Flutamide

Flutamide

Clinical data
Trade names	Eulexin, others
Other names	Niftolide; SCH-13521; 4'-Nitro-3'-trifluoromethyl-isobutyranilide
AHFS/Drugs.com	Monograph
MedlinePlus	a697045
Pregnancy category	D
Routes of administration	By mouth
Drug class	Nonsteroidal antiandrogen
ATC code	L02BB01 ( WHO )
Legal status
Legal status	US: WARNING [1] In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	Complete (>90%) [2]
Protein binding	Flutamide: 94–96% [2] Hydroxyflutamide: 92–94% [2]
Metabolism	Liver (CYP1A2) [3] [4]
Metabolites	Hydroxyflutamide [5] [4]
Elimination half-life	Flutamide: 5–6 hours [6] [4] Hydroxyflutamide: 8–10 hours [7] [8] [4] [2]
Excretion	Urine (mainly) [2] Feces (4.2%) [2]
Identifiers
IUPAC name 2-Methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propanamide
CAS Number	13311-84-7  Y
PubChem CID	3397
IUPHAR/BPS	6943
DrugBank	DB00499  Y
ChemSpider	3280  Y
UNII	76W6J0943E
KEGG	D00586  Y
ChEBI	CHEBI:5132  Y
ChEMBL	ChEMBL806  Y
CompTox Dashboard (EPA)	DTXSID7032004
ECHA InfoCard	100.033.024
Chemical and physical data
Formula	C11H11F3N2O3
Molar mass	276.215 g·mol−1
3D model (JSmol)	Interactive image
Melting point	111.5 to 112.5 °C (232.7 to 234.5 °F)
SMILES CC(C)C(=O)NC1=CC(=C(C=C1)[N+](=O)[O-])C(F)(F)F
InChI InChI=1S/C11H11F3N2O3/c1-6(2)10(17)15-7-3-4-9(16(18)19)8(5-7)11(12,13)14/h3-6H,1-2H3,(H,15,17) Y Key:MKXKFYHWDHIYRV-UHFFFAOYSA-N Y
(verify)

Flutamide, sold under the brand name Eulexin among others, is a nonsteroidal antiandrogen (NSAA) which is used primarily to treat prostate cancer. ^{[9] [10]} It is also used in the treatment of androgen-dependent conditions like acne, excessive hair growth, and high androgen levels in women. ^[11] It is taken by mouth, usually three times per day. ^[12]

Side effects in men include breast tenderness and enlargement, feminization, sexual dysfunction, and hot flashes. Conversely, the medication has fewer side effects and is better-tolerated in women with the most common side effect being dry skin. Diarrhea and elevated liver enzymes can occur in both sexes. Rarely, flutamide can cause liver damage, lung disease, sensitivity to light, elevated methemoglobin, elevated sulfhemoglobin, and deficient neutrophils. ^{[13] [14] [15] [16]} Numerous cases of liver failure and death have been reported, which has limited the use of flutamide. ^[13]

Flutamide acts as a selective antagonist of the androgen receptor (AR), competing with androgens like testosterone and dihydrotestosterone (DHT) for binding to ARs in tissues like the prostate gland. By doing so, it prevents their effects and stops them from stimulating prostate cancer cells to grow. Flutamide is a prodrug to a more active form. Flutamide and its active form stay in the body for a relatively short time, which makes it necessary to take flutamide multiple times per day.^{[ citation needed ]}

Flutamide was first described in 1967 and was first introduced for medical use in 1983. ^[17] It became available in the United States in 1989. The medication has largely been replaced by newer and improved NSAAs, namely bicalutamide and enzalutamide, due to their better efficacy, tolerability, safety, and dosing frequency (once per day), and is now relatively little-used. ^{[6] [18]} It is on the World Health Organization's List of Essential Medicines. ^[19]

Medical uses

Prostate cancer

GnRH is released by the hypothalamus in a pulsatile fashion; this causes the anterior pituitary gland to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH stimulates the testes to produce testosterone, which is metabolized to DHT by the enzyme 5α-reductase.^{[ citation needed ]}

DHT, and to a significantly smaller extent, testosterone, stimulate prostate cancer cells to grow. Therefore, blocking these androgens can provide powerful treatment for prostate cancer, especially metastatic disease. Normally administered are GnRH analogues, such as leuprorelin or cetrorelix. Although GnRH agonists stimulate the same receptors that GnRH does, since they are present continuously and not in a pulsatile manner, they serve to inhibit the pituitary gland and therefore block the whole chain. However, they initially cause a surge in activity; this is not solely a theoretical risk but may cause the cancer to flare. Flutamide was initially used at the beginning of GnRH agonist therapy to block this surge, and it and other NSAAs continue in this use. In contrast to GnRH agonists, GnRH antagonists don't cause an initial androgen surge, and are gradually replacing GnRH agonists in clinical use.^{[ citation needed ]}

There have been studies to investigate the benefit of adding an antiandrogen to surgical orchiectomy or its continued use with a GnRH analogue (combined androgen blockade (CAB)). Adding antiandrogens to orchiectomy showed no benefit, while a small benefit was shown with adding antiandrogens to GnRH analogues.^{[ citation needed ]}

Unfortunately, therapies which lower testosterone levels, such as orchiectomy or GnRH analogue administration, also have significant side effects. Compared to these therapies, treatment with antiandrogens exhibits "fewer hot flashes, less of an effect on libido, less muscle wasting, fewer personality changes, and less bone loss." However, antiandrogen therapy alone is less effective than surgery. Nevertheless, given the advanced age of many with prostate cancer, as well as other features, many men may choose antiandrogen therapy alone for a better quality of life. ^[20]

Flutamide has been found to be similarly effective in the treatment of prostate cancer to bicalutamide, although indications of inferior efficacy, including greater compensatory increases in testosterone levels and greater reductions in PSA levels with bicalutamide, were observed. ^{[21] [22]} The medication, at a dosage of 750 mg/day (250 mg three times daily), has also been found to be equivalent in effectiveness to 250 mg/day oral cyproterone acetate as a monotherapy in the treatment of prostate cancer in a large-scale clinical trial of 310 patients, though its side effect and toxicity profiles (including gynecomastia, diarrhea, nausea, loss of appetite, and liver disturbances) were regarded as considerably worse than those of cyproterone acetate. ^[23]

A dosage of 750 mg/day flutamide (250 mg/three times a day) is roughly equivalent in terms of effectiveness to 50 mg/day bicalutamide when used as the antiandrogen component in combined androgen blockade in the treatment of advanced prostate cancer. ^[24]

Flutamide has been used to prevent the effects of the testosterone flare at the start of GnRH agonist therapy in men with prostate cancer. ^{[25] [26] [27] [28] [29] [30] [31] [32] [ excessive citations ]}

The combination of flutamide with an estrogen such as ethinylestradiol sulfonate has been used as a form of combined androgen blockade and as an alternative to the combination of flutamide with surgical or medical castration. ^[33]

Skin and hair conditions

Flutamide has been researched and used extensively in the treatment of androgen-dependent skin and hair conditions in women including acne, seborrhea, hirsutism, and scalp hair loss, as well as in hyperandrogenism (e.g., in polycystic ovary syndrome or congenital adrenal hyperplasia), and is effective in improving the symptoms of these conditions. The dosages used are lower than those used in the treatment of prostate cancer. Although flutamide continues to be used for these indications, its use in recent years has been limited due to the risk of potentially fatal hepatotoxicity, and it is no longer recommended as a first- or second-line therapy. ^{[34] [35] [36] [37]} The related NSAA bicalutamide has also been found to be effective in the treatment of hirsutism in women and appears to have comparable effectiveness to that of flutamide, ^{[38] [39] [40]} but has a far lower and only small risk of hepatotoxicity in comparison. ^{[41] [42] [43]}

Aside from its risk of liver toxicity and besides other nonsteroidal antiandrogens, it has been said that flutamide is likely the best typically used antiandrogen medication for the treatment of androgen-dependent symptoms in women. ^[44] This is related to its high effectiveness and minimal side effects. ^[44]

Acne and seborrhea

Flutamide has been found to be effective in the treatment of acne and seborrhea in women in a number of studies. ^{[45] [46]} In a long-term study of 230 women with acne, 211 of whom also had seborrhea, very-low-dose flutamide alone or in combination with an oral contraceptive caused a marked decrease in acne and seborrhea after 6 months of treatment, with maximal effect by 1 year of treatment and benefits maintained in the years thereafter. ^{[45] [47]} In the study, 97% of the women reported satisfaction with the control of their acne with flutamide. ^[48] In another study, flutamide decreased acne and seborrhea scores by 80% in only 3 months. ^{[49] [5]} In contrast, spironolactone decreased symptoms by only 40% in the same time period, suggesting superior effectiveness for flutamide for these indications. ^{[49] [50]} Flutamide has, in general, been found to reduce symptoms of acne by as much as 90% even at low doses, with several studies showing complete acne clearance. ^{[46] [51] [5]}

Excessive hair growth

Improvement of facial hirsutism in a woman with hyperandrogenism before (top) and after (bottom) treatment with 125 mg/day flutamide and an oral contraceptive for 6 months (click image to view a larger version).

Flutamide has been found to be effective in the treatment of hirsutism (excessive body/facial hair growth) in numerous studies. ^{[34] [52] [38]} It possesses moderate effectiveness for this indication, and the overall quality of the evidence is considered to be moderate. ^{[52] [34]} The medication shows equivalent or superior effectiveness to other antiandrogens including spironolactone, cyproterone acetate, and finasteride in the treatment of hirsutism, although its relatively high risk of hepatotoxicity makes it unfavorable compared to these other options. ^{[5] [34]} It has been used to treat hirsutism at dosages ranging from 62.5 mg/day to 750 mg/day. ^[44] A study found that multiple dosages of flutamide significantly reduced hirsutism in women with polycystic ovary syndrome and that there were no significant differences in the effectiveness for dosages of 125 mg/day, 250 mg/day, and 375 mg/day. ^{[34] [50] [53]} In addition, a study found that combination of 125 mg/day flutamide with finasteride was no more effective than 125 mg/day flutamide alone in the treatment of hirsutism. ^[54] These findings support the use of flutamide at lower doses for hirsutism without loss of effectiveness, which may help to lower the risk of hepatotoxicity. ^[34] However, the risk has been found to remain even at very low doses. ^[13]

Scalp hair loss

Flutamide has been found to be effective in the treatment of female pattern hair loss in a number of studies. ^{[55] [56] [57] [58]} In one study of 101 pre- and postmenopausal women, flutamide alone or in combination with an oral contraceptive produced a marked decrease in hair loss scores after 1 year of treatment, with maximum effect after 2 years of treatment and benefits maintained for another 2 years. ^{[58] [59]} In a small study of flutamide with an oral contraceptive, the medication caused an increase in cosmetically acceptance hair density in 6 of 7 women with diffuse scalp hair loss. ^[60] In a comparative study, flutamide significantly improved scalp hair growth (21% reduction in Ludwig scores) in hyperandrogenic women after 1 year of treatment, whereas cyproterone acetate and finasteride were ineffective. ^{[58] [61]}

