Flutamide

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Flutamide
Clinical data
Trade namesEulexin, others
Other namesNiftolide; SCH-13521; 4'-Nitro-3'-trifluoromethyl-isobutyranilide
AHFS/Drugs.comMonograph
MedlinePlusa697045
Pregnancy
category
  • D
Routes of
administration		By mouth
Drug classNonsteroidal antiandrogen
ATC code
Legal status
Legal status
  • US: WARNING[1]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
BioavailabilityComplete (>90%)[2]
Protein bindingFlutamide: 94–96%[2]
Hydroxyflutamide: 92–94%[2]
MetabolismLiver (CYP1A2)[8][4]
MetabolitesHydroxyflutamide[3][4]
Elimination half-lifeFlutamide: 5–6 hours[5][4]
Hydroxyflutamide: 8–10 hours[6][7][4][2]
ExcretionUrine (mainly)[2]
Feces (4.2%)[2]
Identifiers
  • 2-Methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propanamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.033.024 Edit this at Wikidata
Chemical and physical data
FormulaC11H11F3N2O3
Molar mass276.212 g/mol g·mol−1
3D model (JSmol)
Melting point111.5 to 112.5 °C (232.7 to 234.5 °F)
  • O=C(Nc1cc(c(cc1)[N+]([O-])=O)C(F)(F)F)C(C)C
  • 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) checkY
  • Key:MKXKFYHWDHIYRV-UHFFFAOYSA-N checkY
  (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 drug has fewer side effects and is better-tolerated in women. 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.

Flutamide was discovered in 1967 and was first introduced for medical use in 1983. It became available in the United States in 1989. The drug 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.[5][17]

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.

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.[18]

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.[19][20] The drug, 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.[21]

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.[22][23][24][25] 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,[26][27][28] but has a far lower and only small risk of hepatotoxicity in comparison.[29][30][31]

Acne and seborrhea

Flutamide has been found to be effective in the treatment of acne and seborrhea in women in a number of studies.[32][33] 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.[32][34] In the study, 97% of the women reported satisfaction with the control of their acne with flutamide.[35] In another study, flutamide decreased acne and seborrhea scores by 80% in only 3 months.[36][3] In contrast, spironolactone decreased symptoms by only 40% in the same time period, suggesting superior effectiveness for flutamide for these indications.[36][37] Flutamide has, in general, been found to reduce symptoms of acne by as much as 90%, with several studies showing complete clearance.[33][38][3]

Excessive hair growth

Flutamide has been found to be effective in the treatment of hirsutism (excessive body/facial growth) in numerous studies.[22][39][26] It possesses moderate effectiveness for this indication, and the overall quality of the evidence is considered to be moderate.[39][22] The drug 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.[3][22] 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 500 mg/day.[37] This supports the use of flutamide at lower doses for hirsutism without loss of effectiveness, which may help to lower the risk of hepatotoxicity.[22] 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.[40] 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.[40][41] In a small study of flutamide with an oral contraceptive, the drug caused an increase in cosmetically acceptance hair density in 6 of 7 women with diffuse scalp hair loss.[42] 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 failed to do so.[40][43]

Transgender hormone therapy

Flutamide has been used as a component of feminizing hormone therapy for transgender women.[44] However, its use for this purpose is discouraged due to reports of hepatotoxicity in prostate cancer patients at comparable doses.[31][45]

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.[46] Others include hot flashes, decreased muscle mass, decreased bone mass and an associated increased risk of fractures, depression,[21] and sexual dysfunction including reduced libido and erectile dysfunction.[8] In women, flutamide is, generally, relatively well-tolerated, and does not interfere with ovulation.[47] The only common side effect reported with flutamide in women is dry skin (75%), which is attributable to diminished androgen-mediated sebum production.[3] General side effects that may occur in either sex include dizziness, anorexia, gastrointestinal side effects such as nausea, vomiting, and diarrhea, a greenish-bluish discoloration of the urine,[3] and hepatic changes.[21][8][48] 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.[49][21][7]

Gynecomastia

Flutamide, as a monotherapy, causes gynecomastia and breast tenderness in most men.[46] However, more than 90% of cases of gynecomastia with NSAAs including flutamide are mild to moderate.[50][51][49] 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.[52] In a comparative trial of combined androgen blockade for prostate cancer, the rate of diarrhea was 26% for flutamide and 12% for bicalutamide.[52] Moreover, 6% of flutamide-treated patients discontinued the drug due to diarrhea, whereas only 0.5% of bicalutamide-treated patients did so.[52] In the case of antiandrogen monotherapy for prostate cancer, the rates of diarrhea are 5–20% for flutamide, 2–5% for bicalutamide, and 2–4% for nilutamide.[52] In contrast to diarrhea, the rates of nausea and vomiting are similar among the three drugs.[52]

