Comparison of bicalutamide with other antiandrogens

Comparison of the nonsteroidal antiandrogen (NSAA) bicalutamide with other antiandrogens reveals differences between the medications in terms of efficacy, tolerability, safety, and other parameters. Relative to the other first-generation NSAAs, flutamide and nilutamide, bicalutamide shows improved potency, efficacy, tolerability, and safety, and has largely replaced these medications in clinical practice. Compared to the second-generation NSAAs, enzalutamide and apalutamide, bicalutamide has inferior potency and efficacy but similar tolerability and safety and a lower propensity for drug interactions.

Relative to steroidal antiandrogens like cyproterone acetate and spironolactone, bicalutamide has better selectivity in its action, superior efficacy as an antagonist of the androgen receptor, and better tolerability. Bicalutamide also shows a better safety profile than cyproterone acetate. When used as a high-dosage monotherapy, bicalutamide shows slightly inferior effectiveness in the treatment of prostate cancer compared to castration and GnRH analogues but a different and potentially superior tolerability and safety profile. Unlike antigonadotropic antiandrogens like cyproterone acetate and GnRH analogues, bicalutamide does not suppress production of testosterone or estradiol and instead actually increases it, which has an important involvement in the differential side-effect profiles of the medications.

Overview

Bicalutamide and the other nonsteroidal antiandrogens (NSAAs), since their introduction, have largely replaced cyproterone acetate (CPA), an older drug and steroidal antiandrogen (SAA), in the treatment of prostate cancer.[1][2][3][4] Bicalutamide was the third NSAA to be marketed, with flutamide and nilutamide preceding, and followed by enzalutamide.[5][6] Relative to the earlier antiandrogens, bicalutamide has substantially reduced toxicity, and in contrast to them, is said to have an excellent and favorable safety profile.[4][7][8][9] For these reasons, as well as superior potency, tolerability, and pharmacokinetics, bicalutamide is preferred and has largely replaced flutamide and nilutamide in clinical practice.[10][11][12] In accordance, bicalutamide is the most widely used antiandrogen in the treatment of prostate cancer.[13][14][15] Between January 2007 and December 2009, it accounted in the U.S. for about 87.2% of NSAA prescriptions.[16] Prior to the 2012 approval of enzalutamide, a newer and improved NSAA with greater potency and efficacy,[7] bicalutamide was regarded as the standard-of-care antiandrogen in the treatment of the prostate cancer.[6][7][17]

First-generation NSAAs

Comparison of first-generation NSAAs
PropertyFlutamideNilutamideBicalutamide
Half-life5–6 hours~2 days~7 days
AR RBA25%20%100%
Dosage250 mg t.i.d.100 mg t.i.d.150 mg o.d.
Unique side
effects/risks		• Diarrhea
• Hepatotoxicity
• Photosensitivity		• Nausea and vomiting
• Visual disturbances
• Alcohol intolerance
• Interstitial pneumonitis		• None[18]
Sources: [19][20][21]
Relative potencies of selected antiandrogens
AntiandrogenRelative potency
Bicalutamide4.3
Hydroxyflutamide3.5
Flutamide3.3
Cyproterone acetate1.0
Zanoterone0.4
Description: Relative potencies of orally administered antiandrogens in antagonizing 0.8 to 1.0 mg/kg s.c. testosterone propionate-induced ventral prostate weight increase in castrated immature male rats. Sources: See template.

Flutamide and nilutamide are first-generation NSAAs, similarly to bicalutamide, and all three drugs possess the same core mechanism of action of being selective AR antagonists.[22] However, bicalutamide is the most potent of the three, with the highest affinity for the AR[23][24] and the longest elimination half-life,[10] and is the safest, least toxic, and best-tolerated.[25] For these reasons, bicalutamide has largely replaced flutamide and nilutamide in clinical use,[26] and is by far the most widely used first-generation NSAA.[16]

Effectiveness

In terms of binding to the AR, the active (R)-enantiomer of bicalutamide has 4-fold greater affinity relative to that of hydroxyflutamide, the active metabolite of flutamide (a prodrug),[27][28] and 5-fold higher affinity relative to that of nilutamide.[21] In addition, bicalutamide possesses the longest elimination half-life of the three drugs,[10] with half-lives of 6–10 days for bicalutamide,[29][30] 5–6 hours for flutamide[4][10] and 8–9 hours for hydroxyflutamide,[4][31][32] and 23–87 hours (mean 56 hours) for nilutamide.[30] Due to the relatively short half-lives of flutamide and hydroxyflutamide, flutamide must be taken three times daily at 8-hour intervals, whereas bicalutamide and nilutamide may be taken once daily.[33] For this reason, dosing of bicalutamide (and nilutamide) is more convenient than with flutamide.[34] The greater AR affinity and longer elimination half-life of bicalutamide allow it to be used at relatively low dosages in comparison to flutamide (750–1500 mg/day) and nilutamide (150–300 mg/day) in the treatment of prostate cancer.[30][35][36]