Other uses

Flutamide has been used in case reports to decrease the frequency of spontaneous orgasms, for instance in men with post-orgasmic illness syndrome. ^{[62] [63] [64]}

Available forms

Flutamide is available in the form of 125 mg oral capsules and 250 mg oral tablets. ^{[65] [66]}

Side effects

The side effects of flutamide are sex-dependent. In men, a variety of side effects related to androgen deprivation may occur, the most common being gynecomastia and breast tenderness. ^[67] Others include hot flashes, decreased muscle mass, decreased bone mass and an associated increased risk of fractures, depression, ^[23] and sexual dysfunction including reduced libido and erectile dysfunction. ^[3] In women, flutamide is, generally, relatively well tolerated, and does not interfere with ovulation. ^[44] The only common side effect of flutamide in women is dry skin (75%), which can be attributed to a reduction of androgen-mediated sebum production. ^{[44] [5]} General side effects that may occur in either sex include dizziness, lack of appetite, gastrointestinal side effects such as nausea, vomiting, and diarrhea, a greenish-bluish discoloration of the urine, ^[5] and hepatic changes. ^{[23] [3] [68]} Because flutamide is a pure antiandrogen, unlike steroidal antiandrogens like cyproterone acetate and megestrol acetate (which additionally possess progestogenic activity), it does not appear to have a risk of cardiovascular side effects (e.g., thromboembolism) or fluid retention. ^{[69] [23] [8]}

• v
• t
• e

Side effects of combined androgen blockade with flutamide

Side effect	Flutamide 750 mg/daya + GnRH agonist (n = 294) (%)b,c	Placebo + GnRH agonist (n = 285) (%)b,c
Hot flashes	61	57
Decreased libido	36	31
Erectile dysfunction	33	29
Diarrhea	12	4
Severe	4	<1
Nausea/vomiting	11	10
Gynecomastia	9	11
Others	7	9
Other gastrointestinal disorders	6	4
Anemia	6	ND
Footnotes:a = 250 mg three times per day at 8-hour intervals. b = Phase III studies of combined androgen blockade (flutamide + GnRH agonist) in men with advanced prostate cancer. c = Incidence ≥5% regardless of causality. Sources: See template.

• v
• t
• e

Side effects of combined androgen blockade with nonsteroidal antiandrogens

Side effect	Bicalutamide 50 mg/day + GnRH agonist (n = 401) (%)a,b	Flutamide 750 mg/dayc + GnRH agonist (n = 407) (%)a,b
Hot flashes	52.6	53.3
Pain (general)	35.4	31.2
Back pain	25.4	25.8
Asthenia	22.2	21.4
Constipation	21.7	17.0
Pelvic pain	21.2	17.2
Infection	17.7	14.0
Nausea	14.0	13.6
Peripheral edema	13.2	10.3
Anemia d	12.7	14.7
Dyspnea	12.7	7.9
Diarrhea	12.2	26.3
Nocturia	12.2	13.5
Hematuria	12.0	6.4
Abdominal pain	11.3	11.3
Dizziness	10.2	8.6
Bone pain	9.2	10.6
Gynecomastia	9.0	7.4
Rash	8.7	7.4
Urinary tract infection	8.7	8.8
Chest pain	8.5	8.4
Hypertension	8.5	7.1
Coughing	8.2	5.9
Pharyngitis	8.0	5.7
Paresthesia	7.7	9.8
Elevated liver enzymes e	7.5	11.3
Markedly elevated f	0.5	2.5
Leading to withdrawal	1.5	2.0
Weight loss	7.5	9.6
Headache	7.2	6.6
Flu-like symptoms	7.0	4.9
Myasthenia	6.7	4.7
Insomnia	6.7	9.6
Erectile dysfunction	6.7	8.6
Flatulence	6.5	5.4
Hyperglycemia	6.5	6.6
Dyspepsia	6.5	5.7
Decreased appetite	6.2	7.1
Sweating	6.2	4.9
Bronchitis	6.0	2.7
Breast pain/tenderness	5.7	3.7
Urinary frequency	5.7	7.1
Elevated alkaline phosphatase	5.5	5.9
Weight gain	5.5	4.4
Arthritis	5.2	7.1
Anxiety	5.0	2.2
Urinary retention	5.0	3.4
Urinary impairment	4.7	3.7
Pneumonia	4.5	4.7
Pathological fracture	4.2	7.9
Depression	4.0	8.1
Vomiting	4.0	6.9
Rhinitis	3.7	5.4
Urinary incontinence	3.7	7.9
Footnotes:a = Phase III studies of combined androgen blockade (bicalutamide or flutamide + GnRH agonist) in men with advanced prostate cancer. b = Incidence >5% regardless of causality. c = 250 mg three times per day at 8-hour intervals. d = Anemia includes hypochromic anemia and iron deficiency anemia. e = Abnormal liver function tests reported as adverse events. f = Elevated >5 times the normal upper limit. Sources: [70] [71] [72]

Gynecomastia

Flutamide, as a monotherapy, causes gynecomastia in 30 to 79% of men, and also produces breast tenderness. ^{[73] [67]} However, more than 90% of cases of gynecomastia with NSAAs including flutamide are mild to moderate. ^{[74] [75] [69]} Tamoxifen, a selective estrogen receptor modulator (SERM) with predominantly antiestrogenic actions, can counteract flutamide-induced gynecomastia and breast pain in men.^{[ citation needed ]}

Diarrhea

Diarrhea is more common and sometimes more severe with flutamide than with other NSAAs. ^[41] In a comparative trial of combined androgen blockade for prostate cancer, the rate of diarrhea was 26% for flutamide and 12% for bicalutamide. ^[41] Moreover, 6% of flutamide-treated patients discontinued the medication due to diarrhea, whereas only 0.5% of bicalutamide-treated patients did so. ^[41] In the case of antiandrogen monotherapy for prostate cancer, the rates of diarrhea are 5 to 20% for flutamide, 2 to 5% for bicalutamide, and 2 to 4% for nilutamide. ^[41] In contrast to diarrhea, the rates of nausea and vomiting are similar among the three medications. ^[41]

Rare reactions

Liver toxicity

Although rare, flutamide has been associated with severe hepatotoxicity and death. ^{[76] [15] [77]} By 1996, 46 cases of severe cholestatic hepatitis had been reported, with 20 fatalities. ^[76] There have been continued case reports since, including liver transplants and death. ^{[78] [79]} A 2021 review of the literature found 15 cases of serious hepatotoxicity in women treated with flutamide, including 7 liver transplantations and 2 deaths. ^[80]

Based on the number of prescriptions written and the number of cases reported in the MedWatch database, the rate of serious hepatotoxicity associated with flutamide treatment was estimated in 1996 as approximately 0.03% (3 per 10,000). ^{[76] [81]} However, other research has suggested that the true incidence of significant hepatotoxicity with flutamide may be much greater, as high as 0.18 to 10%. ^{[82] [83] [13] [78] [84] [85]} Flutamide is also associated with liver enzyme elevations in up to 42 to 62% of patients, although marked elevations in liver enzymes (above 5 times upper normal limit) occur only in 3 to 5%. ^{[86] [87]} The risk of hepatotoxicity with flutamide is much higher than with nilutamide or bicalutamide. ^{[41] [42] [43]} Lower doses of the medication appear to have a possibly reduced but still significant risk. ^{[78] [88]} Liver function should be monitored regularly with liver function tests during flutamide treatment. ^[89] In addition, due to the high risk of serious hepatotoxicity, flutamide should not be used in the absence of a serious indication. ^[84]

The mechanism of action of flutamide-induced hepatotoxicity is thought to be due to mitochondrial toxicity. ^{[90] [91] [92]} Specifically, flutamide and particularly its major metabolite hydroxyflutamide inhibit enzymes in the mitochondrial electron transport chain in hepatocytes, including respiratory complexes I (NADH ubiquinone oxidoreductase), II (succinate dehydrogenase), and V (ATP synthase), and thereby reduce cellular respiration via ATP depletion and hence decrease cell survival. ^{[90] [91] [92]} Inhibition of taurocholate (a bile acid) efflux has also been implicated in flutamide-induced hepatotoxicity. ^{[90] [93]} In contrast to flutamide and hydroxyflutamide, which severely compromise hepatocyte cellular respiration in vitro, bicalutamide does not significantly do so at the same concentrations and is regarded as non-mitotoxic. ^{[90] [92]} It is thought that the nitroaromatic group of flutamide and hydroxyflutamide enhance their mitochondrial toxicity; bicalutamide, in contrast, possesses a cyano group in place of the nitro moiety, greatly reducing the potential for such toxicity. ^{[91] [94]}

The hepatotoxicity of flutamide appears to depend on hydrolysis of flutamide catalyzed by an arylacetamide deacetalyse enzyme. ^[13] This is analogous to the hepatotoxicity that occurs with the withdrawn paracetamol (acetominophen)-related medication phenacetin. ^[13] In accordance, the combination of paracetamol (acetaminophen) and flutamide appears to result in additive to synergistic hepatotoxicity, indicating a potential drug interaction. ^{[13] [93]}

Hepatotoxicity with flutamide may be cross-reactive with that of cyproterone acetate. ^[95]

Others

Flutamide has also been associated with interstitial pneumonitis (which can progress to pulmonary fibrosis). ^[15] The incidence of interstitial pneumonitis with flutamide was found to be 0.04% (4 per 10,000) in a large clinical cohort of 41,700 prostate cancer patients. ^[14] A variety of case reports have associated flutamide with photosensitivity. ^[15] Flutamide has been associated with several case reports of methemoglobinemia. ^{[96] [16]} Bicalutamide does not appear to share this risk with flutamide. ^[16] Flutamide has also been associated with reports of sulfhemoglobinemia and neutropenia. ^[16]

Birth defects

Out of the available endocrine-disrupting compounds looked at, flutamide has a notable effect on anogenital distance in rats. ^{[97] [98]} )

Pharmacology

Pharmacodynamics

Hydroxyflutamide, the active form of flutamide.

Antiandrogenic activity

• v
• t
• e

Affinities ^{[lower-alpha 1] [99]}

Compound	RBA Tooltip Relative binding affinity [lower-alpha 2]
Metribolone	100
Dihydrotestosterone	85
Cyproterone acetate	7.8
Bicalutamide	1.4
Nilutamide	0.9
Hydroxyflutamide	0.57
Flutamide	<0.0057
Notes: At androgen receptors; measured in human prostate tissue. Relative to Metribolone, which is by definition 100%

• v
• t
• e

Relative potencies of selected antiandrogens

Antiandrogen	Relative potency
Bicalutamide	4.3
Hydroxyflutamide	3.5
Flutamide	3.3
Cyproterone acetate	1.0
Zanoterone	0.4
Description: Relative potencies of orally administered antiandrogens in antagonizing 0.8 to 1.0 mg/kg s.c. Tooltip subcutaneous injection testosterone propionate-induced ventral prostate weight increase in castrated immature male rats. Higher values mean greater potency. Sources: See template.