Rare reactions

Liver toxicity

Although rare, flutamide has been associated with severe hepatotoxicity and death.[53][15][54] By 1996, 46 cases of severe cholestatic hepatitis had been reported, with 20 fatalities.[53] There have been continued case reports since, including liver transplants and death.[55][56] Based on the number of prescriptions written, the rate of serious hepatotoxicity associated with flutamide treatment is estimated to be 0.03% (3 per 10,000).[53] However, other researchers have suggested that the incidence of significant hepatotoxicity may be as high as 6 to 9%.[55] Another source reported a rate of 0.36%.[57] Flutamide is also associated with liver enzyme elevations in 42 to 62% of patients.[58] The risk of hepatotoxicity with flutamide treatment is far higher than with nilutamide or bicalutamide.[29][30][31] Lower dosages of the drug appear to have a reduced but still significant risk.[55][59] Liver function should be monitored regularly with liver function tests during flutamide treatment.[60] In addition, due to the high risk of serious hepatotoxicity, flutamide should not be used in the absence of a serious indication.[57]

The mechanism of action of flutamide-induced hepatotoxicity is thought to be due to mitochondrial toxicity.[61][62][63] 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.[61][62][63] Inhibition of taurocholate (a bile acid) efflux has also been implicated in flutamide-induced hepatotoxicity.[61][64] 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.[61][63] 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.[62][65]

The combination of paracetamol (acetaminophen) and flutamide may result in additive to synergistic hepatotoxicity, indicating a potential drug interaction.[64]

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.[66][16] Bicalutamide does not share this risk with flutamide.[16] Flutamide has also been associated with reports of sulfhemoglobinemia and neutropenia.[16]

Pharmacology

Pharmacodynamics

Antiandrogenic activity

Flutamide acts as a selective, competitive, silent antagonist of the androgen receptor (AR).[6] Its active metabolite, hydroxyflutamide, has between 10- to 25-fold higher affinity for the AR than does flutamide, and hence is a more powerful antiandrogen in comparison.[6][49][67][68] However, at high concentrations, unlike flutamide, hydroxyflutamide is able to weakly activate the AR.[6][69] 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.[70] In accordance with its selectivity for the AR, flutamide possesses no progestogenic, (direct) estrogenic, glucocorticoid, or antigonadotropic activity.[3][71] 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 drug does not cause menstrual irregularities in women.[32][71] This is in contrast to steroidal antiandrogens like spironolactone and cyproterone acetate.[32] Similarly to nilutamide, bicalutamide, and enzalutamide, flutamide crosses the blood–brain barrier and exerts central antiandrogen actions.[72]

Flutamide has been found to be slightly more potent than cyproterone acetate and substantially more potent than spironolactone as an antiandrogen in rats.[73] This is in spite of the fact that it has on the order of 10-fold lower affinity for the AR relative to cyproterone acetate.[74] Hydroxyflutamide shows about 2- to 4-fold lower affinity for the rat and human AR than does bicalutamide.[75] 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.[75] 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.[75] 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.[75] 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.[75] Also, bicalutamide has been shown to be 5-fold more potent than flutamide in rats and 50-fold more potent than flutamide in dogs.[75] Taken together, flutamide appears to be a considerably less potent and efficacious antiandrogen than is bicalutamide.[75]

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.[76] In accordance, flutamide has been found to slightly but significantly lower androgen levels in GnRH analogue-treated male prostate cancer patients[77] and women with polycystic ovary syndrome.[3] As such, flutamide is a weak inhibitor of androgen biosynthesis.[70] However, the clinical significance of this action may be limited when flutamide is given without a GnRH analogue to non-castrated men, as the drug 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.[25]

Other activities

In addition to its antiandrogenic activity, flutamide has been identified as a putative ligand of the aryl hydrocarbon receptor.[78]

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.[3] Levels of hydroxyflutamide are approximately 50-fold higher than those of flutamide at steady-state.[79] The plasma protein binding of flutamide and hydroxyflutamide is high; 94 to 96% and 92 to 94%, respectively.[2] Flutamide is metabolized by CYP1A2 (via α-hydroxylation) in the liver during first-pass metabolism[8] to its main metabolite hydroxyflutamide (which accounts for 23% of an oral dose of flutamide one hour post-ingestion),[3] and to at least five other, minor metabolites.[4] Flutamide is excreted in various forms in the urine, the primary form being 2-amino-5-nitro-4-(trifluoromethyl)phenol.[80]