While it has not been directly compared to nilutamide,[37] the effectiveness of bicalutamide has been found to be at least equivalent to that of flutamide in the treatment of prostate cancer in a direct head-to-head comparison.[38][39] Moreover, indications of superior efficacy, including significantly greater relative decreases and increases in levels of prostate-specific antigen (PSA) and testosterone, respectively, were observed.[38][39]

Relative affinities of first-generation nonsteroidal antiandrogens for the androgen receptor
SpeciesIC50 (nM)RBA (ratio)
Bicalutamide2-HydroxyflutamideNilutamideBica / 2-OH-fluBica / niluRef
Rat190700ND4.0ND[40]
Rat~400~900~9002.32.3[41]
RatNDNDND3.3ND[42]
Rata35954565186201.35.2[43]
Human~300~700~5002.51.6[44]
Human~100~300ND~3.0ND[45]
Humana2490234553001.02.1[43]
Footnotes: a = Controversial data. Sources: See template.

Tolerability and safety

Comparative tolerability of NSAAs
Side effectFlutNiluBicaEnza
Gynecomastia[46]+++++++++++
Breast pain[46]+++++++++++
Hot flashes++–++
Fatigue––+++
Nausea+++–+
Diarrhea++–++
Constipation––++
Back pain––++
Visual disturbances–++––
Alcohol intolerance–+––
Hypertension–––+
Seizures–––+
Hepatotoxicity+–––
Key: –: Not reported; +: ≥ 1%, < 20%;
++: ≥ 20%, < 40%; +++: ≥ 40%. Sources: [47]

The core side effects of NSAAs such as gynecomastia, sexual dysfunction, and hot flashes occur at similar rates with the different drugs.[48][49] Conversely, bicalutamide is associated with a significantly lower rate of diarrhea compared to flutamide.[37][50] In fact, the incidence of diarrhea did not differ between the bicalutamide and placebo groups (6.3% vs. 6.4%, respectively) in the EPC trial,[51] whereas diarrhea occurs in up to 20% of patients treated with flutamide.[37][30] The rate of nausea and vomiting appears to be lower with bicalutamide and flutamide than with nilutamide (approximately 30% incidence of nausea with nilutamide, usually rated as mild-to-moderate).[52][53] In addition, bicalutamide (and flutamide) is not associated with alcohol intolerance, visual disturbances, or a high rate of interstitial pneumonitis.[37][50] In terms of toxicity and rare reactions, as described above, bicalutamide appears to have the lowest relative risks of hepatotoxicity and interstitial pneumonitis, with respective incidences far below those of flutamide and nilutamide.[30][54][55][56] In contrast to flutamide and nilutamide, no unique or specific complications have been linked to bicalutamide.[18]

Side effects of combined androgen blockade with nonsteroidal antiandrogens
Side effectBicalutamide 50 mg/day +
GnRH agonist (n = 401) (%)a,b		Flutamide 750 mg/dayc +
GnRH agonist (n = 407) (%)a,b
Hot flashes52.653.3
Pain (general)35.431.2
Back pain25.425.8
Asthenia22.221.4
Constipation21.717.0
Pelvic pain21.217.2
Infection17.714.0
Nausea14.013.6
Peripheral edema13.210.3
Anemiad12.714.7
Dyspnea12.77.9
Diarrhea12.226.3
Nocturia12.213.5
Hematuria12.06.4
Abdominal pain11.311.3
Dizziness10.28.6
Bone pain9.210.6
Gynecomastia9.07.4
Rash8.77.4
Urinary tract infection8.78.8
Chest pain8.58.4
Hypertension8.57.1
Coughing8.25.9
Pharyngitis8.05.7
Paresthesia7.79.8
Elevated liver enzymese7.511.3
  Markedly elevatedf0.52.5
Weight loss7.59.6
Headache7.26.6
Flu-like symptoms7.04.9
Myasthenia6.74.7
Insomnia6.79.6
Erectile dysfunction6.78.6
Flatulence6.55.4
Hyperglycemia6.56.6
Dyspepsia6.55.7
Decreased appetite6.27.1
Sweating6.24.9
Bronchitis6.02.7
Breast pain/tenderness5.73.7
Urinary frequency5.77.1
Elevated alkaline phosphatase5.55.9
Weight gain5.54.4
Arthritis5.27.1
Anxiety5.02.2
Urinary retention5.03.4
Urinary impairment4.73.7
Pneumonia4.54.7
Pathological fracture4.27.9
Depression4.08.1
Vomiting4.06.9
Rhinitis3.75.4
Urinary incontinence3.77.9
Footnotes: a = Phase III studies of combined androgen blockade (bicalutamide or flutamide + GnRH agonist) in men with advanced prostate cancer. b = Incidence >5% regardless of causality. c = 250 mg three times per day at 8-hour intervals. d = Anemia includes hypochromic anemia and iron deficiency anemia. e = Abnormal liver function tests reported as adverse events. f = Elevated >5 times the normal upper limit. Sources: [57][58][59]