Androgen receptor antagonistic potency of spironolactone, cyproterone acetate, and flutamide in castrated male rats treated with exogenous testosterone (as measured by inhibition of androgen-dependent ventral prostate weight). Bicalutamide is a much more potent androgen receptor antagonist than flutamide both in animals and in humans.

Flutamide acts as a selective, competitive, silent antagonist of the androgen receptor (AR). ^[7] Its active form, hydroxyflutamide, has between 10- and 25-fold higher affinity for the AR than does flutamide, and hence is a much more potent AR antagonist in comparison. ^{[7] [69] [104] [105]} However, at high concentrations, unlike flutamide, hydroxyflutamide is able to weakly activate the AR. ^{[7] [106]} Flutamide has far lower affinity for the AR than do steroidal antiandrogens like spironolactone and cyproterone acetate, and it is a relatively weak antiandrogen in terms of potency by weight, but the large dosages at which flutamide is used appear to compensate for this. ^[107] In accordance with its selectivity for the AR, flutamide does not interact with the progesterone, estrogen, glucocorticoid, or mineralocorticoid receptor, ^[108] and possesses no intrinsic progestogenic, estrogenic, glucocorticoid, or antigonadotropic activity. ^{[5] [109]} However, it can have some indirect estrogenic effects via increased levels of estradiol secondary to AR blockade, and this involved in the gynecomastia it can produce. Because flutamide does not have any estrogenic, progestogenic, or antigonadotropic activity, the medication does not cause menstrual irregularities in women. ^{[45] [109]} This is in contrast to steroidal antiandrogens like spironolactone and cyproterone acetate. ^[45] Similarly to nilutamide, bicalutamide, and enzalutamide, flutamide crosses the blood–brain barrier and exerts central antiandrogen actions. ^[110]

Flutamide has been found to be equal to slightly more potent than cyproterone acetate and substantially more potent than spironolactone as an antiandrogen in bioassays. ^{[99] [100]} This is in spite of the fact that hydroxyflutamide has on the order of 10-fold lower affinity for the AR relative to cyproterone acetate. ^{[99] [111]} Hydroxyflutamide shows about 2- to 4-fold lower affinity for the rat and human AR than does bicalutamide. ^[112] In addition, whereas bicalutamide has an elimination half-life of around 6 days, hydroxyflutamide has an elimination half-life of only 8 to 10 hours, a roughly 17-fold difference. ^[112] In accordance, at dosages of 50 mg/day bicalutamide and 750 mg/day flutamide (a 15-fold difference), circulating levels of flutamide at steady-state have been found to be approximately 7.5-fold lower than those of bicalutamide. ^[112] Moreover, whereas flutamide at this dosage has been found to produce a 75% reduction in prostate-specific antigen levels in men with prostate cancer, a fall of 90% has been demonstrated with this dosage of bicalutamide. ^[112] In accordance, 50 mg/day bicalutamide has been found to possess equivalent or superior effectiveness to 750 mg/day flutamide in a large clinical trial for prostate cancer. ^[112] Also, bicalutamide has been shown to be 5-fold more potent than flutamide in rats and 50-fold more potent than flutamide in dogs. ^[112] Taken together, flutamide appears to be a considerably less potent and efficacious antiandrogen than is bicalutamide. ^[112]

Dose-ranging studies of flutamide in men with benign prostatic hyperplasia and prostate cancer alone and in combination with a GnRH agonist have been performed. ^{[113] [114]}

Flutamide increases testosterone levels by 5- to 10-fold in gonadally intact male rats. ^[115]

• v
• t
• e

Relative affinities of first-generation nonsteroidal antiandrogens for the androgen receptor

Species	IC50 Tooltip Half maximal inhibitory concentration (nM)			RBA Tooltip Relative binding affinity (ratio)
	Bicalutamide	2-Hydroxyflutamide	Nilutamide	Bica / 2-OH-flu	Bica / nilu	Ref
Rat	190	700	ND	4.0	ND	[116]
Rat	~400	~900	~900	2.3	2.3	[117]
Rat	ND	ND	ND	3.3	ND	[118]
Rata	3595	4565	18620	1.3	5.2	[119]
Human	~300	~700	~500	2.5	1.6	[120]
Human	~100	~300	ND	~3.0	ND	[121]
Humana	2490	2345	5300	1.0	2.1	[119]
Footnotes:a = Controversial data. Sources: See template.

• v
• t
• e

Plasma levels and binding potential of flutamide and bicalutamide during first week

Day	Total levels (ng/mL)		Free levels (ng/mL)		Ratios
	Bicalutamide	Flutamidea	Bicalutamide	Flutamidea	Free	Binding potentialb
1	901	940	36.0	66	0.55	2.18
2	1613	1500	64.5	105	0.61	2.46
3	2345	1500	93.8	105	0.89	3.57
4	2969	1500	118.8	105	1.13	4.53
7	4259	1500	170.4	105	1.62	6.49
Notes: During first week of treatment. Dosages not provided. Footnotes:a = As 2-hydroxyflutamide (the active form of flutamide). b = Assumes, on the basis of ligand binding assays, that bicalutamide possesses 4-fold greater affinity for the androgen receptor than 2-hydroxyflutamide. Sources: See template.

CYP17A1 inhibition

Flutamide and hydroxyflutamide have been found in vitro to inhibit CYP17A1 (17α-hydroxylase/17,20-lyase), an enzyme which is required for the biosynthesis of androgens. ^[122] In accordance, flutamide has been found to slightly but significantly lower androgen levels in GnRH analogue-treated male prostate cancer patients ^[123] and women with polycystic ovary syndrome. ^[5] In a directly comparative study of flutamide monotherapy (375 mg once daily) versus bicalutamide monotherapy (80 mg once daily) in Japanese men with prostate cancer, after 24 weeks of treatment flutamide decreased dehydroepiandrosterone (DHEA) levels by about 44% while bicalutamide increased them by about 4%. ^[22] As such, flutamide is a weak inhibitor of androgen biosynthesis. ^[107] However, the clinical significance of this action may be limited when flutamide is given without a GnRH analogue to non-castrated men, as the medication markedly elevates testosterone levels into the high normal male range via prevention of AR activation-mediated negative feedback on the hypothalamic–pituitary–gonadal axis in this context. ^[37]

Other activities

Flutamide has been identified as an agonist of the aryl hydrocarbon receptor. ^{[124] [125]} This may be involved in the hepatotoxicity of flutamide. ^[124]

Pharmacokinetics

The absorption of flutamide is complete upon oral ingestion. ^[2] Food has no effect on the bioavailability of flutamide. ^[2] Steady-state levels of hydroxyflutamide, the active form of flutamide, are achieved after 2 to 4 days administration. ^[5] Levels of hydroxyflutamide are approximately 50-fold higher than those of flutamide at steady-state. ^[126]

The plasma protein binding of flutamide and hydroxyflutamide are high; 94 to 96% and 92 to 94%, respectively. ^[2] Flutamide and its metabolite hydroxyflutamide are known to be transported by the multidrug resistance-associated protein 1 (MRP1; ABCC1). ^{[127] [128]}

Flutamide is metabolized by CYP1A2 (via α-hydroxylation) in the liver during first-pass metabolism ^[3] to its main metabolite hydroxyflutamide (which accounts for 23% of an oral dose of flutamide one hour post-ingestion), ^[5] and to at least five other, minor metabolites. ^[4] Flutamide has at least 10 inactive metabolites total, including 4-nitro-3-fluoro-methylaniline. ^[129]

Flutamide is excreted in various forms in the urine, the primary form being 2-amino-5-nitro-4-(trifluoromethyl)phenol. ^[130]

Flutamide and hydroxyflutamide have elimination half-lives of 4.7 hours and 6 hours in adults, respectively. ^{[129] [6] [4]} However, the half-life of hydroxyflutamide is extended to 8 hours after a single dose and to 9.6 hours at steady state) in elderly individuals. ^{[129] [8] [7] [4] [2]} The elimination half-lives of flutamide and hydroxyflutamide are regarded as too short to allow for once-daily dosing, and for this reason, flutamide is instead administered three times daily at 8-hour intervals. ^[131] In contrast, the newer NSAAs nilutamide, bicalutamide, and enzalutamide all have much longer half-lives, ^[8] and this allows for once-daily administration in their cases. ^[132]

Chemistry

Unlike the hormones with which it competes, flutamide is not a steroid; rather, it is a substituted anilide. Hence, it is described as nonsteroidal in order to distinguish it from older steroidal antiandrogens such as cyproterone acetate and megestrol acetate.

Synthesis

Synthesis. Patents:

Schotten–Baumann reaction between 4-nitro-3-(trifluoromethyl)aniline [393-11-3] (1) with isobutanoyl chloride [79-30-1] (2) in the presence of triethylamine.

History

Flutamide was first synthesized in 1967 by Neri and colleagues at Schering Plough Corporation. ^{[10] [140] [8] [134]} It was originally synthesized as a bacteriostatic agent, but was subsequently, and serendipitously found to possess antiandrogen activity. ^{[5] [134]} The code name of flutamide during development was SCH-13521. ^[141] Clinical research of the medication began in 1971, ^[142] and it was first marketed in 1983, specifically in Chile under the brand name Drogenil and in West Germany under the brand name Flugerel. ^{[143] [144]} Flutamide was not introduced in the United States until 1989; it was specifically approved by the U.S. Food and Drug Administration for the treatment of metastatic prostate cancer in combination with a gonadotropin-releasing hormone (GnRH) analogue. ^[145] The medication was first studied for the treatment of hirsutism in women in 1989. ^{[146] [147] [148]} It was the first "pure antiandrogen" to be studied in the treatment of hirsutism. ^[146] Flutamide was the first NSAA to be introduced, and was followed by nilutamide in 1989 and then bicalutamide in 1995. ^[149]

Society and culture

Generic names

Flutamide is the generic name of the drug and its INN Tooltip International Nonproprietary Name, USAN Tooltip United States Adopted Name, BAN Tooltip British Approved Name, DCF Tooltip Dénomination Commune Française, and JAN Tooltip Japanese Accepted Name. ^{[150] [9] [10]} Its names in Latin, German, and Spanish are flutamidum, flutamid, and flutamida, respectively. ^{[150] [9]} The medication has also been referred to by the name niftolide. ^[10]

Brand names

Brand names of flutamide include or have included Cebatrol, Cytomid, Drogenil, Etaconil, Eulexin, Flucinom, Flumid, Flutacan, Flutamid, Flutamida, Flutamin, Flutan, Flutaplex, Flutasin, Fugerel, Profamid, and Sebatrol, among others. ^{[150] [9] [10]}

Availability

Flutamide is marketed widely throughout the world, including in the United States, Canada, Europe, Australia, New Zealand, South Africa, Central and South America, East and Southeast Asia, India, and the Middle East. ^{[150] [9]}

Research

Prostate cancer

The combination of an estrogen and flutamide as a form of combined androgen blockade for the treatment of prostate cancer has been researched. ^{[151] [152] [153] [154] [155]}

