration (FDA) as the first drug to specifically treat endometriosis in the early 1970s.^[2] Although effective for endometriosis, its use is limited by its masculinizing side-effects.^[3] Its role as a treatment for endometriosis has been largely replaced by the GnRH agonists.

Chemistry

The agent is fat-soluble. It is an isoxazole of testosterone with isolated weak androgenic activity and no estrogenic or progestagenic effects.^[2]

Mechanism of action

Danazol exhibits hypoestrogenic, hyperandrogenic effects that cause atrophy of the endometrium, which can alleviate the symptoms of endometriosis.^[4]

Danazol prevents ovulation by suppressing the increase of luteinizing hormone during the middle of the menstrual cycle.^[5]^[6] Danazol inhibits ovarian steroidogenesis resulting in decreased secretion of estradiol and may increase androgens. Danazol displaces testosterone from sex hormone-binding globulin (SHBG), displacing it and increasing serum testosterone levels.^[5] Danazol also directly stimulates androgen and progesterone receptors.^[5]

Pituitary hormones are largely unaffected, although luteinizing hormone may be slightly elevated.^[7]

Indications

Danazol has been used—mostly off-label—for other indications, namely in the management of menorrhagia, fibrocystic breast disease, immune thrombocytopenic purpura ,premenstrual syndrome, breast pain (mastodynia) and hereditary angioedema.^[8] Although not currently a standard treatment for menorrhagia, danazol has resulted in significant relief in young women with menorrhagia in a study, and, because of a lack of significant adverse effects, it was proposed as an alternative treatment.^[9] Low-dose danazol has also been investigated in the treatment of diabetic macular edema in a phase 3 trial.^[10]^[11]

Side effects

Androgenic side effects are of concern, as some women taking danazol may experience unwanted hair growth (hirsutism), acne, deepening of the voice (sometimes irreversible), or adverse blood lipid profiles.^[5] Danazol may also cause hot flashes, elevation of liver enzyme levels, and mood changes.^[5] Some patients who use danazol experience weight gain and fluid retention. Due to these limitations, danazol is seldom prescribed continuously beyond six months.

The use of danazol for endometriosis has been linked to an increased risk of ovarian cancer.^[12] Patients with endometriosis have specific risk factors for ovarian cancer, so this may not apply for other uses.

Danazol, like most other androgenic agents, has been linked with an increased risk of liver tumors. These are generally benign.^[13]

Unlike GnRH agonists, danazol does not induce osteoporosis. Also, symptoms of hot flushes tend to be less common or severe.

Contraindications

Danazol is contraindicated during pregnancy because it could masculinize a female fetus. Females taking danazol should also take effective contraceptive therapy to prevent pregnancy.^[5]

Since danazol is metabolized by the liver, it cannot be used by patients with liver disease, and in patients receiving long-term therapy, liver function must be monitored on a periodic basis.

History

Danazol was synthesized by a team of scientists at Sterling Winthrop in Rensselaer, New York by a team that included Helmutt Neumann, Gordon Potts, W.T. Ryan, and Frederik W. Stonner.^[14]

References

^ ^a ^b ^c ^d Brayfield, A, ed. (30 October 2013). "Danazol". Martindale: The Complete Drug Reference. Pharmaceutical Press. Retrieved 1 April 2014.
^ ^a ^b Dmowski WP, Scholer HF, Mahesh VB, Greenblatt RB (1971). "Danazol--a synthetic steroid derivative with interesting physiologic properties". Fertil. Steril. 22 (1): 9–18. PMID 5538758.
^ Selak V, Farquhar C, Prentice A, Singla A (2007). Farquhar, Cindy, ed. "Danazol for pelvic pain associated with endometriosis". Cochrane database of systematic reviews (Online) (4): CD000068. doi:10.1002/14651858.CD000068.pub2. PMID 17943735.
^ Fedele, L; Marchini, M; Bianchi, S; Baglioni, A; Bocciolone, L; Nava, S (July 1990). "Endometrial patterns during danazol and buserelin therapy for endometriosis: comparative structural and ultrastructural study.". Obstetrics and gynecology 76 (1): 79–84. PMID 2113661.
^ ^a ^b ^c ^d ^e ^f Hoffman, Barbara L; Schorge JO; Schaffer JI; Halvorson LM; Bradshaw KD; Cunningham FG; Calver LE. Williams Gynecology: Chapter 10, Endometriosis (2nd ed.). New York: McGraw-Hill Medical. ISBN 9780071716727.
^ Floyd, WS (1980). "Danazol: endocrine and endometrial effects.". Int J Fertil. 25 (1): 75–80. PMID 6104649.
^ Steingold KA, Lu JK, Judd HL, Meldrum DR (1986). "Danazol inhibits steroidogenesis by the human ovary in vivo". Fertil Steril 45 (5): 649–54. PMID 3084301.
^ Rod Flower; Humphrey P. Rang; Maureen M. Dale; Ritter, James M. (2007). Rang & Dale's pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-06911-5.
^ "Efficacy of vaginal danazol treatment in women with menorrhagia during fertile age". Fertil. Steril. 92 (4): 1351–4. October 2009. doi:10.1016/j.fertnstert.2008.08.017. PMID 18930222.
^ "A Safety and Efficacy Study of Oral Danazol (a Previously Approved Drug)in the Treatment of Diabetic Macular Edema". Clinicaltrials.gov. Ampio Pharmaceuticals. Inc. Retrieved 27 June 2015.
^ "Ampio Pharmaceuticals Announces Additional Statistically Significant Study Results for Optina™ in the Treatment of Diabetic Macular Edema (DME)". Ampio Pharmaceuticals. Inc. Retrieved 27 June 2015.
^ Cottreau CM, Ness RB, Modugno F, Allen GO, Goodman MT (2003). "Endometriosis and Its Treatment with Danazol or Lupron in Relation to Ovarian Cancer". Clinical Cancer Research 9 (14): 5142–4. PMID 14613992.
^ Velazquez I, Alter BP (2004). "Androgens and liver tumors: Fanconi's anemia and non-Fanconi's conditions". Am. J. Hematol. 77 (3): 257–67. doi:10.1002/ajh.20183. PMID 15495253.
^ G.P. Ellis and G.B. Ellis, doi:10.1016/S0079-6468(08)70187-5 (1979), pp. 126, note 158, 130, notes 1513, 2369, citing doi:10.1021/jm00299a034