Second-generation NSAAs

Enzalutamide, along with the in-development apalutamide and darolutamide, are newer, second-generation NSAAs.[60] Similarly to bicalutamide and the other first-generation NSAAs, they possess the same core mechanism of action of selective AR antagonism but are thought to bind to the androgen receptor with higher affinity, prevent nuclear translocation and DNA binding, and induce apoptosis without agonist activity. Theoretically such increased affinity may make them more efficacious.[60] This is because cancer cells use different mechanisms to adapt and this increased affinity for the receptor make it more likely to bind to mutated receptors, to increased production of the receptors, and perhaps other mechanisms of resistance.[60]

Effectiveness

In comparison to bicalutamide, enzalutamide has 5- to 8-fold higher affinity for the AR,[61][62][63][64] possesses mechanistic differences resulting in improved AR deactivation,[61][65] shows increased (though by no means complete) resistance to AR mutations in prostate cancer cells causing a switch from antagonist to agonist activity,[61][66] and has an even longer elimination half-life (8–9 days versus ~6 days for bicalutamide).[67] In accordance, clinical findings suggest that enzalutamide is a significantly more potent and effective antiandrogen in comparison to first-generation NSAAs such as bicalutamide, flutamide, and nilutamide.[68][47] Moreover, the medication has demonstrated greater clinical effectiveness in the treatment of prostate cancer in direct head-to-head comparisons with bicalutamide.[69]

Tolerability and safety

In terms of tolerability, enzalutamide and bicalutamide appear comparable in most regards, with a similar moderate negative effect on sexual function and activity for instance.[68] However, enzalutamide has a risk of seizures and other central side effects such as anxiety and insomnia related to off-target GABAA receptor inhibition that bicalutamide does not appear to have.[67][70] On the other hand, unlike with all of the earlier NSAAs (flutamide, nilutamide, and bicalutamide), there has been no evidence of hepatotoxicity or elevated liver enzymes in association with enzalutamide treatment in clinical trials.[71][72] In addition to differences in adverse effects, enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19 and poses a high risk of major drug interactions (CYP3A4 alone being involved in the metabolism of approximately 50 to 60% of clinically important drugs),[73][74] whereas drug interactions are few and minimal with bicalutamide.[75][9]

Steroidal antiandrogens

SAAs include cyproterone acetate (CPA), megestrol acetate, chlormadinone acetate, and spironolactone.[76][77] These drugs are steroids, and similarly to NSAAs, act as competitive antagonists of the AR, reducing androgenic activity in the body.[78]: 79  In contrast to NSAAs however, they are non-selective, also binding to other steroid hormone receptors, and exhibit a variety of other activities including progestogenic, antigonadotropic, glucocorticoid, and/or antimineralocorticoid.[76][77] In addition, they are not silent antagonists of the AR, but are rather weak partial agonists with the capacity for both antiandrogenic and androgenic actions.[78][79][80] Of the SAAs, CPA is the only one that has been widely used in the treatment of prostate cancer.[28]: 488  As antiandrogens, the SAAs have largely been replaced by the NSAAs and are now rarely used in the treatment of prostate cancer, due to the superior selectivity, efficacy, and tolerability profiles of NSAAs.[1][2][3][4] However, some of them, namely CPA and spironolactone, are still commonly used in the management of certain androgen-dependent conditions (e.g., acne and hirsutism in women) and as the antiandrogen component of feminizing hormone therapy for transgender women.[35]: 1195–6 [81]

Effectiveness

In a large-scale clinical trial that compared 750 mg/day flutamide and 250 mg/day CPA monotherapies in the treatment of men with prostate cancer, the two drugs were found to have equivalent effectiveness on all endpoints.[82] In addition, contrarily to the case of men, flutamide has been found in various clinical studies to be more effective than CPA (and particularly spironolactone) in the treatment of androgen-dependent conditions such as acne and hirsutism in women.[83][84][85] This difference in effectiveness in men and women may be related to the fact that NSAAs like flutamide significantly increase androgen levels in men,[35] which counteracts their antiandrogenic potency,[86] but do not increase androgen levels in women.[87] (In contrast to NSAAs, CPA, due to its progestogenic and hence antigonadotropic activity, does not increase and rather suppresses androgen levels in both sexes.)[35]