Enlarged prostate

Flutamide has been studied in the treatment of benign prostatic hyperplasia (BPH; enlarged prostate) in men in several clinical studies. ^{[156] [157]} It has been found to reduce prostate volume by about 25%, which is comparable to the reduction achieved with the 5α-reductase inhibitor finasteride. ^[158] Unfortunately, it has been associated with side effects in these studies including gynecomastia and breast tenderness (in about 50% of patients), gastrointestinal disturbances such as nausea, diarrhea, and flatulence, and hepatotoxicity, although sexual function including libido and erectile potency were maintained. ^[158]

Breast cancer

Flutamide was studied for the treatment of advanced breast cancer in two phase II clinical trials but was found to be ineffective. ^{[159] [160] [161] [162]} Out of a total of 47 patients, only three short-term responses occurred. ^[159] However, the patients in the studies were selected irrespective of AR, ER Tooltip estrogen receptor, PR Tooltip progesterone receptor, or HER2 status, which were all unknown. ^{[160] [163]}

Psychiatric disorders

Flutamide has been studied in the treatment of bulimia nervosa in women. ^{[164] [165] [166] [167]}

Flutamide was found to be effective in the treatment of obsessive–compulsive disorder (OCD) in men with comorbid Tourette's syndrome in one small randomized controlled trial. ^[168] Conversely, it was ineffective in patients with OCD in another study. ^[168] More research is necessary to determine whether flutamide is effective in the treatment of OCD. ^[168]

