Danazol
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| Systematic (IUPAC) name | |
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(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
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| Clinical data | |
| Trade names | Azol, Bonzol, Cyclomen, Danol, Nazol |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a682599 |
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| Legal status | |
| Routes of administration |
Oral |
| Pharmacokinetic data | |
| Metabolism | Hepatic (extensive to 2-hydroxymethyl ethisterone, ethisterone and 17-hydroxymethylethisterone)[1] |
| Biological half-life | 3-6 hours (single dose), 26 hours (repeated dosing)[1] |
| Excretion | Urine, faeces[1] |
| Identifiers | |
| CAS Number | 17230-88-5  |
| ATC code | G03XA01 (WHO) |
| 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 |
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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.
Contents
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
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- ↑ 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