Bicalutamide has been found to be at least as effective as or more effective than flutamide in the treatment of prostate cancer,[38][39] and is considered to be the most potent and efficacious antiandrogen of the three first-generation NSAAs.[82] As such, although bicalutamide has not been compared head-to-head to CPA or spironolactone in the treatment of androgen-dependent conditions, flutamide has been found to be either equivalent or more effective than them in clinical studies, and the same would consequently be expected of bicalutamide. Accordingly, a study comparing the efficacy of 50 mg/day bicalutamide versus 300 mg/day CPA in preventing the PSA flare at the start of GnRH agonist therapy in men with prostate cancer found that the two regimens were equivalently effective.[88] There was evidence of a slight advantage in terms of speed of onset and magnitude for the CPA group, but the differences were small and did not reach statistical significance.[88] The differences may have been related to the antigonadotropic activity of CPA (which would directly counteract the GnRH agonist-induced increase in gonadal androgen production) and/or the fact that bicalutamide requires 4 to 12 weeks of administration to reach steady-state (maximal) levels.[75][88]

All medically used SAAs are weak partial agonists of the AR rather than silent antagonists, and for this reason, possess inherent androgenicity in addition to their predominantly antiandrogenic actions.[78][79][80] In accordance, although CPA produces feminization of and ambiguous genitalia in male fetuses when administered to pregnant animals,[89] it has been found to produce masculinization of the genitalia of female fetuses of pregnant animals.[79] Additionally, all SAAs, including CPA and spironolactone, have been found to stimulate and significantly accelerate the growth of androgen-sensitive tumors in the absence of androgens, whereas NSAAs like flutamide have no effect and can in fact antagonize the stimulation caused by SAAs.[79][80][90] Accordingly, unlike NSAAs, the addition of CPA to castration has never been found in any controlled study to prolong survival in prostate cancer to a greater extent than castration alone.[79] In fact, a meta-analysis found that the addition of CPA to castration actually reduces the long-term effectiveness of ADT and causes an increase in mortality (mainly due to cardiovascular complications induced by CPA).[91] Also, there are two case reports of spironolactone actually accelerating progression of metastatic prostate cancer in castrated men treated with it for heart failure, and for this reason, spironolactone has been regarded as contraindicated in patients with prostate cancer.[92][93] Because of their intrinsic capacity to activate the AR, SAAs are incapable of maximally depriving the body of androgen signaling, and will always maintain at least some degree of AR activation.[80][90]

Due to its progestogenic (and by extension antigonadotropic) activity, CPA is able to suppress circulating testosterone levels by 70 to 80% in men at high dosages.[25][94] In contrast, NSAAs increase testosterone levels by up to 2-fold via blockade of the AR, a difference that is due to their lack of concomitant antigonadotropic action.[95] However, in spite of the combined AR antagonism and marked suppression of androgen levels by CPA (and hence a sort of CAB profile of antiandrogen action), monotherapy with an NSAA, CPA, or a GnRH analogue/castration all have about the same effectiveness in the treatment of prostate cancer,[94][19] whereas CAB in the form of the addition of bicalutamide (but not of CPA) to castration has slightly but significantly greater comparative effectiveness in slowing the progression of prostate cancer and extending life.[79][19] These differences may be related to the inherent androgenicity of CPA, which likely serves to limit its clinical efficacy as an antiandrogen in prostate cancer.[78][79][80][96]

Tolerability and safety

Due to the different hormonal activities of NSAAs like bicalutamide and SAAs like CPA, they possess different profiles of adverse effects.[18] CPA is regarded as having an unfavorable side effect profile,[37] and the tolerability of bicalutamide is considered to be superior.[3][55] Due to its strong antigonadotropic effects and suppression of androgen and estrogen levels, CPA is associated with marked sexual dysfunction (including loss of libido and impotence) similar to that seen with castration,[37][18][97] and osteoporosis,[98] whereas such side effects occur minimally with NSAAs like bicalutamide.[75][18] In addition, CPA has been associated with coagulation changes[91] and thrombosis,[79][97] fluid retention,[97] cardiovascular side effects (e.g., ischemic cardiomyopathy),[99][100] and adverse effects on serum lipid profiles,[37][79][18] with severe cardiovascular complications[18] occurring in approximately 10% of men with prostate cancer.[52] In contrast, bicalutamide and other NSAAs are not associated with these adverse effects.[101] Moreover, high doses of CPA are associated with hepatotoxicity,[37][102] whereas the risk of hepatotoxicity is smaller with bicalutamide.[103][104] CPA has also been associated with psychological side effects such as depression, fatigue, and irritability.[105][106][107][108]