Flutamide has a fairly short elimination half-life of 5 to 6 hours.[5][4] However, the elimination half-life of its active form, hydroxyflutamide, is somewhat longer at about 8 to 10 ours.[6][7][4][2] Although hydroxyflutamide has an elimination half-life of 8 to 10 hours in elderly men, it has been reported to possess a shorter elimination half-life in younger men.[7] The elimination half-lives of flutamide and hydroxyflutamide are regarded as too short to allow for once-daily dosing, and the drug is instead administered three times daily at 8-hour intervals.[81] In contrast, the newer NSAAs nilutamide, bicalutamide, and enzalutamide all have much longer half-lives,[7] and this allows for once-daily administration in their cases.[82]

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

Flutamide synthesis.[83][84][85] Schering, DE 2130450  DE 2261293  U.S. patent 3,847,988 U.S. patent 4,144,270

History

Flutamide was first synthesized in 1967 by Neri and colleagues at Schering Plough Corporation.[10][86][7][87] It was originally synthesized as a bacteriostatic agent, but was subsequently, and serendipitously found to possess antiandrogen activity.[3][87] The code name of flutamide during development was SCH-13521.[88] Clinical research of the drug began in 1971,[89] and it was first marketed in 1983, specifically in West Germany under the brand name Flugerel.[90][91] 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.[92] The drug was first studied for the treatment of hirsutism in women in women in 1991.[93][94] Flutamide was the first NSAA to be introduced, and was followed by nilutamide in 1989 and then bicalutamide in 1995.[95]

Society and culture

Generic names

Flutamide is the generic name of the drug and its INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, BANTooltip British Approved Name, DCFTooltip Dénomination Commune Française, and JANTooltip Japanese Accepted Name.[96][9][10] Its names in Latin, German, and Spanish are flutamidum, flutamid, and flutamida, respectively.[96][9]

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.[96][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.[96][9]

Research

Benign prostatic hyperplasia

Flutamide has been studied in the treatment of benign prostatic hyperplasia in men in several clinical studies.[97][98] It has been found to reduce prostate volume by about 25%, which is comparable to the reduction achieved with the 5α-reductase inhibitor finasteride.[99] 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.[99]

Bulimia nervosa

Flutamide has been studied in the treatment of bulimia nervosa in women.[100][101][102][103]