References

1. "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 Oct 2023.
2. "Flutamide Capsules USP".
3. Lehne RA (2013). "Chapter 103: Anticancer Drugs II: Hormonal Agents, Targeted Drugs, and Other Noncytotoxic Anticancer Drugs". Pharmacology for Nursing Care. Elsevier Health Sciences. pp. 1297–. ISBN   978-1-4377-3582-6.
4. Chabner BA, Longo DL (8 November 2010). Cancer Chemotherapy and Biotherapy: Principles and Practice. Lippincott Williams & Wilkins. pp. 679–. ISBN   978-1-60547-431-1.
5. Diamanti-Kandarakis E (September 1999). "Current aspects of antiandrogen therapy in women". Current Pharmaceutical Design. 5 (9): 707–723. doi:10.2174/1381612805666230111201150. PMID   10495361.
6. Gulley JL (2011). Prostate Cancer. Demos Medical Publishing. pp. 81–. ISBN   978-1-935281-91-7.
7. Lemke TL, Williams DA (24 January 2012). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 1373–. ISBN   978-1-60913-345-0.
8. Piotrowski Z, Greenberg RE (1 March 1999). "Antiandrogen Monotherapy in the Treatment of Prostate Cancer". In Denis LJ, Griffiths K, Kaisary AV, Murphy GP (eds.). Textbook of Prostate Cancer: Pathology, Diagnosis and Treatment: Pathology, Diagnosis and Treatment. CRC Press. pp. 279–280. ISBN   978-1-85317-422-3.
9. Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 466–. ISBN   978-3-88763-075-1.
10. Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 573–. ISBN   978-1-4757-2085-3.
11. "Polycystic Ovary Syndrome - Treatment - NHS Choices". Nhs.uk. 2011-10-17. Retrieved 2013-01-04.
12. Mungadi IA, Shittu OB, Abdulwahab-Ahmed A (30 November 2013). "Prostate Cancer". In Mungadi IA, Mbibu HN, Eltahawy E, Abdulwahab-Ahmed A (eds.). Manual of Medical Treatment in Urology. JP Medical Ltd. pp. 120–. ISBN   978-93-5090-844-0.
13. Giorgetti R, di Muzio M, Giorgetti A, Girolami D, Borgia L, Tagliabracci A (March 2017). "Flutamide-induced hepatotoxicity: ethical and scientific issues". European Review for Medical and Pharmacological Sciences. 21 (1 Suppl): 69–77. PMID   28379593.
14. Bennett CL, Raisch DW, Sartor O (October 2002). "Pneumonitis associated with nonsteroidal antiandrogens: presumptive evidence of a class effect". Annals of Internal Medicine. 137 (7): 625. doi:10.7326/0003-4819-137-7-200210010-00029. PMID   12353966. An estimated 0.77% of the 6,480 nilutamide-treated patients, 0.04% of the 41,700 flutamide-treated patients, and 0.01% of the 86,800 bicalutamide-treated patients developed pneumonitis during the study period.
15. Aronson JK (19 April 2010). Meyler's Side Effects of Drugs in Cancer and Immunology. Elsevier. pp. 318–319. ISBN   978-0-08-093288-0.
16. McLeod DG (1997). "Tolerability of Nonsteroidal Antiandrogens in the Treatment of Advanced Prostate Cancer". The Oncologist. 2 (1): 18–27. doi: 10.1634/theoncologist.2-1-18 . PMID   10388026.
17. Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 515. ISBN   9783527607495.
18. Wirth MP, Hakenberg OW, Froehner M (1 January 2008). "Adjuvant Hormonal Treatment - The Bicalutamide Early Prostate Cancer Program". In Moser L (ed.). Controversies in the Treatment of Prostate Cancer. Karger Medical and Scientific Publishers. pp. 41–42. ISBN   978-3-8055-8524-8. Latest studies suggest that [flutamide] also reduces adrenal and ovarian androgen synthesis [58,59]. [...] No alteration in the hormone levels has been observed in patients treated with flutamide for 6 or 12 months [61,62]. However in other studies flutamide decreased circulating concentrations of DHEAS as well as androstenedione, total testosterone and 3a-androstanediol glucuronide, in young women with PCOS [41,59]. These effects may be due to inhibition of adrenal 17-20 lyase [17,63]. Although there was no effect on gonadotropin response to GnRH, basal levels of FSH showed a rise associated with a small fall of LH [64].
19. World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl: 10665/345533 . WHO/MHP/HPS/EML/2021.02.
20. Scher, Howard I. (2005). "Hyperplastic and Malignant Diseases of the Prostate". In Dennis L. Kasper, Anthony S. Fauci, Dan L. Longo, Eugene Braunwald, Stephen L. Hauser, & J. Larry Jameson (Eds.), Harrison's Principles of Internal Medicine (16th edition), pp. 548–9. New York: McGraw-Hill.
21. Helsen C, Van den Broeck T, Voet A, Prekovic S, Van Poppel H, Joniau S, et al. (August 2014). "Androgen receptor antagonists for prostate cancer therapy". Endocrine-Related Cancer. 21 (4): T105–T118. doi: 10.1530/ERC-13-0545 . PMID   24639562.
22. Nakai Y, Tanaka N, Anai S, Miyake M, Tatsumi Y, Fujimoto K (August 2015). "A Randomized Control Trial Comparing the Efficacy of Antiandrogen Monotherapy: Flutamide vs. Bicalutamide". Hormones & Cancer. 6 (4): 161–167. doi:10.1007/s12672-015-0226-1. PMC   10355925 . PMID   26024831. S2CID   10625154.
23. Slovin SF (29 September 2015). "Sipuleucel-T - A Model for Immunotherapy Trial Development". In Mydlo JH, Godec CJ (eds.). Prostate Cancer: Science and Clinical Practice. Elsevier Science. pp. 516–521, 534–540. ISBN   978-0-12-800592-7.
24. Fradet Y (February 2004). "Bicalutamide (Casodex) in the treatment of prostate cancer". Expert Review of Anticancer Therapy. 4 (1): 37–48. doi:10.1586/14737140.4.1.37. PMID   14748655. S2CID   34153031.
25. Thompson IM (2001). "Flare Associated with LHRH-Agonist Therapy". Reviews in Urology. 3 (Suppl 3): S10–S14. PMC   1476081 . PMID   16986003.
26. Scaletscky R, Smith JA (April 1993). "Disease flare with gonadotrophin-releasing hormone (GnRH) analogues. How serious is it?". Drug Safety. 8 (4): 265–270. doi:10.2165/00002018-199308040-00001. PMID   8481213. S2CID   36964191.
27. Noguchi K, Uemura H, Harada M, Miura T, Moriyama M, Fukuoka H, et al. (February 2001). "Inhibition of PSA flare in prostate cancer patients by administration of flutamide for 2 weeks before initiation of treatment with slow-releasing LH-RH agonist". International Journal of Clinical Oncology. 6 (1): 29–33. doi:10.1007/PL00012076. PMID   11706524. S2CID   23123697.
28. Schulze H, Senge T (October 1990). "Influence of different types of antiandrogens on luteinizing hormone-releasing hormone analogue-induced testosterone surge in patients with metastatic carcinoma of the prostate". The Journal of Urology. 144 (4): 934–941. doi:10.1016/S0022-5347(17)39625-8. PMID   2144596.
29. Tsushima T, Nasu Y, Saika T, Maki Y, Noda M, Suyama B, et al. (2001). "Optimal starting time for flutamide to prevent disease flare in prostate cancer patients treated with a gonadotropin-releasing hormone agonist". Urologia Internationalis. 66 (3): 135–139. doi:10.1159/000056592. PMID   11316974. S2CID   38018788.
30. Labrie F, Dupont A, Belanger A, Lachance R (October 1987). "Flutamide eliminates the risk of disease flare in prostatic cancer patients treated with a luteinizing hormone-releasing hormone agonist". The Journal of Urology. 138 (4): 804–806. doi:10.1016/S0022-5347(17)43380-5. PMID   3309363.
31. Crawford ED, Eisenberger MA, McLeod DG, Spaulding JT, Benson R, Dorr FA, et al. (August 1989). "A controlled trial of leuprolide with and without flutamide in prostatic carcinoma". The New England Journal of Medicine. 321 (7): 419–424. doi:10.1056/NEJM198908173210702. PMID   2503724.
32. Ferrari P, Castagnetti G, Ferrari G, Pollastri CA, Tavoni F, Dotti A (December 1993). "Combination treatment in M1 prostate cancer". Cancer. 72 (12 Suppl): 3880–3885. doi: 10.1002/1097-0142(19931215)72:12+<3880::AID-CNCR2820721724>3.0.CO;2-4 . PMID   8252509. S2CID   21911154.
33. Schnorr D (7 March 2013). "Palliativtherapie des hämatogen metastasierten Prostatakarzinoms". In Hinkelbein W, Miller K, Wiegel T (eds.). Prostatakarzinom — urologische und strahlentherapeutische Aspekte: urologische und strahlentherapeutische Aspekte[Prostate carcinoma — urological and radiotherapeutic aspects: urological and radiotherapeutic aspects]. Springer-Verlag. pp. 99–. ISBN   978-3-642-60064-7.
34. Somani N, Turvy D (July 2014). "Hirsutism: an evidence-based treatment update". American Journal of Clinical Dermatology. 15 (3): 247–266. doi:10.1007/s40257-014-0078-4. PMID   24889738. S2CID   45234892.
35. Ostrzenski A (2002). "Hyperandrogenism". Gynecology: Integrating Conventional, Complementary, and Natural Alternative Therapy. Lippincott Williams & Wilkins. pp. 86–. ISBN   978-0-7817-2761-7.
36. Olsen EA (26 June 2008). "Female Pattern Hair Loss". In Blume-Peytavi U, Whiting DA, Trüeb RM (eds.). Hair Growth and Disorders. Springer Science & Business Media. pp. 181–. ISBN   978-3-540-46911-7.
37. Matsumoto AM (2001). "Clinical Use and Abuse of Androgens and Antiandrogens". In Becker KL (ed.). Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. pp. 1196, 1208. ISBN   978-0-7817-1750-2.
38. Müderri̇s, İ. İ., & Öner, G. (2009). Flutamide and Bicalutamide Treatment in Hirsutism. Turkiye Klinikleri Journal of Endocrinology-Special Topics, 2(2), 110. http://www.turkiyeklinikleri.com/article/en-hirsutizm-tedavisinde-flutamid-ve-bikalutamid-kullanimi-55753.html
39. Erem C (2013). "Update on idiopathic hirsutism: diagnosis and treatment". Acta Clinica Belgica. 68 (4): 268–274. doi:10.2143/ACB.3267. PMID   24455796. S2CID   39120534.
40. Müderris II, Bayram F, Ozçelik B, Güven M (February 2002). "New alternative treatment in hirsutism: bicalutamide 25 mg/day". Gynecological Endocrinology. 16 (1): 63–66. doi:10.1080/gye.16.1.63.66. PMID   11915584. S2CID   6942048.
41. Kolvenbag GJ, Furr BJ (2009). "Nonsteroidal Antiandrogens". In Jordan VC, Furr VJ (eds.). Hormone Therapy in Breast and Prostate Cancer. Humana Press. pp. 347–368. doi:10.1007/978-1-59259-152-7_16. ISBN   978-1-60761-471-5.
42. Dansette P, Snyder RR, Monks TJ, Jollow DJ, Sipes IG, Greim H, et al. (6 December 2012). Biological Reactive Intermediates Vi: Chemical and Biological Mechanisms in Susceptibility to and Prevention of Environmental Diseases. Springer Science & Business Media. pp. 37–. ISBN   978-1-4615-0667-6.
43. Ramon J, Denis LJ (5 June 2007). Prostate Cancer. Springer Science & Business Media. pp. 256–. ISBN   978-3-540-40901-4.
44. Moghetti P (8 November 2007). "Ovarian Suppression and Treatment of Hirsutism". In Azziz R (ed.). Androgen Excess Disorders in Women. Springer Science & Business Media. pp. 384–. ISBN   978-1-59745-179-6.
45. Husein-ElAhmed H (2015). "Management of acne vulgaris with hormonal therapies in adult female patients". Dermatologic Therapy. 28 (3): 166–172. doi: 10.1111/dth.12231 . PMID   25845307. S2CID   2628354.
46. Bettoli V, Zauli S, Virgili A (July 2015). "Is hormonal treatment still an option in acne today?". The British Journal of Dermatology. 172 (Suppl 1): 37–46. doi:10.1111/bjd.13681. PMID   25627824. S2CID   35615492.
47. Paradisi R, Fabbri R, Porcu E, Battaglia C, Seracchioli R, Venturoli S (October 2011). "Retrospective, observational study on the effects and tolerability of flutamide in a large population of patients with acne and seborrhea over a 15-year period". Gynecological Endocrinology. 27 (10): 823–829. doi:10.3109/09513590.2010.526664. PMID   21117864. S2CID   20250916.
48. Trivedi MK, Shinkai K, Murase JE (March 2017). "A Review of hormone-based therapies to treat adult acne vulgaris in women". International Journal of Women's Dermatology. 3 (1): 44–52. doi:10.1016/j.ijwd.2017.02.018. PMC   5419026 . PMID   28492054.
49. Shelley WB, Shelley ED (2001). Advanced Dermatologic Therapy II. W. B. Saunders. ISBN   978-0-7216-8258-7.
50. Layton AM (October 2010). "Treatment of hyperandrogenism in polycystic ovary syndrome". In Balen A, Franks S, Homburg R, Kehoe S (eds.). Current Management of Polycystic Ovary Syndrome. Cambridge University Press. pp. 132–. ISBN   978-1-906985-41-7.
51. Nguyen HL, Tollefson MM (August 2017). "Endocrine disorders and hormonal therapy for adolescent acne". Current Opinion in Pediatrics. 29 (4): 455–465. doi:10.1097/MOP.0000000000000515. PMID   28562419. S2CID   4640778.
52. Schmidt TH, Shinkai K (October 2015). "Evidence-based approach to cutaneous hyperandrogenism in women". Journal of the American Academy of Dermatology. 73 (4): 672–690. doi:10.1016/j.jaad.2015.05.026. PMID   26138647.
53. Calaf J, López E, Millet A, Alcañiz J, Fortuny A, Vidal O, et al. (September 2007). "Long-term efficacy and tolerability of flutamide combined with oral contraception in moderate to severe hirsutism: a 12-month, double-blind, parallel clinical trial". The Journal of Clinical Endocrinology and Metabolism. 92 (9): 3446–3452. doi: 10.1210/jc.2006-2798 . hdl: 10668/684 . PMID   17566093.
54. Yasa C, Dural Ö, Bastu E, Uğurlucan FG (2016). "Hirsutism, Acne, and Hair Loss: Management of Hyperandrogenic Cutaneous Manifestations of Polycystic Ovary Syndrome". Gynecology Obstetrics & Reproductive Medicine. 23 (2): 110–119. doi: 10.21613/GORM.2016.613 . ISSN   1300-4751.
55. Kelly Y, Blanco A, Tosti A (September 2016). "Androgenetic Alopecia: An Update of Treatment Options". Drugs. 76 (14): 1349–1364. doi:10.1007/s40265-016-0629-5. PMID   27554257. S2CID   35875856.
56. Brough KR, Torgerson RR (March 2017). "Hormonal therapy in female pattern hair loss". International Journal of Women's Dermatology. 3 (1): 53–57. doi:10.1016/j.ijwd.2017.01.001. PMC   5419033 . PMID   28492055.
57. van Zuuren EJ, Fedorowicz Z, Carter B (November 2012). "Evidence-based treatments for female pattern hair loss: a summary of a Cochrane systematic review". The British Journal of Dermatology. 167 (5): 995–1010. doi:10.1111/j.1365-2133.2012.11166.x. PMID   23039053. S2CID   205263486.
58. Levy LL, Emer JJ (August 2013). "Female pattern alopecia: current perspectives". International Journal of Women's Health. 5: 541–556. doi: 10.2147/IJWH.S49337 . PMC   3769411 . PMID   24039457.
59. Paradisi R, Porcu E, Fabbri R, Seracchioli R, Battaglia C, Venturoli S (April 2011). "Prospective cohort study on the effects and tolerability of flutamide in patients with female pattern hair loss". The Annals of Pharmacotherapy. 45 (4): 469–475. doi:10.1345/aph.1P600. PMID   21487083. S2CID   38456195.
60. Diamanti-Kandarakis E (September 1999). "Current aspects of antiandrogen therapy in women". Current Pharmaceutical Design. 5 (9): 707–723. doi:10.2174/1381612805666230111201150. PMID   10495361. Several trials demonstrated complete clearing of acne with flutamide [62,77]. Flutamide used in combination with an [oral contraceptive], at a dose of 500mg/d, flutamide caused a dramatic decrease (80%) in total acne, seborrhea and hair loss score after only 3 months of therapy [53]. When used as a monotherapy in lean and obese PCOS, it significantly improves the signs of hyperandrogenism, hirsutism and particularly acne [48]. [...] flutamide 500mg/d combined with an [oral contraceptive] caused an increase in cosmetically acceptable hair density, in sex of seven women suffering from diffuse androgenetic alopecia [53].