It has been said that the only advantage of CPA over castration is its relatively low incidence of hot flashes, a benefit that is mediated by its progestogenic activity.[97] Due to increased estrogen levels, bicalutamide and other NSAAs are similarly associated with low rates of hot flashes (9.2% for bicalutamide vs. 5.4% for placebo in the EPC trial).[75] One advantage of CPA over NSAAs is that, because it suppresses estrogen levels rather than increases them, it is associated with only a low rate of what is generally only slight gynecomastia (4–20%),[97][109][48] whereas NSAAs are associated with rates of gynecomastia of up to 80%.[110] Although NSAA monotherapy has many tolerability advantages in comparison to CPA, a few of these advantages, such as preservation of sexual function and interest and BMD (i.e., no increased incidence of osteoporosis) and low rates of hot flashes, are lost when NSAAs are combined with castration.[111] However, the risk and severity of gynecomastia with NSAAs are also greatly diminished in this context.[48][46]

Unlike spironolactone, bicalutamide has no antimineralocorticoid activity,[97] and for this reason, has no risk of hyperkalemia (which can, rarely/in severe cases, result in hospitalization or death)[112] or other antimineralocorticoid side effects such as urinary frequency, dehydration, hypotension, hyponatremia, metabolic acidosis, or decreased renal function that may occur with spironolactone treatment.[113][114][115] In women, unlike CPA and spironolactone,[116] bicalutamide does not produce menstrual irregularity or amenorrhea, nor does it interfere with ovulation.[117][118]

Castration and GnRH analogues

Castration consists of either medical castration with a GnRH analogue or surgical castration via orchiectomy.[31] GnRH analogues include GnRH agonists like leuprorelin or goserelin and GnRH antagonists like cetrorelix.[31] They are powerful antigonadotropins and work by abolishing the GnRH-induced secretion of gonadotropins, in turn ceasing gonadal production of sex hormones.[31] Medical and surgical castration achieve essentially the same effect, decreasing circulating testosterone levels by approximately 95%.[31][119]

Effectiveness

Bicalutamide monotherapy has been reported to be roughly equivalent in effectiveness compared to GnRH analogues and castration in the treatment of prostate cancer.[4][78][82] A meta-analysis concluded that there is a slight effectiveness advantage for GnRH analogues/castration, but the differences trended towards but did not reach statistical significance in that study.[4][78][82][120] In mPC, the median survival time was found to be only 6 weeks shorter with bicalutamide monotherapy in comparison to GnRH analogue monotherapy.[121] However, a 2015 Cochrane review reported lower overall survival times (HR = 1.24), greater clinical progression (RR = 1.14–1.26), and treatment failure (RR = 1.14–1.27) with NSAA monotherapy compared to monotherapy with a GnRH agonist or surgical castration.[122]

Tolerability and safety

Monotherapy with NSAAs including bicalutamide, flutamide, nilutamide, and enzalutamide shows a significantly lower risk of certain side effects, including hot flashes, depression, fatigue, loss of libido, and decreased sexual activity, relative to treatment with GnRH analogues, CAB (NSAA and GnRH analogue combination), CPA, or surgical castration in prostate cancer.[51][49][123][124] For example, 60% of men reported complete loss of libido with bicalutamide relative to 85% for CAB and 69% reported complete loss of erectile function relative to 93% for CAB.[51] Another large study reported a rate of impotence of only 9.3% with bicalutamide relative to 6.5% for standard care (the controls), a rate of decreased libido of only 3.6% with bicalutamide relative to 1.2% for standard care, and a rate of 9.2% with bicalutamide for hot flashes relative to 5.4% for standard care.[125] One other study reported decreased libido, impotence, and hot flashes in only 3.8%, 16.9%, and 3.1% of bicalutamide-treated patients, respectively, relative to 1.3%, 7.1%, and 3.6% for placebo.[126] It has been proposed that due to the lower relative effect of NSAAs on sexual interest and activity, with two-thirds of advanced mPC patients treated with them retaining sexual interest, these drugs may result in improved quality of life and thus be preferable for those who wish to retain sexual interest and function relative to other antiandrogen therapies in prostate cancer.[49] Also, bicalutamide differs from GnRH analogues (which decrease BMD and significantly increase the risk of bone fractures)[127] in that it has well-documented benefits on BMD, effects that are likely due to increased levels of estrogen.[120][128]

A 2015 Cochrane review found that NSAA monotherapy for prostate cancer had a greater risk of treatment discontinuation due to adverse effects than monotherapy with a GnRH agonist or surgical castration (RR = 1.82).[122] This included a greatly increased risk of breast pain (RR = 22.97) and gynecomastia (RR = 8.43).[122] The risk of other adverse effects, such as hot flashes (RR = 0.23), was decreased with NSAA monotherapy.[122] The quality of the evidence was deemed moderate.[122]