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. ^ a b c d e f g h i j https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=d037fb0c-881f-43d2-8693-aa1342d0130a&type=display
  3. ^ a b c d e f g h i j k Bentham Science Publishers (September 1999). Current Pharmaceutical Design. Bentham Science Publishers. pp. 712–717.
  4. ^ a b c d e f g Bruce A. Chabner; Dan L. Longo (8 November 2010). Cancer Chemotherapy and Biotherapy: Principles and Practice. Lippincott Williams & Wilkins. pp. 679–. ISBN 978-1-60547-431-1.
  5. ^ a b c James Leonard Gulley (2011). Prostate Cancer. Demos Medical Publishing. pp. 81–. ISBN 978-1-935281-91-7.
  6. ^ a b c d e Thomas L. Lemke; David A. Williams (24 January 2012). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 1373–. ISBN 978-1-60913-345-0.
  7. ^ a b c d e f Louis J Denis; Keith Griffiths; Amir V Kaisary; Gerald P Murphy (1 March 1999). Textbook of Prostate Cancer: Pathology, Diagnosis and Treatment: Pathology, Diagnosis and Treatment. CRC Press. pp. 279–280. ISBN 978-1-85317-422-3.
  8. ^ a b c d Richard A. Lehne (2013). Pharmacology for Nursing Care. Elsevier Health Sciences. pp. 1297–. ISBN 1-4377-3582-7.
  9. ^ a b c d e Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 466–. ISBN 978-3-88763-075-1.
  10. ^ a b c d J. Elks (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. ^ Ismaila A Mungadi; Hyacinth N Mbibu; Ehab Eltahawy; Abdullahi Abdulwahab-Ahmed (30 November 2013). Manual of Medical Treatment in Urology. JP Medical Ltd. pp. 120–. ISBN 978-93-5090-844-0.
  13. ^ a b c Giorgetti R, di Muzio M, Giorgetti A, Girolami D, Borgia L, Tagliabracci A (2017). "Flutamide-induced hepatotoxicity: ethical and scientific issues". Eur Rev Med Pharmacol Sci. 21 (1 Suppl): 69–77. PMID 28379593.
  14. ^ a b Bennett CL, Raisch DW, Sartor O (2002). "Pneumonitis associated with nonsteroidal antiandrogens: presumptive evidence of a class effect". Ann. Intern. Med. 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. ^ a b c d Jeffrey K. Aronson (19 April 2010). Meyler's Side Effects of Drugs in Cancer and Immunology. Elsevier. pp. 318–319. ISBN 978-0-08-093288-0.
  16. ^ a b c d McLeod DG (1997). "Tolerability of Nonsteroidal Antiandrogens in the Treatment of Advanced Prostate Cancer". Oncologist. 2 (1): 18–27. PMID 10388026.
  17. ^ Lutz Moser (1 January 2008). 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].
  18. ^ 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.
  19. ^ Helsen C, Van den Broeck T, Voet A, Prekovic S, Van Poppel H, Joniau S, Claessens F (Aug 2014). "Androgen receptor antagonists for prostate cancer therapy". Endocrine-Related Cancer. 21 (4): T105-18. doi:10.1530/ERC-13-0545. PMID 24639562.
  20. ^ Nakai Y, Tanaka N, Anai S, Miyake M, Tatsumi Y, Fujimoto K (2015). "A Randomized Control Trial Comparing the Efficacy of Antiandrogen Monotherapy: Flutamide vs. Bicalutamide". Horm Cancer. 6 (4): 161–7. doi:10.1007/s12672-015-0226-1. PMID 26024831.
  21. ^ a b c d Jack H. Mydlo; Ciril J. Godec (29 September 2015). Prostate Cancer: Science and Clinical Practice. Elsevier Science. pp. 516–521, 534–540. ISBN 978-0-12-800592-7.
  22. ^ a b c d e Somani N, Turvy D (2014). "Hirsutism: an evidence-based treatment update". Am J Clin Dermatol. 15 (3): 247–66. doi:10.1007/s40257-014-0078-4. PMID 24889738.
  23. ^ Adam Ostrzenski (2002). Gynecology: Integrating Conventional, Complementary, and Natural Alternative Therapy. Lippincott Williams & Wilkins. pp. 86–. ISBN 978-0-7817-2761-7.
  24. ^ Ulrike Blume-Peytavi; David A. Whiting; Ralph M. Trüeb (26 June 2008). Hair Growth and Disorders. Springer Science & Business Media. pp. 181–. ISBN 978-3-540-46911-7.
  25. ^ a b Kenneth L. Becker (2001). Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. pp. 1196, 1208. ISBN 978-0-7817-1750-2.
  26. ^ a b 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
  27. ^ Erem C (2013). "Update on idiopathic hirsutism: diagnosis and treatment". Acta Clinica Belgica. 68 (4): 268–74. doi:10.2143/ACB.3267. PMID 24455796.
  28. ^ Müderris II, Bayram F, Ozçelik B, Güven M (Feb 2002). "New alternative treatment in hirsutism: bicalutamide 25 mg/day". Gynecological Endocrinology. 16 (1): 63–6. doi:10.1080/713602986. PMID 11915584.
  29. ^ a b Jordan, Virgil Craig; Furr, B. J. A. (5 February 2010). Hormone Therapy in Breast and Prostate Cancer. Springer Science & Business Media. pp. 350–. ISBN 978-1-59259-152-7. {{cite book}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  30. ^ a b Dansette, Patrick; Snyder, Robert R.; Monks, Terrence J.; Jollow, David J.; Sipes, I. Glenn; Greim, Helmut; Gibson, G. Gordon; Delaforge, Marcel (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. {{cite book}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  31. ^ a b c Ramon, J.; Denis, L.J. (5 June 2007). Prostate Cancer. Springer Science & Business Media. pp. 256–. ISBN 978-3-540-40901-4. {{cite book}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  32. ^ a b c d Husein-ElAhmed H (2015). "Management of acne vulgaris with hormonal therapies in adult female patients". Dermatol Ther. 28 (3): 166–72. doi:10.1111/dth.12231. PMID 25845307.