61. Carmina E, Lobo RA (January 2003). "Treatment of hyperandrogenic alopecia in women". Fertility and Sterility. 79 (1): 91–95. doi: 10.1016/s0015-0282(02)04551-x . PMID   12524069.
62. Waldinger MD, Schweitzer DH (2002). "Postorgasmic illness syndrome: two cases". Journal of Sex & Marital Therapy. 28 (3): 251–255. doi:10.1080/009262302760328280. PMID   11995603. S2CID   27162173.
63. Reinert AE, Simon JA (July 2017). ""Did You Climax or Are You Just Laughing at Me?" Rare Phenomena Associated With Orgasm". Sexual Medicine Reviews. 5 (3): 275–281. doi:10.1016/j.sxmr.2017.03.004. PMID   28454896.
64. Paulos MR, Avelliino GJ (January 2020). "Post-orgasmic illness syndrome: history and current perspectives". Fertility and Sterility. 113 (1): 13–15. doi: 10.1016/j.fertnstert.2019.11.021 . PMID   32033716. S2CID   211064753.
65. Brueggemeier RW (2 March 2018). "Analogs and Antagonists of Male Sex Hormones". In Meyers RA (ed.). Translational Medicine: Molecular Pharmacology and Drug Discovery. Wiley. pp. 46–. doi:10.1002/3527600906.mcb.200500066.pub2 (inactive 2024-09-01). ISBN   978-3-527-68719-0.
66. Thomson Micromedex, United States Pharmacopeia (November 2002). Consumer Drug Reference 2003. Consumer Reports Books. ISBN   978-0-89043-971-5.
67. Chentli F, Belhimer F (July 2013). "Severe gynecomastia due to anti androgens intake: A case report and literature review". Indian Journal of Endocrinology and Metabolism. 17 (4): 730–732. doi: 10.4103/2230-8210.113770 . PMC   3743379 . PMID   23961495.
68. Roberts J, Snyder DL, Friedman E (14 August 1996). "Pharmacology of Cancer Chemotherapeutic and Immunotherapeutic Agents". Handbook of Pharmacology on Aging. CRC Press. pp. 334–. ISBN   978-0-8493-8306-9.
69. Pratt WB (1994). "Drugs Affecting Endocrine Function". The Anticancer Drugs. Oxford University Press. pp. 219–220. ISBN   978-0-19-506739-2.
70. "Casodex Product Monograph" (PDF). Retrieved 24 September 2018. Table 1 Incidence of Adverse Reactions (≥ 5% in Either Treatment Group) Regardless of Causality [...] Increased Liver Enzyme Test: [...] [Number of Patients (%)] [...] CASODEX Plus LHRH Analog (n=401): 30 (7 [7.5%) [...] Flutamide Plus LHRH Analog (n=407): 46 (11 [11.3%]).
71. "NU-Bicalutamide Product Monograph" (PDF). Retrieved 24 September 2018. Adverse event reports of abnormal liver function test results occurred in 7% of patients. These changes were frequently transient and rarely severe, resolving or improving with continued therapy or following cessation of therapy. Hepatic failure and interstitial lung disease (see WARNINGS AND PRECAUTIONS) have been observed in post-marketed data and fatal outcomes have been reported for both. [...] The most common adverse events leading to withdrawal of study medication were abnormal liver function tests (1.5%) [...] Table 1 Incidence Of Adverse Events (≥ 5% In Either Treatment Group) Regardless Of Causality [...] Increased Liver Enzyme Test^b [Number of Patients (%)] [...] CASODEX Plus LHRH Analogue (n=401): 30 (7 [7.5%]) [...] Flutamide Plus LHRH Analogue (n=407): 46 (11 [11.3%]) [...] During the first few months of use, you may be monitored by your physician for signs of changes in your liver function. In approximately 2.0% of patients, such changes may lead to withdrawal of therapy.
72. Blackledge GR (1996). "Clinical progress with a new antiandrogen, Casodex (bicalutamide)". Eur. Urol. 29 Suppl 2: 96–104. doi:10.1159/000473847. PMID   8717470. Casodex has been administered to over 3,900 subjects and patients and, in general, has been well tolerated. [...] Elevations of liver transaminases have been seen with Casodex, but these are usually transient, resolving either on continued therapy or on temporary cessation of therapy. In a randomised comparison with flutamide, elevations of transaminases were both less frequent and less severe than with flutamide. No cases of fulminant hepatic failure or death due to hepatic failure have been seen with Casodex in any of the clinical trials.
73. Di Lorenzo G, Autorino R, Perdonà S, De Placido S (December 2005). "Management of gynaecomastia in patients with prostate cancer: a systematic review". The Lancet. Oncology. 6 (12): 972–979. doi:10.1016/S1470-2045(05)70464-2. PMID   16321765.
74. Gillatt D (August 2006). "Antiandrogen treatments in locally advanced prostate cancer: are they all the same?". Journal of Cancer Research and Clinical Oncology. 132 (S1): S17–S26. doi:10.1007/s00432-006-0133-5. PMID   16845534. S2CID   23888640. Unlike CPA, non-steroidal antiandrogens appear to be better tolerated than castration, allowing patients to maintain sexual activity, physical ability, and bone mineral density, but these agents have a higher incidence of gynecomastia and breast pain (mild to moderate in > 90% of cases).
75. Goldspiel BR, Kohler DR (June 1990). "Flutamide: an antiandrogen for advanced prostate cancer". DICP. 24 (6): 616–623. doi:10.1177/106002809002400612. PMID   2193461. S2CID   26125621. [...] They [in patients treated with flutamide] observed mild gynecomastia in 30 patients (57 percent), moderate gynecomastia in 19 (36 percent), and massive gynecomastia in 4 patients (8 percent). Complaints of nipple and areolar tenderness were noted in 50/53 patients (94 per- cent)." Airhart et al. reported that 42 percent of patients receiving flutamide 750 mg/d or 1500 mg/d developed gynecomastia within 12 weeks of starting treatment with an apparent direct correlation between the dose of flutamide administered and the severity of gynecomastia.25 In another study, two of five evaluable patients developed moderate gynecomastia with mild tenderness at four and eight weeks after starting flutamide 750 mg/d. Patients with preexisting gynecomastia as a result of previous endocrine therapy with estrogens sustained no worsening of their gynecomastia and may have improved symptomatically." Keating et al."
76. DeLeve LD (16 October 2002). "Cancer Chemotherapy". In Kaplowitz N (ed.). Drug-Induced Liver Disease. CRC Press. pp. 618–619. ISBN   978-0-203-90912-6.
77. Thole Z, Manso G, Salgueiro E, Revuelta P, Hidalgo A (2004). "Hepatotoxicity induced by antiandrogens: a review of the literature". Urologia Internationalis. 73 (4): 289–295. doi:10.1159/000081585. PMID   15604569. S2CID   24799765.
78. Brahm J, Brahm M, Segovia R, Latorre R, Zapata R, Poniachik J, et al. (2011). "Acute and fulminant hepatitis induced by flutamide: case series report and review of the literature". Annals of Hepatology. 10 (1): 93–98. doi: 10.1016/S1665-2681(19)31595-9 . PMID   21301018.
79. García Cortés M, Andrade RJ, Lucena MI, Sánchez Martínez H, Fernández MC, Ferrer T, et al. (July 2001). "Flutamide-induced hepatotoxicity: report of a case series". Revista Espanola de Enfermedades Digestivas. 93 (7): 423–432. PMID   11685939.
80. Malešević N, Bokan G, Đajić V (2020). "Flutamide Induced Liver Injury in Female Patients". European Journal of Medical and Health Sciences. 2 (5). doi: 10.24018/ejmed.2020.2.5.476 . ISSN   2593-8339.
81. Wysowski DK, Fourcroy JL (January 1996). "Flutamide hepatotoxicity". The Journal of Urology. 155 (1): 209–212. doi:10.1016/S0022-5347(01)66596-0. PMID   7490837.
82. Hejmej A, Bilinska B (October 2018). "The effects of flutamide on cell-cell junctions in the testis, epididymis, and prostate". Reproductive Toxicology. 81: 1–16. Bibcode:2018RepTx..81....1H. doi:10.1016/j.reprotox.2018.06.014. PMID   29958919. S2CID   49613890. Despite its efficacy, some patients develop severe hepatotoxicity (cholestatic hepatitis) in the first 3–4 months of therapy (reported incidence of less than 1% to about 10%) [60,61]
83. Chitturi S, Farrell GC (2013). "Adverse Effects of Hormones and Hormone Antagonists on the Liver". Drug-Induced Liver Disease. Academic Press. pp. 605–619. doi:10.1016/B978-0-12-387817-5.00033-9. ISBN   9780123878175. The frequency of liver injury with flutamide ranges from 0.18% to 5% of persons exposed, [...]
84. Aronson JK (21 February 2009). "Antiandrogens". Meyler's Side Effects of Endocrine and Metabolic Drugs. Elsevier. pp. 153–. ISBN   978-0-08-093292-7.
85. Cetin M, Demirci D, Unal A, Altinbaş M, Güven M, Unlühizarci K (March 1999). "Frequency of flutamide induced hepatotoxicity in patients with prostate carcinoma". Human & Experimental Toxicology. 18 (3): 137–140. Bibcode:1999HETox..18..137C. doi: 10.1177/096032719901800301 . PMID   10215102. S2CID   32523042.
86. Hussain S, Haidar A, Bloom RE, Zayouna N, Piper MH, Jafri SM (2014). "Bicalutamide-induced hepatotoxicity: A rare adverse effect". The American Journal of Case Reports. 15: 266–270. doi:10.12659/AJCR.890679. PMC   4068966 . PMID   24967002.
87. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. National Institute of Diabetes and Digestive and Kidney Diseases. 2012. PMID   31643176.
88. Bruni V, Peruzzi E, Dei M, Nannini S, Seravalli V, Sisti G, et al. (October 2012). "Hepatotoxicity with low- and ultralow-dose flutamide: a surveillance study on 203 hyperandrogenic young females". Fertility and Sterility. 98 (4): 1047–1052. doi: 10.1016/j.fertnstert.2012.06.018 . PMID   22795685.
89. Ünlühizarci K, Keleştimur F (21 December 2009). "Anti-Androgens". In Diamanti-Kandarakis E, Nestler JE, Panidis D, Pasquali R (eds.). Insulin Resistance and Polycystic Ovarian Syndrome: Pathogenesis, Evaluation, and Treatment. Springer Science & Business Media. pp. 75–. ISBN   978-1-59745-310-3.
90. Ball AL, Kamalian L, Alfirevic A, Lyon JJ, Chadwick AE (October 2016). "Identification of the Additional Mitochondrial Liabilities of 2-Hydroxyflutamide When Compared With its Parent Compound, Flutamide in HepG2 Cells". Toxicological Sciences. 153 (2): 341–351. doi:10.1093/toxsci/kfw126. PMC   5036617 . PMID   27413113.
91. Coe KJ, Jia Y, Ho HK, Rademacher P, Bammler TK, Beyer RP, et al. (September 2007). "Comparison of the cytotoxicity of the nitroaromatic drug flutamide to its cyano analogue in the hepatocyte cell line TAMH: evidence for complex I inhibition and mitochondrial dysfunction using toxicogenomic screening". Chemical Research in Toxicology. 20 (9): 1277–1290. doi:10.1021/tx7001349. PMC   2802183 . PMID   17702527.
92. Marroquin LD, Hynes J, Dykens JA, Jamieson JD, Will Y (June 2007). "Circumventing the Crabtree effect: replacing media glucose with galactose increases susceptibility of HepG2 cells to mitochondrial toxicants". Toxicological Sciences. 97 (2): 539–547. doi: 10.1093/toxsci/kfm052 . PMID   17361016.
93. Kostrubsky SE, Strom SC, Ellis E, Nelson SD, Mutlib AE (October 2007). "Transport, metabolism, and hepatotoxicity of flutamide, drug-drug interaction with acetaminophen involving phase I and phase II metabolites". Chemical Research in Toxicology. 20 (10): 1503–1512. doi:10.1021/tx7001542. PMID   17900172.
94. Boelsterli UA, Ho HK, Zhou S, Leow KY (October 2006). "Bioactivation and hepatotoxicity of nitroaromatic drugs". Current Drug Metabolism. 7 (7): 715–727. doi:10.2174/138920006778520606. PMID   17073576.
95. Fisher AD, Bandini E, Casale H, Maggi M (29 November 2011). "Paraphilic Disorders: Diagnosis and Treatment". Hormonal Therapy for Male Sexual Dysfunction. Wiley. pp. 94–110. doi:10.1002/9781119963820.ch8. hdl:2158/426102. ISBN   9780470657607.
96. Khan AM, Singh NT, Bilgrami S (April 1997). "Flutamide induced methemoglobinemia". The Journal of Urology. 157 (4): 1363. doi:10.1016/s0022-5347(01)64982-6. PMID   9120948.
97. Schwartz CL, Christiansen S, Vinggaard AM, Axelstad M, Hass U, Svingen T (February 2019). "Anogenital distance as a toxicological or clinical marker for fetal androgen action and risk for reproductive disorders". Archives of Toxicology. 93 (2): 253–272. Bibcode:2019ArTox..93..253S. doi: 10.1007/s00204-018-2350-5 . PMID   30430187.
98. Kita DH, Meyer KB, Venturelli AC, Adams R, Machado DL, Morais RN, et al. (August 2016). "Manipulation of pre and postnatal androgen environments and anogenital distance in rats". Toxicology. 368–369: 152–161. Bibcode:2016Toxgy.368..152K. doi: 10.1016/j.tox.2016.08.021 . PMID   27639664.
99. Ayub M, Levell MJ (August 1989). "The effect of ketoconazole related imidazole drugs and antiandrogens on [3H] R 1881 binding to the prostatic androgen receptor and [3H]5 alpha-dihydrotestosterone and [3H]cortisol binding to plasma proteins". J. Steroid Biochem. 33 (2): 251–5. doi:10.1016/0022-4731(89)90301-4. PMID   2788775.
100. Yamasaki K, Sawaki M, Noda S, Muroi T, Takakura S, Mitoma H, et al. (February 2004). "Comparison of the Hershberger assay and androgen receptor binding assay of twelve chemicals". Toxicology. 195 (2–3): 177–186. Bibcode:2004Toxgy.195..177Y. doi:10.1016/j.tox.2003.09.012. PMID   14751673.
101. Furr BJ (1996). "The development of Casodex (bicalutamide): preclinical studies". European Urology. 29 (Suppl 2): 83–95. doi:10.1159/000473846. PMID   8717469.
102. Furr BJ, Tucker H (January 1996). "The preclinical development of bicalutamide: pharmacodynamics and mechanism of action". Urology. 47 (1A Suppl): 13–25, discussion 29–32. doi:10.1016/S0090-4295(96)80003-3. PMID   8560673.
103. Kolvenbag GJ, Furr BJ, Blackledge GR (December 1998). "Receptor affinity and potency of non-steroidal antiandrogens: translation of preclinical findings into clinical activity". Prostate Cancer and Prostatic Diseases. 1 (6): 307–314. doi:10.1038/sj.pcan.4500262. PMID   12496872. S2CID   33497597.
104. Shen HC, Taplin ME, Balk SP (14 September 2010). "Androgen Receptor Antagonists". In Figg W, Chau CH, Small EJ (eds.). Drug Management of Prostate Cancer. Springer Science & Business Media. pp. 71–. ISBN   978-1-60327-829-4.
105. DICP: The Annals of Pharmacotherapy. Harvey Whitney Books Company. 1990. p. 617. Additionally, 2-hydroxyflutamide has approximately a 25-fold greater affinity for androgen receptors than does flutamide.
106. Masiello D, Cheng S, Bubley GJ, Lu ML, Balk SP (July 2002). "Bicalutamide functions as an androgen receptor antagonist by assembly of a transcriptionally inactive receptor". The Journal of Biological Chemistry. 277 (29): 26321–26326. doi: 10.1074/jbc.M203310200 . PMID   12015321.
107. Wheeler CJ, Keye WR, Peterson CM (23 March 2010). "Polycyctic Ovary Syndrome". In Carrell DT, Peterson CM (eds.). Reproductive Endocrinology and Infertility: Integrating Modern Clinical and Laboratory Practice. Springer Science & Business Media. pp. 163–. ISBN   978-1-4419-1436-1.