References

  1. 1 2 Lemke TL, Williams DA (2008). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 121, 1288, 1290. ISBN 978-0-7817-6879-5. Archived from the original on 8 September 2017.
  2. 1 2 Kaliks RA, Del Giglio A (2008). "Management of advanced prostate cancer" (PDF). Revista da Associação Médica Brasileira. 54 (2): 178–82. doi:10.1590/S0104-42302008000200025. PMID 18506331. Archived (PDF) from the original on 10 May 2017.
  3. 1 2 3 Payen O, Top S, Vessières A, Brulé E, Lauzier A, Plamont M, McGlinchey MJ, Müller-Bunz H, Jaouen G (2011). "Synthesis and biological activity of ferrocenyl derivatives of the non-steroidal antiandrogens flutamide and bicalutamide". Journal of Organometallic Chemistry. 696 (5): 1049–1056. doi:10.1016/j.jorganchem.2010.10.051. Cyproterone acetate was one of the first steroidal antiandrogen clinically used but its side-effects, especially the interaction with the progestin and glucocorticoid receptor, made this drug less popular than the nonsteroidal antiandrogens such as nilutamide [3,4], flutamide [5–7] and bicalutamide [8].
  4. 1 2 3 4 5 6 7 Chabner BA, Longo DL (8 November 2010). Cancer Chemotherapy and Biotherapy: Principles and Practice. Lippincott Williams & Wilkins. pp. 679–680. ISBN 978-1-60547-431-1. From a structural standpoint, antiandrogens are classified as steroidal, including cyproterone [acetate] (Androcur) and megestrol [acetate], or nonsteroidal, including flutamide (Eulexin, others), bicalutamide (Casodex), and nilutamide (Nilandron). The steroidal antiandrogens are rarely used.
  5. ↑ Bégué J, Bonnet-Delpon D (2 June 2008). Bioorganic and Medicinal Chemistry of Fluorine. John Wiley & Sons. pp. 327–. ISBN 978-0-470-28187-1.
  6. 1 2 Regitz-Zagrosek V (2 October 2012). Sex and Gender Differences in Pharmacology. Springer Science & Business Media. pp. 575–. ISBN 978-3-642-30725-6. Archived from the original on 24 June 2016.
  7. 1 2 3 Vogelzang NJ (September 2012). "Enzalutamide—a major advance in the treatment of metastatic prostate cancer". The New England Journal of Medicine. 367 (13): 1256–7. doi:10.1056/NEJMe1209041. PMID 23013078. S2CID 32314622. The first nonsteroidal antiandrogen agents — flutamide, nilutamide, and bicalutamide2 — were shown to be less effective than castration in cases of metastatic castration-resistant prostate cancer, but bicalutamide is still widely used as a moderately effective secondary hormone therapy because of an excellent safety profile.
  8. ↑ Weber GF (22 July 2015). Molecular Therapies of Cancer. Springer. pp. 318–. ISBN 978-3-319-13278-5. Compared to flutamide and nilutamide, bicalutamide has a 2-fold increased affinity for the Androgen Receptor, a longer half-life, and substantially reduced toxicities. Based on a more favorable safety profile relative to flutamide, bicalutamide is indicated for use in combination therapy with a Gonadotropin Releasing Hormone analog for the treatment of advanced metastatic prostate carcinoma.
  9. 1 2 Kolvenbag GJ, Blackledge GR (January 1996). "Worldwide activity and safety of bicalutamide: a summary review". Urology. 47 (1A Suppl): 70–9, discussion 80–4. doi:10.1016/s0090-4295(96)80012-4. PMID 8560681. Bicalutamide is a new antiandrogen that offers the convenience of once-daily administration, demonstrated activity in prostate cancer, and an excellent safety profile. Because it is effective and offers better tolerability than flutamide, bicalutamide represents a valid first choice for antiandrogen therapy in combination with castration for the treatment of patients with advanced prostate cancer.
  10. 1 2 3 4 Gulley JL (2011). Prostate Cancer. Demos Medical Publishing. pp. 81–. ISBN 978-1-935281-91-7. Archived from the original on 25 April 2016.
  11. ↑ Moser L (1 January 2008). Controversies in the Treatment of Prostate Cancer. Karger Medical and Scientific Publishers. pp. 41–42. ISBN 978-3-8055-8524-8. Archived from the original on 16 May 2016.
  12. ↑ Gulley JL (20 December 2011). Prostate Cancer. Demos Medical Publishing. pp. 505–. ISBN 978-1-935281-91-7.