  33. ^ a b Bettoli V, Zauli S, Virgili A (2015). "Is hormonal treatment still an option in acne today?". Br. J. Dermatol. 172 Suppl 1: 37–46. doi:10.1111/bjd.13681. PMID 25627824.
  34. ^ Paradisi R, Fabbri R, Porcu E, Battaglia C, Seracchioli R, Venturoli S (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". Gynecol. Endocrinol. 27 (10): 823–9. doi:10.3109/09513590.2010.526664. PMID 21117864.
  35. ^ Trivedi MK, Shinkai K, Murase JE (2017). "A Review of hormone-based therapies to treat adult acne vulgaris in women". Int J Womens Dermatol. 3 (1): 44–52. doi:10.1016/j.ijwd.2017.02.018. PMC 5419026. PMID 28492054.
  36. ^ a b Walter Brown Shelley; E. Dorinda Shelley (2001). Advanced Dermatologic Therapy II. W. B. Saunders. ISBN 978-0-7216-8258-7.
  37. ^ a b Adam Balen; Stephen Franks; Roy Homburg; Sean Kehoe (October 2010). Current Management of Polycystic Ovary Syndrome. Cambridge University Press. pp. 132–. ISBN 978-1-906985-41-7.
  38. ^ Nguyen HL, Tollefson MM (2017). "Endocrine disorders and hormonal therapy for adolescent acne". Curr. Opin. Pediatr. 29 (4): 455–465. doi:10.1097/MOP.0000000000000515. PMID 28562419.
  39. ^ a b Schmidt TH, Shinkai K (2015). "Evidence-based approach to cutaneous hyperandrogenism in women". J. Am. Acad. Dermatol. 73 (4): 672–90. doi:10.1016/j.jaad.2015.05.026. PMID 26138647.
  40. ^ a b c Levy LL, Emer JJ (2013). "Female pattern alopecia: current perspectives". Int J Womens Health. 5: 541–56. doi:10.2147/IJWH.S49337. PMC 3769411. PMID 24039457.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  41. ^ Paradisi R, Porcu E, Fabbri R, Seracchioli R, Battaglia C, Venturoli S (2011). "Prospective cohort study on the effects and tolerability of flutamide in patients with female pattern hair loss". Ann Pharmacother. 45 (4): 469–75. doi:10.1345/aph.1P600. PMID 21487083.
  42. ^ Diamanti-Kandarakis E (September 1999). "Current aspects of antiandrogen therapy in women". Current Pharmaceutical Design. 5 (9): 707–23. 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].
  43. ^ Carmina E, Lobo RA (2003). "Treatment of hyperandrogenic alopecia in women". Fertil. Steril. 79 (1): 91–5. PMID 12524069.
  44. ^ Baudewijntje P.C. Kreukels; Thomas D. Steensma; Annelou L.C. de Vries (1 July 2013). Gender Dysphoria and Disorders of Sex Development: Progress in Care and Knowledge. Springer Science & Business Media. pp. 280–. ISBN 978-1-4614-7441-8.
  45. ^ Dahl, M., Feldman, J., Goldberg, J.M., Jaberi, A., Bockting, W.O., and Knudson, G. (2006). Endocrine therapy for transgender adults in British Columbia: Suggested guidelines. Vancouver, BC: Vancouver Health Authority.
  46. ^ a b Farida, Chentli; Faiza, Belhimer (2013). "Severe gynecomastia due to anti androgens intake: A case report and literature review". Indian Journal of Endocrinology and Metabolism. 17 (4): 730. doi:10.4103/2230-8210.113770. ISSN 2230-8210.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  47. ^ Ricardo Azziz (8 November 2007). Androgen Excess Disorders in Women. Springer Science & Business Media. pp. 384–. ISBN 978-1-59745-179-6.
  48. ^ Jay Roberts; David L. Snyder; Eitan Friedman (14 August 1996). Handbook of Pharmacology on Aging. CRC Press. pp. 334–. ISBN 978-0-8493-8306-9.
  49. ^ a b c William B. Pratt (1994). The Anticancer Drugs. Oxford University Press. pp. 219–220. ISBN 978-0-19-506739-2.
  50. ^ Gillatt, David (2006). "Antiandrogen treatments in locally advanced prostate cancer: are they all the same?". Journal of Cancer Research and Clinical Oncology. 132 (S1): 17–26. doi:10.1007/s00432-006-0133-5. ISSN 0171-5216. PMID 16845534. 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).
  51. ^ Goldspiel BR, Kohler DR (1990). "Flutamide: An Antiandrogen for Advanced Prostate Cancer". Ann Pharmacother. 24 (6): 616–623. doi:10.1177/106002809002400612. PMID 2193461. [...] 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."
  52. ^ a b c d e JORDAN V. CRAIG; B.J.A. Furr (5 February 2010). Hormone Therapy in Breast and Prostate Cancer. Springer Science & Business Media. pp. 356–. ISBN 978-1-59259-152-7.
  53. ^ a b c Neil Kaplowitz (16 October 2002). Drug-Induced Liver Disease. CRC Press. pp. 618–619. ISBN 978-0-203-90912-6.
  54. ^ Thole, Zebron; Manso, Gloria; Salgueiro, Esther; Revuelta, Pilar; Hidalgo, Agustin (2004). "Hepatotoxicity Induced by Antiandrogens: A Review of the Literature". Urologia Internationalis. 73 (4): 289–295. doi:10.1159/000081585. ISSN 0042-1138. PMID 15604569.
