Danazol

Chemical Properties

White Solid

Originator

Danol,Winthrop,UK,1974

Uses

anterior pituitary suppressant

Uses

Anterior pituitary supressant. Anabolic steroid derivative of ethisterone, with mild androgenic side effects (an impeded androgen). Antigonadotropin

Uses

Danazol is an anterior pituitary supressant. Danazol is an anabolic steroid derivative of ethisterone, with mild androgenic side effects (an impeded androgen). Antigonadotropin.

Indications

Danazol, a synthetic androgen, has been used to treat the pruritus of primary biliary cirrhosis, urticaria, and also idiopathic pruritus. It has been used for treatment of pruritus associated with polycythemia vera and systemic lupus erythematosus.

Definition

ChEBI: Danazol is a 17beta-hydroxy steroid and a terminal acetylenic compound. It has a role as an anti-estrogen, an estrogen antagonist and a geroprotector. It derives from a hydride of a pregnane.

Manufacturing Process

Danazol was prepared from 4.32 grams of 17α-ethynyl-2-hydroxymethylene4-androsten-17β-ol-3-one, 1.00 gram of hydroxylamine hydrochloride, 1.12 grams of fused sodium acetate and 135 ml of acetic acid. To a 500 ml, 3- necked flask, equipped with a sealed Hershberg-type stirrer, a reflux condenser and a stopper, was added the above androstenone derivative in 300 ml of 95% ethanol. Stirring was commenced and a slurry of fused sodium acetate and hydroxylamine hydrochloride in glacial acetic acid was added.
The mixture was refluxed gently on a steam bath for 1? hours. Fifteen minutes after initiating the reaction, the reaction mixture gave a negative ferric chloride test. Most of the ethanol and acetic acid were removed by distillation in vacuo, 300 ml of water and 300 ml of ether were added to the concentrate, and the mixture was shaken. The layers were separated, the aqueous layer extracted with fresh ether, and the combined ether extracts were washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness in vacuo. The residue was crystallized by trituration with ether, and the crystals were collected by filtration, washed with hexane and dried. The mother liquors were concentrated to dryness and dissolved in a minimum amount of acetone, whereupon a second crop was obtained. The two crops were combined, dissolved in ethyl acetate, decolorized with activated charcoal, and recovered by concentration.
The mixture was refluxed gently on a steam bath for 1? hours. Fifteen minutes after initiating the reaction, the reaction mixture gave a negative ferric chloride test. Most of the ethanol and acetic acid were removed by distillation in vacuo, 300 ml of water and 300 ml of ether were added to the concentrate, and the mixture was shaken. The layers were separated, the aqueous layer extracted with fresh ether, and the combined ether extracts were washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness in vacuo. The residue was crystallized by trituration with ether, and the crystals were collected by filtration, washed with hexane and dried. The mother liquors were concentrated to dryness and dissolved in a minimum amount of acetone, whereupon a second crop was obtained. The two crops were combined, dissolved in ethyl acetate, decolorized with activated charcoal, and recovered by concentration.

brand name

Danocrine (Sanofi Aventis).

Therapeutic Function

Anterior pituitary suppressant

General Description

Danazol, 17α-pregna-2,4-dien-20-yno-[2,3-d]isoxazol-17-ol, is a weak androgen that, in spite ofthe 17α-ethinyl group, has little estrogenic or progestogenicactivity. Danazol has been called a synthetic steroidwith diverse biological effects. Danazol binds to sexhormone–binding globulin (SHBG) and decreases the hepaticsynthesis of this estradiol and testosterone carrier.Free testosterone thus increases. Danazol inhibits FSH andLH production by the hypothalamus and pituitary. It bindsto PRs, GRs, ARs, and ERs. Although the exact mechanismof action is unclear, danazol alters endometrial tissueso that it becomes inactive and atrophic, which allowsdanazol to be an effective treatment for endometriosis.Danazol is also used to treat hereditary angioedema and fibrocysticbreast disease.

Biological Activity

danazol showed weak androgenic effects.danazol is a derivative of testosterone and ethisterone. an androgen is any natural or synthetic agent stimulating or controling the development and maintenance of male characteristics by binding to androgen receptors. this includes the activity of the primary male sex organs and development of male secondary sex characteristics.

Biochem/physiol Actions

Danazol is a weak androgen; anterior pituitary suppressant.

Side effects

Danazol, a synthetic analogue of 17α-ethynyl testosterone, induces amenorrhea, anovulation and endometrial atrophy via suppression of the hypothalamicpituitary-ovary (HPO) axis. This causes an estrogen-deficient state, but it also causes an increase in androgen production. Danazol generally is not well tolerated because of its androgenic and anabolic side effects, including acne, decreased breast size, facial hair, weight gain, and oily skin. This type of therapy is not a viable option for women with liver disease or hyperlipidemia. Because danazol is teratogenic , it is recommended that effective contraception be utilized during treatment.

Veterinary Drugs and Treatments

Because of expense and unpredictable efficacy, danazol is not commonly used in veterinary medicine, but has been used as adjunctive therapy (with corticosteroids) in the treatment of canine immunemediated thrombocytopenia and hemolytic anemia, particularly if the patient becomes refractory to glucocorticoids and other immunosuppressive therapy. There is apparently synergism when danazol is combined with corticosteroids for these indications. Once remission is attained, some dogs may have their dosage reduced or other medications may be eliminated and be controlled with danazol alone. In humans, danazol has been used for the treatment of endometriosis, fibrocystic breast disease, idiopathic thrombocytopenic purpura and a variety of other conditions.

in vitro

previous study found that danazol as low as 1 micrometer could suppress lh-stimulated testosterone and androstenedione production in cultured leydig cells. the addition of danazol to a preparation of testicular microsomes elicited a type i cytochrome p-450 binding spectrum. danazol could inhibit progesterone and 17alpha-hydroxy-progesterone binding to microsomal p-450 [1].

in vivo

the purpose of a previous study was to examine the role of androgen and estrogen receptors in danazol suppression of luteinizing hormone (lh) in the rat. the estrogen receptor antagonist, ly 156758, partially antagonized the suppressed levels of lh after administration of danazol to ovariectomized rats. in contrast, the androgen receptor antagonist, flutamide, had no effect on suppressed lh levels after danazol treatment, but did partially reverse the inhibition of lh 24 hr after danazol administration to ovariectomized rats [2].

References

[1] barbieri rl, canick ja, ryan kj. danazol inhibits steroidogenesis in the rat testis in vitro. endocrinology. 1977 dec;101(6):1676-82.
[2] snyder bw, beecham gd, winneker rc. danazol suppression of luteinizing hormone in the rat: evidence for mediation by both androgen and estrogen receptors. proc soc exp biol med. 1990 may;194(1):54-7.
[3] cole rm, raghavan d, caterson i, teriana n, pearson b, boulas j, rosen m. danazol treatment of advanced prostate cancer: clinical and hormonal effects. prostate. 1986;9(1):15-20.