  13. ↑ Mukherji D, Pezaro CJ, De-Bono JS (February 2012). "MDV3100 for the treatment of prostate cancer". Expert Opinion on Investigational Drugs. 21 (2): 227–33. doi:10.1517/13543784.2012.651125. PMID 22229405. S2CID 46339544.
  14. ↑ Pchejetski D, Alshaker H, Stebbing J (2014). "Castrate-resistant prostate cancer: the future of antiandrogens" (PDF). Trends in Urology & Men's Health. 5 (1): 7–10. doi:10.1002/tre.371.
  15. ↑ Campbell T (22 January 2014). "Slowing Sales for Johnson & Johnson's Zytiga May Be Good News for Medivation". The Motley Fool. Archived from the original on 26 August 2016. Retrieved 20 July 2016. [...] the most commonly prescribed treatment for metastatic castration resistant prostate cancer: bicalutamide. That was sold as AstraZeneca's billion-dollar-a-year drug Casodex before losing patent protection in 2008. AstraZeneca still generates a few hundred million dollars in sales from Casodex, [...]
  16. 1 2 Chang S (10 March 2010), Bicalutamide BPCA Drug Use Review in the Pediatric Population (PDF), U.S. Department of Health and Human Service, archived (PDF) from the original on 24 October 2016, retrieved 20 July 2016
  17. ↑ Horwich A (11 February 2010). Systemic Treatment of Prostate Cancer. Annals of Oncology. Vol. 17 Suppl 10. OUP Oxford. pp. 44–. doi:10.1093/annonc/mdl262. ISBN 978-0-19-956142-1. PMID 17018726.
  18. 1 2 3 4 5 6 7 Aronson JK (21 February 2009). Meyler's Side Effects of Endocrine and Metabolic Drugs. Elsevier. pp. 150–152. ISBN 978-0-08-093292-7. In contrast [to flutamide and nilutamide], no specific non-pharmacological complications have been linked to bicalutamide, while diarrhea and abnormal liver function occur less often than with flutamide.
  19. 1 2 3 Wirth MP, Hakenberg OW, Froehner M (February 2007). "Antiandrogens in the treatment of prostate cancer". European Urology. 51 (2): 306–13, discussion 314. doi:10.1016/j.eururo.2006.08.043. PMID 17007995.
  20. ↑ Reid P, Kantoff P, Oh W (1999). "Antiandrogens in prostate cancer". Invest New Drugs. 17 (3): 271–84. doi:10.1023/A:1006344807086. PMID 10665479. S2CID 12658622.
  21. 1 2 Gao W, Bohl CE, Dalton JT (September 2005). "Chemistry and structural biology of androgen receptor". Chemical Reviews. 105 (9): 3352–70. doi:10.1021/cr020456u. PMC 2096617. PMID 16159155. RBA (%): R-bicalutamide: 0.4%; Flutamide: 0.01%; Hydroxyflutamide: 0.1%; Nilutamide: 0.08%
  22. ↑ Saad F, Eisenberger MA (20 August 2014). Management of Castration Resistant Prostate Cancer. Springer. pp. 79–. ISBN 978-1-4939-1176-9.
  23. ↑ Resnick MI, Thompson IM (2000). Advanced Therapy of Prostate Disease. PMPH-USA. pp. 379–. ISBN 978-1-55009-102-1. Archived from the original on 10 June 2016.
  24. ↑ Furr BJ (2009). "Research on reproductive medicine in the pharmaceutical industry". Human Fertility. 1 (1): 56–63. doi:10.1080/1464727982000198131. PMID 11844311.
  25. 1 2 Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA (25 August 2011). Campbell-Walsh Urology: Expert Consult Premium Edition: Enhanced Online Features and Print, 4-Volume Set. Elsevier Health Sciences. pp. 2938–2939, 2946. ISBN 978-1-4160-6911-9. Archived from the original on 5 May 2016.
  26. ↑ Bunce CM, Campbell MJ (11 March 2010). Nuclear Receptors: Current Concepts and Future Challenges. Springer Science & Business Media. pp. 160, 167. ISBN 978-90-481-3303-1. Archived from the original on 10 June 2016.
  27. ↑ Wirth M, Altwein JE, Schmitz-Drager B, Kuptz S (1998). Molecular Biology of Prostate Cancer. Walter de Gruyter. pp. 92–. ISBN 978-3-11-016159-5.
  28. 1 2 Smith HJ, Williams H (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.
  29. ↑ Skidmore-Roth L (17 April 2013). Mosby's 2014 Nursing Drug Reference – Elsevieron VitalSource. Elsevier Health Sciences. pp. 193–194. ISBN 978-0-323-22267-9.