  55. ^ a b c Brahm J, Brahm M, Segovia R, Latorre R, Zapata R, Poniachik J, Buckel E, Contreras L (2011). "Acute and fulminant hepatitis induced by flutamide: case series report and review of the literature". Ann Hepatol. 10 (1): 93–8. PMID 21301018.
  56. ^ García Cortés M, Andrade RJ, Lucena MI, Sánchez Martínez H, Fernández MC, Ferrer T, Martín-Vivaldi R, Peláez G, Suárez F, Romero-Gómez M, Montero JL, Fraga E, Camargo R, Alcántara R, Pizarro MA, García-Ruiz E, Rosemary-Gómez M (2001). "Flutamide-induced hepatotoxicity: report of a case series". Rev Esp Enferm Dig. 93 (7): 423–32. PMID 11685939.
  57. ^ a b Jeffrey K. Aronson (21 February 2009). Meyler's Side Effects of Endocrine and Metabolic Drugs. Elsevier. pp. 153–. ISBN 978-0-08-093292-7.
  58. ^ Jafri, Syed-Mohammed R. (2014). "Bicalutamide-induced hepatotoxicity: A rare adverse effect". American Journal of Case Reports. 15: 266–270. doi:10.12659/AJCR.890679. ISSN 1941-5923. PMC 4068966. PMID 24967002.
  59. ^ Bruni, Vincenzina; Peruzzi, Elena; Dei, Metella; Nannini, Sara; Seravalli, Viola; Sisti, Giovanni; Fambrini, Massimiliano (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. ISSN 0015-0282. PMID 22795685.
  60. ^ Evanthia Diamanti-Kandarakis; John E. Nestler; Dimitrios Panidis; Renato Pasquali (21 December 2009). Insulin Resistance and Polycystic Ovarian Syndrome: Pathogenesis, Evaluation, and Treatment. Springer Science & Business Media. pp. 75–. ISBN 978-1-59745-310-3.
  61. ^ a b c d Ball, Amy L.; Kamalian, Laleh; Alfirevic, Ana; Lyon, Jonathan J.; Chadwick, Amy E. (2016). "Identification of the Additional Mitochondrial Liabilities of 2-Hydroxyflutamide When Compared With its Parent Compound, Flutamide in HepG2 Cells". Toxicological Sciences: kfw126. doi:10.1093/toxsci/kfw126. ISSN 1096-6080. PMID 27413113.
  62. ^ a b c Coe, Kevin J.; Jia, Yankai; Ho, Han Kiat; Rademacher, Peter; Bammler, Theo K.; Beyer, Richard P.; Farin, Frederico M.; Woodke, Libby; Plymate, Stephen R.; Fausto, Nelson; Nelson, Sidney D. (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. ISSN 0893-228X. PMC 2802183. PMID 17702527.
  63. ^ a b c Marroquin, L. D.; Hynes, J.; Dykens, J. A.; Jamieson, J. D.; Will, Y. (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. ISSN 1096-6080. PMID 17361016.
  64. ^ a b Kostrubsky, Seva E.; Strom, Stephen C.; Ellis, Ewa; Nelson, Sidney D.; Mutlib, Abdul E. (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. ISSN 0893-228X.
  65. ^ Boelsterli, Urs; Ho, Han; Zhou, Shufeng; Yeow Leow, Koon (2006). "Bioactivation and Hepatotoxicity of Nitroaromatic Drugs". Current Drug Metabolism. 7 (7): 715–727. doi:10.2174/138920006778520606. ISSN 1389-2002. PMID 17073576.
  66. ^ Khan AM, Singh NT, Bilgrami S (1997). "Flutamide induced methemoglobinemia". J. Urol. 157 (4): 1363. PMID 9120948.
  67. ^ William Figg; Cindy H. Chau; Eric J. Small (14 September 2010). Drug Management of Prostate Cancer. Springer Science & Business Media. pp. 71–. ISBN 978-1-60327-829-4.
  68. ^ 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.
  69. ^ Masiello, D.; Cheng, S.; Bubley, G. J.; Lu, M. L.; Balk, S. P. (2002). "Bicalutamide Functions as an Androgen Receptor Antagonist by Assembly of a Transcriptionally Inactive Receptor". Journal of Biological Chemistry. 277 (29): 26321–26326. doi:10.1074/jbc.M203310200. ISSN 0021-9258. PMID 12015321.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  70. ^ a b Douglas T. Carrell; C. Matthew Peterson (23 March 2010). Reproductive Endocrinology and Infertility: Integrating Modern Clinical and Laboratory Practice. Springer Science & Business Media. pp. 163–. ISBN 978-1-4419-1436-1.
  71. ^ a b J. Larry Jameson; Leslie J. De Groot (18 May 2010). Endocrinology: Adult and Pediatric. Elsevier Health Sciences. pp. 2401–. ISBN 1-4557-1126-8.
  72. ^ Hormones - Antineoplastics: Advances in Research and Application: 2011 Edition: ScholarlyPaper. ScholarlyEditions. 9 January 2012. pp. 9–. ISBN 978-1-4649-4785-8.
  73. ^ Yamasaki K, Sawaki M, Noda S, Muroi T, Takakura S, Mitoma H, Sakamoto S, Nakai M, Yakabe Y (2004). "Comparison of the Hershberger assay and androgen receptor binding assay of twelve chemicals". Toxicology. 195 (2–3): 177–86. PMID 14751673.
  74. ^ Feau, C. (2009). Novel Small Molecule Antagonists of the Interaction of the Androgen Receptor and Transcriptional Co-regulators. Saint Jude Children's Research Hospital Memphis TN. http://www.dtic.mil/docs/citations/ADA499611
  75. ^ a b c d e f g Furr, B J A (1997). "Relative potencies of flutamide and 'Casodex'". Endocrine Related Cancer. 4 (2): 197–202. doi:10.1677/erc.0.0040197. ISSN 1351-0088.
  76. ^ Ayub, M.; Levell, M.J. (1987). "Inhibition of rat testicular 17α-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. ISSN 0022-4731. PMID 2956461.