108. Diamanti-Kandarakis E, Tolis G, Duleba AJ (1995). "Androgens and therapeutic aspects of antiandrogens in women". Journal of the Society for Gynecologic Investigation. 2 (4): 577–592. doi:10.1177/107155769500200401. PMID   9420861. S2CID   32242838.
109. Barner RB, Ehrmann DA, Rosenfield RL (18 May 2010). "Hyperandrogenism, Hirsutism, and the Polycystic Ovary Syndrome". In Jameson JL, De Groot LJ (eds.). Endocrinology: Adult and Pediatric. Elsevier Health Sciences. pp. 2401–. ISBN   978-1-4557-1126-0.
110. Hormones - Antineoplastics: Advances in Research and Application: 2011 Edition: ScholarlyPaper. ScholarlyEditions. 9 January 2012. pp. 9–. ISBN   978-1-4649-4785-8.
111. Feau C (2009). "Novel Small Molecule Antagonists of the Interaction of the Androgen Receptor and Transcriptional Co-regulators". Memphis TN: Saint Jude Children's Research Hospital. Archived from the original on 2017-06-11.
112. Furr BJ (1997). "Relative potencies of flutamide and 'Casodex'". Endocrine-Related Cancer. 4 (2): 197–202. doi:10.1677/erc.0.0040197 (inactive 2024-09-01). ISSN   1351-0088.
113. Narayan P, Trachtenberg J, Lepor H, Debruyne FM, Tewari A, Stone N, et al. (April 1996). "A dose-response study of the effect of flutamide on benign prostatic hyperplasia: results of a multicenter study". Urology. 47 (4): 497–504. doi:10.1016/S0090-4295(99)80484-1. hdl: 2066/23543 . PMID   8638357. S2CID   10400855.
114. Akaza H, Isaka S, Usami M, Kanetake H, Kotake T, Koiso K, et al. (November 1996). "Recommended dose of flutamide with LH-RH agonist therapy in patients with advanced prostate cancer". International Journal of Urology. 3 (6): 468–471. doi:10.1111/j.1442-2042.1996.tb00578.x. PMID   9170575. S2CID   11365242.
115. Shain SA, Huot RI (October 1988). "Antiandrogen effects in models of androgen responsive cancer". Journal of Steroid Biochemistry. 31 (4B): 711–718. doi:10.1016/0022-4731(88)90022-2. PMID   3059063.
116. Furr BJ, Valcaccia B, Curry B, Woodburn JR, Chesterson G, Tucker H (June 1987). "ICI 176,334: a novel non-steroidal, peripherally selective antiandrogen". The Journal of Endocrinology. 113 (3): R7–R9. doi:10.1677/joe.0.113R007. PMID   3625091.
117. Teutsch G, Goubet F, Battmann T, Bonfils A, Bouchoux F, Cerede E, et al. (January 1994). "Non-steroidal antiandrogens: synthesis and biological profile of high-affinity ligands for the androgen receptor". The Journal of Steroid Biochemistry and Molecular Biology. 48 (1): 111–119. doi:10.1016/0960-0760(94)90257-7. PMID   8136296. S2CID   31404295.
118. Winneker RC, Wagner MM, Batzold FH (December 1989). "Studies on the mechanism of action of Win 49596: a steroidal androgen receptor antagonist". Journal of Steroid Biochemistry. 33 (6): 1133–1138. doi:10.1016/0022-4731(89)90420-2. PMID   2615358.
119. Luo S, Martel C, Leblanc G, Candas B, Singh SM, Labrie C, et al. (1996). "Relative potencies of Flutamide and Casodex: preclinical studies". Endocrine Related Cancer. 3 (3): 229–241. doi:10.1677/erc.0.0030229. ISSN   1351-0088.
120. Ayub M, Levell MJ (August 1989). "The effect of ketoconazole related imidazole drugs and antiandrogens on [3H] R 1881 binding to the prostatic androgen receptor and [3H]5 alpha-dihydrotestosterone and [3H]cortisol binding to plasma proteins". Journal of Steroid Biochemistry. 33 (2): 251–255. doi:10.1016/0022-4731(89)90301-4. PMID   2788775.
121. Kemppainen JA, Wilson EM (July 1996). "Agonist and antagonist activities of hydroxyflutamide and Casodex relate to androgen receptor stabilization". Urology. 48 (1): 157–163. doi:10.1016/S0090-4295(96)00117-3. PMID   8693644.
122. Ayub M, Levell MJ (July 1987). "Inhibition of rat testicular 17 alpha-hydroxylase and 17,20-lyase activities by anti-androgens (flutamide, hydroxyflutamide, RU23908, cyproterone acetate) in vitro". Journal of Steroid Biochemistry. 28 (1): 43–47. doi:10.1016/0022-4731(87)90122-1. PMID   2956461.
123. Ayub M, Levell MJ (March 1990). "Suppression of plasma androgens by the antiandrogen flutamide in prostatic cancer patients treated with Zoladex, a GnRH analogue". Clinical Endocrinology. 32 (3): 329–339. doi:10.1111/j.1365-2265.1990.tb00874.x. PMID   2140542. S2CID   22823754.
124. Gao X, Xie C, Wang Y, Luo Y, Yagai T, Sun D, et al. (November 2016). "The antiandrogen flutamide is a novel aryl hydrocarbon receptor ligand that disrupts bile acid homeostasis in mice through induction of Abcc4". Biochemical Pharmacology. 119: 93–104. doi:10.1016/j.bcp.2016.08.021. PMC   5061623 . PMID   27569425.
125. Koch DC, Jang HS, O'Donnell EF, Punj S, Kopparapu PR, Bisson WH, et al. (December 2015). "Anti-androgen flutamide suppresses hepatocellular carcinoma cell proliferation via the aryl hydrocarbon receptor mediated induction of transforming growth factor-β1". Oncogene. 34 (50): 6092–6104. doi: 10.1038/onc.2015.55 . PMID   25867062.
126. DeVita VT, Lawrence TS, Rosenberg SA (29 September 2015). Lymphomas and Leukemias: Cancer: Principles & Practice of Oncology. Wolters Kluwer Health. pp. 1029–. ISBN   978-1-4963-3828-0.
127. Zhou SF, Wang LL, Di YM, Xue CC, Duan W, Li CG, et al. (2008). "Substrates and inhibitors of human multidrug resistance associated proteins and the implications in drug development". Current Medicinal Chemistry. 15 (20): 1981–2039. doi:10.2174/092986708785132870. PMID   18691054.
128. Grzywacz MJ, Yang JM, Hait WN (May 2003). "Effect of the multidrug resistance protein on the transport of the antiandrogen flutamide". Cancer Research. 63 (10): 2492–2498. PMID   12750271.
129. "Error" (PDF).
130. Analytical Profiles of Drug Substances and Excipients. Academic Press. 19 March 2001. pp. 155–. ISBN   978-0-08-086122-7.
131. Acosta WR (1 October 2009). LWW's Foundations in Pharmacology for Pharmacy Technicians . Lippincott Williams & Wilkins. pp.  300–. ISBN   978-0-7817-6624-1.
132. Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA (25 August 2011). Campbell-Walsh Urology: Expert Consult Premium Edition: Enhanced Online Features and Print, 4-Volume Set. Elsevier Health Sciences. pp. 2939–. ISBN   978-1-4160-6911-9.
133. Stabile RG, Dicks AP (2003). "Microscale Synthesis and Spectroscopic Analysis of Flutamide, an Antiandrogen Prostate Cancer Drug". Journal of Chemical Education. 80 (12): 1439. Bibcode:2003JChEd..80.1439S. doi:10.1021/ed080p1439.
134. Baker JW, Bachman GL, Schumacher I, Roman DP, Tharp AL (January 1967). "Synthesis and bacteriostatic activity of some nitrotrifluoromethylanilides". Journal of Medicinal Chemistry. 10 (1): 93–95. doi:10.1021/jm00313a020. PMID   6031711.
135. Bandgar BP, Sawant SS (2006). "Novel and Gram-Scale Green Synthesis of Flutamide". Synthetic Communications. 36 (7): 859–864. doi:10.1080/00397910500464848. S2CID   98825198.
136. DE 2130450,Neri RO, Topliss JG,"Substituierte Anilide [Substituted anilides]",published 1972-12-21, assigned to Sherico Ltd.  
137. DE 2261293,Gold EH,"Substituierte Imidate [Substituted imidates]",published 1973-07-05, assigned to Sherico Ltd.  
138. US 3847988,Gold E,issued 1974, assigned to Merck Sharp and Dohme Corp 
139. US 4144270,Neri RO, Topliss JG,issued 1979, assigned to Merck Sharp and Dohme Corp 
140. Thurston DE (10 October 2005). "The Chemotherapy of Cancer". In Smith HJ, Williams G (eds.). Smith and Williams' Introduction to the Principles of Drug Design and Action (Fourth ed.). CRC Press. pp. 489–. ISBN   978-0-203-30415-0.
141. Vojtišková M, Poláčkova M, Viklický V, Voráčová B, Hilgertová J (12 May 2014). "Comparison of the biological effects of three types of testosterone inhibitors in mice.". In Boettcher B (ed.). Immunological Influence on Human Fertility: Proceedings of the Workshop on Fertility in Human Reproduction, University of Newcastle, Australia, July 11-13, 1977. Elsevier Science. pp. 167–. ISBN   978-1-4832-6895-8.
142. The Irish Reports: Containing Reports of Cases Argued and Determined in the Court of Appeal, the High Court of Justice, the Court of Bankruptcy, in Ireland, and the Irish Land Commission. Incorporated Council of Law Reporting for Ireland. 1990. p. 501.
143. William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. Elsevier. pp. 1695–. ISBN   978-0-8155-1856-3.
144. The Irish Reports: Containing Reports of Cases Argued and Determined in the Court of Appeal, the High Court of Justice, the Court of Bankruptcy, in Ireland, and the Irish Land Commission. Incorporated Council of Law Reporting for Ireland. 1990. pp. 501–502.
145. Cleve A, Fritzemeier KH, Haendler B, Heinrich N, Möller C, Schwede W, et al. (2 October 2012). "Pharmacology and clinical use of sex steroid hormone receptor modulators". In Regitz-Zagrosek V (ed.). Sex and Gender Differences in Pharmacology. Springer Science & Business Media. pp. 575–. ISBN   978-3-642-30725-6.
146. Sciarra F, Toscano V, Concolino G, Di Silverio F (November 1990). "Antiandrogens: clinical applications". The Journal of Steroid Biochemistry and Molecular Biology. 37 (3): 349–362. doi:10.1016/0960-0760(90)90484-3. PMID   2147859. S2CID   20274398.
147. Motta T, Maggi G, Perra M, Azzolari E, Casazza S, D'Alberton A (October 1991). "Flutamide in the treatment of hirsutism". International Journal of Gynaecology and Obstetrics. 36 (2): 155–157. doi:10.1016/0020-7292(91)90772-w. PMID   1683319. S2CID   37481872.
148. Motta T, Maggi G, D'Alberton A (September 1994). "Flutamide and hirsutism". Journal of Endocrinological Investigation. 17 (8): 673. doi:10.1007/BF03349685. PMID   7868809. S2CID   2237184.
149. Bégué JP, Bonnet-Delpon D (2 June 2008). "Flourinated Drugs". Bioorganic and Medicinal Chemistry of Fluorine. John Wiley & Sons. pp. 327–. ISBN   978-0-470-28187-1.
150. "Flutamide: Uses, Dosage, Side Effects & Warnings".
151. Vozianov AF, Reznikov AG, Varga SV (1995). "Endocrine changes underlying clinical effects of low-dose estrogen-antiandrogen treatment of prostatic cancer". Endocrine Regulations. 29 (1): 25–28. ISSN   0013-7200.
152. Vozianov OF, Rieznikov OH, Klymenko IO, Varga SV, Synitsyn PV, Chaĭkovs'ka LV, et al. (1996). "[The correlation of the hormonal and clinical effects in patients with prostatic cancer undergoing niftolid treatment in combination with low doses of synestrol]" [The correlation of the hormonal and clinical effects in patients with prostatic cancer undergoing niftolid treatment in combination with low doses of synestrol]. Likars'ka Sprava (in Ukrainian) (1–2): 107–110. PMID   9005063.
153. Vozianov AF, Reznikov AG, Klimenko IA, Chaikovskaya LV (January 1998). "Benefits of low dose estrogen-antiandrogen treatment of prostate cancer". Naunyn-Schmiedebergs Archiv für Pharmakologie. 358 (1): R532. ISSN   0028-1298.
154. Reznikov AG, Chaikovskaya LV (January 1998). "Mechanisms of potentiating effect of low dose estrogens on flutamide-induced suppression of normal and cancerous prostate". Naunyn-Schmiedebergs Archiv für Pharmakologie. 358 (1): R545. ISSN   0028-1298.
155. Reznikov, AG, Chaikovskaya, LV, Polyakova, LI, et al. (September 1999). "Effects of combined treatment with niftolide and low doses of antitumor estrogen preparation, chlorotrianizene, on rat prostate". Eksperimentalʹnai͡a onkologii͡a [Experimental Oncology]. 21 (3–4): 269–273. ISSN   0204-3564.
156. Oesterling JE (February 1994). "Endocrine therapies for symptomatic benign prostatic hyperplasia". Urology. 43 (2 Suppl): 7–16. doi:10.1016/0090-4295(94)90212-7. PMID   7509536.
157. Stone NN (October 1989). "Flutamide in treatment of benign prostatic hypertrophy". Urology. 34 (4 Suppl): 64–8, discussion 87–96. doi:10.1016/0090-4295(89)90236-7. PMID   2477936.
158. Lee M, Sharifi R (April 1997). "Benign prostatic hyperplasia: diagnosis and treatment guideline". The Annals of Pharmacotherapy. 31 (4): 481–486. doi:10.1177/106002809703100415. PMID   9101011. S2CID   20498549.
159. Howell A, Dodwell DJ, Anderson H (March 1990). "New endocrine approaches to breast cancer". Baillière's Clinical Endocrinology and Metabolism. 4 (1): 67–84. doi:10.1016/S0950-351X(05)80316-7. PMID   1975167.
160. Rahim B, O'Regan R (February 2017). "AR Signaling in Breast Cancer". Cancers. 9 (3): 21. doi: 10.3390/cancers9030021 . PMC   5366816 . PMID   28245550.
161. Zhao TP, He GF (February 1988). "A phase II clinical trial of flutamide in the treatment of advanced breast cancer". Tumori. 74 (1): 53–56. doi:10.1177/030089168807400109. PMID   3354065. S2CID   12506218.
162. Perrault DJ, Logan DM, Stewart DJ, Bramwell VH, Paterson AH, Eisenhauer EA (September 1988). "Phase II study of flutamide in patients with metastatic breast cancer. A National Cancer Institute of Canada Clinical Trials Group study". Investigational New Drugs. 6 (3): 207–210. doi:10.1007/BF00175399. PMID   3192386. S2CID   46483946.
163. Wu Y, Vadgama JV (April 2017). "Androgen Receptor as a Potential Target for Treatment of Breast Cancer". International Journal of Cancer Research and Molecular Mechanisms. 3 (1). doi:10.16966/2381-3318.129. PMC   5412726 . PMID   28474005.
164. Naessén S, Hirschberg AL (2011). "Sex Hormones and Appetite in Women: A Focus on Bulimia Nervosa". Handbook of Behavior, Food and Nutrition. Springer. pp. 1759–1767. doi:10.1007/978-0-387-92271-3_114. ISBN   978-0-387-92270-6.
165. McElroy SL, Guerdjikova AI, Mori N, O'Melia AM (October 2012). "Current pharmacotherapy options for bulimia nervosa and binge eating disorder". Expert Opinion on Pharmacotherapy. 13 (14): 2015–2026. doi:10.1517/14656566.2012.721781. PMID   22946772. S2CID   1747393.
166. Bergman L, Eriksson E (August 1996). "Marked symptom reduction in two women with bulimia nervosa treated with the testosterone receptor antagonist flutamide". Acta Psychiatrica Scandinavica. 94 (2): 137–139. doi:10.1111/j.1600-0447.1996.tb09838.x. PMID   8883576. S2CID   20033667.
167. Sundblad C, Landén M, Eriksson T, Bergman L, Eriksson E (February 2005). "Effects of the androgen antagonist flutamide and the serotonin reuptake inhibitor citalopram in bulimia nervosa: a placebo-controlled pilot study". Journal of Clinical Psychopharmacology. 25 (1): 85–88. doi:10.1097/01.jcp.0000150222.31007.a9. PMID   15643104. S2CID   45297334.
168. Nomani H, Mohammadpour AH, Moallem SM, YazdanAbad MJ, Barreto GE, Sahebkar A (December 2019). "Anti-Androgen Drugs in the Treatment of Obsessive-Compulsive Disorder: A Systematic Review". Current Medicinal Chemistry. 27 (40): 6825–6836. doi:10.2174/0929867326666191209142209. PMID   31814547. S2CID   208956450.