UpToDate Contents

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1. 子宮内膜症の治療の概要 overview of the treatment of endometriosis
2. 子宮平滑筋腫（子宮筋腫）の治療の概要 overview of treatment of uterine leiomyomas fibroids
3. 自己免疫性溶血性貧血の治療：温暖凝集素 treatment of autoimmune hemolytic anemia warm agglutinins
4. 成人における免疫性血小板減少症（ITP）：セカンドライン療法およびサードライン療法 immune thrombocytopenia itp in adults second and third line therapies
5. C1インヒビター正常を示す遺伝性血管性浮腫（III型HAE） hereditary angioedema with normal c1 inhibitor type iii hae

English Journal

Evaluation of selected angiogenic and inflammatory markers in endometriosis before and after danazol treatment.

Szubert M, Suzin J, Duechler M, Szu Awska A, Czy M, Kowalczyk-Amico K.
Reproduction, fertility, and development.Reprod Fertil Dev.2013 Apr 2. doi: 10.1071/RD12258. [Epub ahead of print]
PMID 23544741

The metabolism of anabolic-androgenic steroids in the greyhound.

McKinney AR, Cawley AT, Young EB, Kerwick CM, Cunnington K, Stewart RT, Ambrus JI, Willis AC, McLeod MD.SourceAustralian Racing Forensic Laboratory. Currently with the Department of the President's Affairs, PO Box 17292, Al Ain, United Arab Emirates. amckinney@mscpc.ae.
Bioanalysis.Bioanalysis.2013 Apr;5(7):769-81. doi: 10.4155/bio.13.40.
Background: Effective control of the use of anabolic-androgenic steroids (AASs) in animal sports is essential in order to ensure both animal welfare and integrity. In order to better police their use in Australian and New Zealand greyhound racing, thorough metabolic studies have been carried out on
PMID 23534422

Japanese Journal

P2-146 マウスにおけるdanazolとmidazolamの薬物相互作用におよぼす投与間隔の影響(一般演題ポスター発表,薬物相互作用,臨床から学び臨床へと還元する医療薬学)

大穂祐介,奥平和穂,西垣隆一郎
日本医療薬学会年会講演要旨集 20, 414, 2010-10-25
NAID 110008109146

不妊合併子宮内膜症治療のためのダナゾールの新しい投与法 (特集子宮内膜症合併不妊の治療法) -- (妊孕性向上のための内膜症治療)