  77. ^ Ayub, M.; Levell, M. J. (1990). "SUPPRESSION OF PLASMA ANDROGENS BY THE ANTIANDROGEN FLUTAMIDE IN PROSTATIC CANCER PATIENTS TREATED WITH ZOLADEX, A GnRH ANALOGUE". Clinical Endocrinology. 32 (3): 329–340. doi:10.1111/j.1365-2265.1990.tb00874.x. ISSN 0300-0664.
  78. ^ Koch DC, Jang HS, O'Donnell EF, Punj S, Kopparapu PR, Bisson WH, Kerkvliet NI, Kolluri SK (2015). "Anti-androgen flutamide suppresses hepatocellular carcinoma cell proliferation via the aryl hydrocarbon receptor mediated induction of transforming growth factor-β1". Oncogene. 34 (50): 6092–104. doi:10.1038/onc.2015.55. PMID 25867062.
  79. ^ Vincent DeVita; Theodore S. Lawrence; Steven A. Rosenberg (29 September 2015). Lymphomas and Leukemias: Cancer: Principles & Practice of Oncology. Wolters Kluwer Health. pp. 1029–. ISBN 978-1-4963-3828-0.
  80. ^ Analytical Profiles of Drug Substances and Excipients. Academic Press. 19 March 2001. pp. 155–. ISBN 978-0-08-086122-7.
  81. ^ W. Renée Acosta (1 October 2009). LWW's Foundations in Pharmacology for Pharmacy Technicians. Lippincott Williams & Wilkins. pp. 300–. ISBN 978-0-7817-6624-1.
  82. ^ Alan J. Wein; Louis R. Kavoussi; Andrew C. Novick; Alan W. Partin; Craig A. Peters (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.
  83. ^ Stabile, R. G.; Dicks, A. P. (2003). "Microscale Synthesis and Spectroscopic Analysis of Flutamide, an Antiandrogen Prostate Cancer Drug". Journal of Chemical Education. 80 (12): 1439. doi:10.1021/ed080p1439.
  84. ^ Baker, J. W.; Bachman, G. L.; Schumacher, I.; Roman, D. P.; Tharp, A. L. (1967). "Synthesis and Bacteriostatic Activity of Some Nitrotrifluoro methylanilides". Journal of Medicinal Chemistry. 10 (1): 93–5. doi:10.1021/jm00313a020. PMID 6031711.
  85. ^ Bandgar, B. P.; Sawant, S. S. (2006). "Novel and Gram‐Scale Green Synthesis of Flutamide". Synthetic Communications. 36 (7): 859–864. doi:10.1080/00397910500464848.
  86. ^ H. John Smith; Hywel Williams (10 October 2005). Smith and Williams' Introduction to the Principles of Drug Design and Action, Fourth Edition. CRC Press. pp. 489–. ISBN 978-0-203-30415-0.
  87. ^ a b Baker JW, Bachman GL, Schumacher I, Roman DP, Tharp AL (1967). "Synthesis and bacteriostatic activity of some nitrotrifluoromethylanilides". J. Med. Chem. 10 (1): 93–5. doi:10.1021/jm00313a020. PMID 6031711.
  88. ^ Barry Boettcher (12 May 2014). 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.
  89. ^ 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.
  90. ^ William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. Elsevier. pp. 1695–. ISBN 978-0-8155-1856-3.
  91. ^ 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.
  92. ^ Vera Regitz-Zagrosek (2 October 2012). Sex and Gender Differences in Pharmacology. Springer Science & Business Media. pp. 575–. ISBN 978-3-642-30725-6.
  93. ^ Motta T, Maggi G, Perra M, Azzolari E, Casazza S, D'Alberton A (1991). "Flutamide in the treatment of hirsutism". Int J Gynaecol Obstet. 36 (2): 155–7. PMID 1683319.
  94. ^ Motta T, Maggi G, D'Alberton A (1994). "Flutamide and hirsutism". J. Endocrinol. Invest. 17 (8): 673. doi:10.1007/BF03349685. PMID 7868809.
  95. ^ Jean-Pierre Bégué; Daniele Bonnet-Delpon (2 June 2008). Bioorganic and Medicinal Chemistry of Fluorine. John Wiley & Sons. pp. 327–. ISBN 978-0-470-28187-1.
  96. ^ a b c d https://www.drugs.com/international/flutamide.html
  97. ^ Oesterling JE (1994). "Endocrine therapies for symptomatic benign prostatic hyperplasia". Urology. 43 (2 Suppl): 7–16. PMID 7509536.
  98. ^ Stone NN (1989). "Flutamide in treatment of benign prostatic hypertrophy". Urology. 34 (4 Suppl): 64–8, discussion 87–96. PMID 2477936.
  99. ^ a b Lee M, Sharifi R (1997). "Benign prostatic hyperplasia: diagnosis and treatment guideline". Ann Pharmacother. 31 (4): 481–6. PMID 9101011.
  100. ^ Naessén, Sabine; Hirschberg, Angelica Lindén (2011). "Sex Hormones and Appetite in Women: A Focus on Bulimia Nervosa": 1759–1767. doi:10.1007/978-0-387-92271-3_114. {{cite journal}}: Cite journal requires |journal= (help)
  101. ^ McElroy SL, Guerdjikova AI, Mori N, O'Melia AM (2012). "Current pharmacotherapy options for bulimia nervosa and binge eating disorder". Expert Opin Pharmacother. 13 (14): 2015–26. doi:10.1517/14656566.2012.721781. PMID 22946772.
  102. ^ Bergman L, Eriksson E (1996). "Marked symptom reduction in two women with bulimia nervosa treated with the testosterone receptor antagonist flutamide". Acta Psychiatr Scand. 94 (2): 137–9. PMID 8883576.
  103. ^ Sundblad C, Landén M, Eriksson T, Bergman L, Eriksson E (2005). "Effects of the androgen antagonist flutamide and the serotonin reuptake inhibitor citalopram in bulimia nervosa: a placebo-controlled pilot study". J Clin Psychopharmacol. 25 (1): 85–8. PMID 15643104.

