Flutamide acts as a selectiveantagonist 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]
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]
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-dependentskin 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][3] 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][3]
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).[36]: 368
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.[3][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]
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 cholestatichepatitis 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]
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]
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).[100]Bicalutamide is a much more potent androgen receptor antagonist than flutamide both in animals and in humans.[101][102][103][22]
Flutamide acts as a selective, competitive, silent antagonist of the androgen receptor (AR).[6] 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.[6][69][104][105] However, at high concentrations, unlike flutamide, hydroxyflutamide is able to weakly activate the AR.[6][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.[3][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]
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 inhibitCYP17A1 (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.[3] In a directly comparative study of flutamide monotherapy (375mg once daily) versus bicalutamide monotherapy (80mg once daily) in Japanese men with prostate cancer, after 24weeks 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]
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 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][5][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][7][6][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,[7] 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.
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][7][134] It was originally synthesized as a bacteriostatic agent, but was subsequently, and serendipitously found to possess antiandrogen activity.[3][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 INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, BANTooltip British Approved Name, DCFTooltip Dénomination Commune Française, and JANTooltip 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]
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 inhibitorfinasteride.[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 IIclinical 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, ERTooltip estrogen receptor, PRTooltip progesterone receptor, or HER2 status, which were all unknown.[160][163]
^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–. ISBN978-93-5090-844-0.
^ abcdefgGiorgetti 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. PMID28379593.
^ abBennett 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. PMID12353966. 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.
^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. ISBN978-3-8055-8524-8. 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].
^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.
^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.
^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. PMID11706524. S2CID23123697.
^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. PMID2144596.
^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. PMID11316974. S2CID38018788.
^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. PMID3309363.
^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. PMID2503724.
^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–. ISBN978-3-642-60064-7.
^Ostrzenski A (2002). "Hyperandrogenism". Gynecology: Integrating Conventional, Complementary, and Natural Alternative Therapy. Lippincott Williams & Wilkins. pp. 86–. ISBN978-0-7817-2761-7.
^ abOlsen 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–. ISBN978-3-540-46911-7.
^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. PMID11915584. S2CID6942048.
^ abBettoli 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. PMID25627824. S2CID35615492.
^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. PMID21117864. S2CID20250916.
^ abSchmidt 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. PMID26138647.
^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. PMID23039053. S2CID205263486.
^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. PMID21487083. S2CID38456195.
^Diamanti-Kandarakis E (September 1999). "Current aspects of antiandrogen therapy in women". Current Pharmaceutical Design. 5 (9): 707–723. doi:10.2174/1381612805666230111201150. PMID10495361. 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].
^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. PMID28454896.
^"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%]).
^"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 Testb [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.
^Blackledge GR (1996). "Clinical progress with a new antiandrogen, Casodex (bicalutamide)". Eur. Urol. 29 Suppl 2: 96–104. doi:10.1159/000473847. PMID8717470. 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.
^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. PMID16321765.
^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. PMID16845534. S2CID23888640. 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).
^Goldspiel BR, Kohler DR (June 1990). "Flutamide: an antiandrogen for advanced prostate cancer". DICP. 24 (6): 616–623. doi:10.1177/106002809002400612. PMID2193461. S2CID26125621. [...] 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."
^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. PMID15604569. S2CID24799765.
^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. PMID11685939.
^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. PMID29958919. S2CID49613890. 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]
^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. ISBN9780123878175. The frequency of liver injury with flutamide ranges from 0.18% to 5% of persons exposed, [...]
^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–. ISBN978-1-59745-310-3.
^ abKostrubsky 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. PMID17900172.
^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. PMID17073576.
^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. ISBN9780470657607.
^ abcAyub 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. PMID2788775.
^ abYamasaki 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. PMID14751673.
^Furr BJ (1996). "The development of Casodex (bicalutamide): preclinical studies". European Urology. 29 (Suppl 2): 83–95. doi:10.1159/000473846. PMID8717469.
^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. PMID8560673.
^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. PMID12496872. S2CID33497597.
^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–. ISBN978-1-60327-829-4.
^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.
^ abWheeler 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–. ISBN978-1-4419-1436-1.
^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. PMID9420861. S2CID32242838.
^ abcdefgFurr BJ (1997). "Relative potencies of flutamide and 'Casodex'". Endocrine-Related Cancer. 4 (2): 197–202. doi:10.1677/erc.0.0040197 (inactive 1 November 2024). ISSN1351-0088.{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)
^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. PMID8638357. S2CID10400855.
^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. PMID9170575. S2CID11365242.
^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. PMID3059063.
^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. PMID3625091.
^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. PMID8136296. S2CID31404295.
^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. PMID2615358.
^ abLuo 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. ISSN1351-0088.
^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. PMID2788775.
^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. PMID8693644.
^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. PMID2956461.
^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. PMID2140542. S2CID22823754.
^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. PMID18691054.
^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. PMID12750271.
^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.
^ abcBaker 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. PMID6031711.
^Bandgar BP, Sawant SS (2006). "Novel and Gram-Scale Green Synthesis of Flutamide". Synthetic Communications. 36 (7): 859–864. doi:10.1080/00397910500464848. S2CID98825198.
^DE 2130450, Neri RO, Topliss JG, "Substituierte Anilide [Substituted anilides]", published 1972-12-21, assigned to Sherico Ltd.
^DE 2261293, Gold EH, "Substituierte Imidate [Substituted imidates]", published 1973-07-05, assigned to Sherico Ltd.
^US 3847988, Gold E, issued 1974, assigned to Merck Sharp and Dohme Corp
^US 4144270, Neri RO, Topliss JG, issued 1979, assigned to Merck Sharp and Dohme Corp
^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–. ISBN978-0-203-30415-0.
^ abSciarra 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. PMID2147859. S2CID20274398.
^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. PMID1683319. S2CID37481872.
^Motta T, Maggi G, D'Alberton A (September 1994). "Flutamide and hirsutism". Journal of Endocrinological Investigation. 17 (8): 673. doi:10.1007/BF03349685. PMID7868809. S2CID2237184.
^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. ISSN0028-1298.
^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. ISSN0028-1298.
^ abHowell 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. PMID1975167.
^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. PMID3192386. S2CID46483946.
^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. ISBN978-0-387-92270-6.
^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. PMID22946772. S2CID1747393.
^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. PMID8883576. S2CID20033667.
^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. PMID15643104. S2CID45297334.
^ abcNomani 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. PMID31814547. S2CID208956450.
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. ISBN978-1-4612-8974-6. PMID2908604.
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. PMID2670515. S2CID262018256.
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. PMID2674980.
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. PMID2689788.
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. PMID1794008. S2CID260959546.
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. PMID28379593.