五十嵐正雄,五十嵐茂雄,峯岸敬 [他]
産科と婦人科 77(7), 712-818, 2010-07
NAID 40017190951

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リンク元

「ダナゾール」

Danazol
Systematic (IUPAC) name
	(1S,2R,13R,14S,17R,18S)-17-ethynyl-2,18-dimethyl-7-oxa-6-azapentacyclo[11.7.0.02,10.04,8.014,18]icosa-4(8),5,9-trien-17-ol
Clinical data
Trade names	Azol, Bonzol, Cyclomen, Danol, Nazol
AHFS/Drugs.com	monograph
MedlinePlus	a682599
Pregnancy; category	AU: D; US: X (Contraindicated); ;
Legal status	AU: S4 (Prescription only); CA: ℞-only; UK: POM (Prescription only); US: ℞-only;
Routes of; administration	Oral
Pharmacokinetic data
Metabolism	Hepatic (extensive to 2-hydroxymethyl ethisterone, ethisterone and 17-hydroxymethylethisterone)
Biological half-life	3-6 hours (single dose), 26 hours (repeated dosing)
Excretion	Urine, faeces
Identifiers
CAS Number	17230-88-5
ATC code	G03XA01
PubChem	CID: 28417
IUPHAR/BPS	6942
DrugBank	DB01406
ChemSpider	26436
UNII	N29QWW3BUO
KEGG	D00289
ChEBI	CHEBI:4315
ChEMBL	CHEMBL1479
Synonyms	17β-hydroxy-2,4,17α-pregnadien-20-yno[2,3-D]isoxazole
Chemical data
Formula	C22H27NO2
Molecular mass	337.5 g/mol
	SMILES C#C[C@]5(O)CC[C@H]4[C@H]3[C@@H]([C@@]2(/C(=C\c1oncc1C2)CC3)C)CC[C@@]45C ;
	InChI InChI=1S/C22H27NO2/c1-4-22(24)10-8-18-16-6-5-15-11-19-14(13-23-25-19)12-20(15,2)17(16)7-9-21(18,22)3/h1,11,13,16-18,24H,5-10,12H2,2-3H3/t16-,17+,18+,20+,21+,22+/m1/s1 ; Key:POZRVZJJTULAOH-LHZXLZLDSA-N ;
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　　[★]

英: danazol
商: ボンゾール
関: ダナゾール療法、ボンゾール療法

エチステロン(17α-エチニルテストステロン)の誘導体。
抗ゴナドトロピン作用(FSH,LHの分泌を抑制)を有し、無月経をきたす。例えば、子宮内膜の偽閉経療法として用いられる。また、乳腺症にも用いられる。
作用機序：(下垂体)LH,FSHを程度低下させ、エストラジオールを中等度低下させる。(子宮体内膜)子宮内膜のアンドロゲンレセプターに結合して増殖を抑制。(NGY.198)

[MD-1] Brayfield, A, ed. (30 October 2013). "Danazol". Martindale: The Complete Drug Reference. Pharmaceutical Press. Retrieved 1 April 2014.

[Dmowski-2] Dmowski WP, Scholer HF, Mahesh VB, Greenblatt RB (1971). "Danazol--a synthetic steroid derivative with interesting physiologic properties". Fertil. Steril. 22 (1): 9–18. PMID 5538758.

[3] Selak V, Farquhar C, Prentice A, Singla A (2007). Farquhar, Cindy, ed. "Danazol for pelvic pain associated with endometriosis". Cochrane database of systematic reviews (Online) (4): CD000068. doi:10.1002/14651858.CD000068.pub2. PMID 17943735.

[4] Fedele, L; Marchini, M; Bianchi, S; Baglioni, A; Bocciolone, L; Nava, S (July 1990). "Endometrial patterns during danazol and buserelin therapy for endometriosis: comparative structural and ultrastructural study.". Obstetrics and gynecology 76 (1): 79–84. PMID 2113661.

[Hoffman-5] ^ ^a ^b ^c ^d ^e ^f Hoffman, Barbara L; Schorge JO; Schaffer JI; Halvorson LM; Bradshaw KD; Cunningham FG; Calver LE. Williams Gynecology: Chapter 10, Endometriosis (2nd ed.). New York: McGraw-Hill Medical. ISBN 9780071716727.

[6] Floyd, WS (1980). "Danazol: endocrine and endometrial effects.". Int J Fertil. 25 (1): 75–80. PMID 6104649.

[7] Steingold KA, Lu JK, Judd HL, Meldrum DR (1986). "Danazol inhibits steroidogenesis by the human ovary in vivo". Fertil Steril 45 (5): 649–54. PMID 3084301.

[8] Rod Flower; Humphrey P. Rang; Maureen M. Dale; Ritter, James M. (2007). Rang & Dale's pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-06911-5.

[9] "Efficacy of vaginal danazol treatment in women with menorrhagia during fertile age". Fertil. Steril. 92 (4): 1351–4. October 2009. doi:10.1016/j.fertnstert.2008.08.017. PMID 18930222.

[10] "A Safety and Efficacy Study of Oral Danazol (a Previously Approved Drug)in the Treatment of Diabetic Macular Edema". Clinicaltrials.gov. Ampio Pharmaceuticals. Inc. Retrieved 27 June 2015.

[11] "Ampio Pharmaceuticals Announces Additional Statistically Significant Study Results for Optina™ in the Treatment of Diabetic Macular Edema (DME)". Ampio Pharmaceuticals. Inc. Retrieved 27 June 2015.

[12] Cottreau CM, Ness RB, Modugno F, Allen GO, Goodman MT (2003). "Endometriosis and Its Treatment with Danazol or Lupron in Relation to Ovarian Cancer". Clinical Cancer Research 9 (14): 5142–4. PMID 14613992.

[13] Velazquez I, Alter BP (2004). "Androgens and liver tumors: Fanconi's anemia and non-Fanconi's conditions". Am. J. Hematol. 77 (3): 257–67. doi:10.1002/ajh.20183. PMID 15495253.

[14] G.P. Ellis and G.B. Ellis, doi:10.1016/S0079-6468(08)70187-5 (1979), pp. 126, note 158, 130, notes 1513, 2369, citing doi:10.1021/jm00299a034

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danazol