Further reading

  • Sogani PC, Whitmore WF (1988). "Flutamide and other antiandrogens in the treatment of advanced prostatic carcinoma". Cancer Treat. Res. 39: 131–45. PMID 2908604.
  • Brogden RN, Clissold SP (1989). "Flutamide. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in advanced prostatic cancer". Drugs. 38 (2): 185–203. PMID 2670515.
  • Neri R (1989). "Pharmacology and pharmacokinetics of flutamide". Urology. 34 (4 Suppl): 19–21, discussion 46–56. PMID 2477934.
  • Newling DW (1989). "The use of flutamide as monotherapy in the treatment of advanced prostate cancer". Prog. Clin. Biol. Res. 303: 117–21. PMID 2674980.
  • Labrie F, Dupont A, Cusan L, Manhès G, Bergeron N, Lacourcière Y, Pineault S, Bélanger A, Monfette G, Emond J (1989). "Combination therapy with castration and flutamide: today's treatment of choice for prostate cancer". J. Steroid Biochem. 33 (4B): 817–21. PMID 2689788.
  • Goldspiel BR, Kohler DR (1990). "Flutamide: an antiandrogen for advanced prostate cancer". DICP. 24 (6): 616–23. PMID 2193461.
  • Brogden RN, Chrisp P (1991). "Flutamide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in advanced prostatic cancer". Drugs Aging. 1 (2): 104–15. PMID 1794008.
  • Labrie F (1993). "Mechanism of action and pure antiandrogenic properties of flutamide". Cancer. 72 (12 Suppl): 3816–27. PMID 8252497.
  • Iversen P, Melezinek I, Schmidt A (2001). "Nonsteroidal antiandrogens: a therapeutic option for patients with advanced prostate cancer who wish to retain sexual interest and function". BJU Int. 87 (1): 47–56. PMID 11121992.
  • Ibáñez L, de Zegher F (2006). "Low-dose flutamide-metformin therapy for hyperinsulinemic hyperandrogenism in non-obese adolescents and women". Hum. Reprod. Update. 12 (3): 243–52. doi:10.1093/humupd/dmi054. PMID 16407452.
  • Brahm J, Brahm M, Segovia R, Latorre R, Zapata R, Poniachik J, Buckel E, Contreras L (2011). "Acute and fulminant hepatitis induced by flutamide: case series report and review of the literature". Ann Hepatol. 10 (1): 93–8. PMID 21301018.
  • Giorgetti R, di Muzio M, Giorgetti A, Girolami D, Borgia L, Tagliabracci A (2017). "Flutamide-induced hepatotoxicity: ethical and scientific issues". Eur Rev Med Pharmacol Sci. 21 (1 Suppl): 69–77. PMID 28379593.


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