Further reading

• Sogani PC, Whitmore WF (1988). "Flutamide and Other Antiandrogens in the Treatment of Advanced Prostatic Carcinoma". Endocrine Therapies in Breast and Prostate Cancer. Cancer Treatment and Research. Vol. 39. Springer. pp. 131–145. doi:10.1007/978-1-4613-1731-9_9. ISBN   978-1-4612-8974-6. PMID   2908604.
• Brogden RN, Clissold SP (August 1989). "Flutamide. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in advanced prostatic cancer". Drugs. 38 (2): 185–203. doi:10.2165/00003495-198938020-00003. PMID   2670515. S2CID   262018256.
• Neri R (October 1989). "Pharmacology and pharmacokinetics of flutamide". Urology. 34 (4 Suppl): 19–21, discussion 46–56. doi:10.1016/0090-4295(89)90230-6. PMID   2477934.
• Newling DW (1989). "The use of flutamide as monotherapy in the treatment of advanced prostate cancer". Progress in Clinical and Biological Research. 303: 117–121. PMID   2674980.
• Labrie F, Dupont A, Cusan L, Manhès G, Bergeron N, Lacourcière Y, et al. (October 1989). "Combination therapy with castration and flutamide: today's treatment of choice for prostate cancer". Journal of Steroid Biochemistry. 33 (4B): 817–821. doi:10.1016/0022-4731(89)90499-8. PMID   2689788.
• Goldspiel BR, Kohler DR (June 1990). "Flutamide: an antiandrogen for advanced prostate cancer". DICP. 24 (6): 616–623. doi:10.1177/106002809002400612. PMID   2193461. S2CID   26125621.
• Brogden RN, Chrisp P (March 1991). "Flutamide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in advanced prostatic cancer". Drugs & Aging. 1 (2): 104–115. doi:10.2165/00002512-199101020-00003. PMID   1794008. S2CID   260959546.
• Labrie F (December 1993). "Mechanism of action and pure antiandrogenic properties of flutamide". Cancer. 72 (12 Suppl): 3816–3827. doi: 10.1002/1097-0142(19931215)72:12+<3816::aid-cncr2820721711>3.0.co;2-3 . PMID   8252497. S2CID   2195250.
• Iversen P, Melezinek I, Schmidt A (January 2001). "Nonsteroidal antiandrogens: a therapeutic option for patients with advanced prostate cancer who wish to retain sexual interest and function". BJU International. 87 (1): 47–56. doi: 10.1046/j.1464-410x.2001.00988.x . PMID   11121992. S2CID   28215804.
• Ibáñez L, de Zegher F (2006). "Low-dose flutamide-metformin therapy for hyperinsulinemic hyperandrogenism in non-obese adolescents and women". Human Reproduction Update. 12 (3): 243–252. doi: 10.1093/humupd/dmi054 . PMID   16407452.
• Brahm J, Brahm M, Segovia R, Latorre R, Zapata R, Poniachik J, et al. (2011). "Acute and fulminant hepatitis induced by flutamide: case series report and review of the literature". Annals of Hepatology. 10 (1): 93–98. doi: 10.1016/S1665-2681(19)31595-9 . PMID   21301018.
• Giorgetti R, di Muzio M, Giorgetti A, Girolami D, Borgia L, Tagliabracci A (March 2017). "Flutamide-induced hepatotoxicity: ethical and scientific issues". European Review for Medical and Pharmacological Sciences. 21 (1 Suppl): 69–77. PMID   28379593.