  30. 1 2 3 4 5 Kolvenbag, Geert J. C. M.; Furr, Barrington J. A. (2009). "Nonsteroidal Antiandrogens". In V. Craig Jordan; Barrington J. A. Furr (eds.). Hormone Therapy in Breast and Prostate Cancer. Humana Press. pp. 347–368. doi:10.1007/978-1-59259-152-7_16. ISBN 978-1-60761-471-5. A case of near-fatal fulminant hepatic failure in a patient on bicalutamide therapy (50 mg) has recently been published (101), but it is uncertain whether this can be attributed to bicalutamide, as the symptoms developed after only two doses in a patient previously exposed to both cyproterone acetate and flutamide (101).
  31. 1 2 3 4 5 Lemke TL, Williams DA (24 January 2012). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 1372–1373. ISBN 978-1-60913-345-0. Archived from the original on 3 May 2016.
  32. ↑ Denis LJ, Griffiths K, Kaisary AV, Murphy GP (1 March 1999). Textbook of Prostate Cancer: Pathology, Diagnosis and Treatment: Pathology, Diagnosis and Treatment. CRC Press. pp. 55, 279–280. ISBN 978-1-85317-422-3. Archived from the original on 3 June 2016.
  33. ↑ Acosta WR (1 October 2009). LWW's Foundations in Pharmacology for Pharmacy Technicians. Lippincott Williams & Wilkins. pp. 300–. ISBN 978-0-7817-6624-1.
  34. ↑ Upfal J (2006). Australian Drug Guide. Black Inc. pp. 282–. ISBN 978-1-86395-174-6. Archived from the original on 8 September 2017.
  35. 1 2 3 4 Becker KL (2001). Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. pp. 1119, 1196, 1208. ISBN 978-0-7817-1750-2. Archived from the original on 8 September 2017.
  36. ↑ Boccardo F (August 2000). "Hormone therapy of prostate cancer: is there a role for antiandrogen monotherapy?". Critical Reviews in Oncology/Hematology. 35 (2): 121–32. doi:10.1016/S1040-8428(00)00051-2. PMID 10936469.
  37. 1 2 3 4 5 6 7 8 Anderson J (March 2003). "The role of antiandrogen monotherapy in the treatment of prostate cancer". BJU International. 91 (5): 455–61. doi:10.1046/j.1464-410X.2003.04026.x. PMID 12603397.
  38. 1 2 3 Helsen C, Van den Broeck T, Voet A, Prekovic S, Van Poppel H, Joniau S, Claessens F (August 2014). "Androgen receptor antagonists for prostate cancer therapy". Endocrine-Related Cancer. 21 (4): T105–18. doi:10.1530/ERC-13-0545. PMID 24639562.
  39. 1 2 3 Nakai Y, Tanaka N, Anai S, Miyake M, Tatsumi Y, Fujimoto K (August 2015). "A Randomized Control Trial Comparing the Efficacy of Antiandrogen Monotherapy: Flutamide vs. Bicalutamide". Hormones & Cancer. 6 (4): 161–7. doi:10.1007/s12672-015-0226-1. PMID 26024831. S2CID 10625154.
  40. ↑ Furr BJ, Valcaccia B, Curry B, Woodburn JR, Chesterson G, Tucker H (June 1987). "ICI 176,334: a novel non-steroidal, peripherally selective antiandrogen". J. Endocrinol. 113 (3): R7–9. doi:10.1677/joe.0.113R007. PMID 3625091.
  41. ↑ Teutsch G, Goubet F, Battmann T, Bonfils A, Bouchoux F, Cerede E, Gofflo D, Gaillard-Kelly M, Philibert D (January 1994). "Non-steroidal antiandrogens: synthesis and biological profile of high-affinity ligands for the androgen receptor". J. Steroid Biochem. Mol. Biol. 48 (1): 111–9. doi:10.1016/0960-0760(94)90257-7. PMID 8136296.
  42. ↑ Winneker RC, Wagner MM, Batzold FH (December 1989). "Studies on the mechanism of action of Win 49596: a steroidal androgen receptor antagonist". J. Steroid Biochem. 33 (6): 1133–8. doi:10.1016/0022-4731(89)90420-2. PMID 2615358.
  43. 1 2 Luo, S; Martel, C; LeBlanc, G; Candas, B; Singh, S M; Labrie, C; Simard, J; Belanger, A; Labrie, F (1996). "Relative potencies of Flutamide and Casodex: preclinical studies". Endocrine Related Cancer. 3 (3): 229–241. doi:10.1677/erc.0.0030229. ISSN 1351-0088.
  44. ↑ Ayub M, Levell MJ (August 1989). "The effect of ketoconazole related imidazole drugs and antiandrogens on [3H] R 1881 binding to the prostatic androgen receptor and [3H]5 alpha-dihydrotestosterone and [3H]cortisol binding to plasma proteins". J. Steroid Biochem. 33 (2): 251–5. doi:10.1016/0022-4731(89)90301-4. PMID 2788775.
  45. ↑ Kemppainen JA, Wilson EM (July 1996). "Agonist and antagonist activities of hydroxyflutamide and Casodex relate to androgen receptor stabilization". Urology. 48 (1): 157–63. doi:10.1016/S0090-4295(96)00117-3. PMID 8693644.
  46. 1 2 3 Bautista-Vidal C, Barnoiu O, García-Galisteo E, Gómez-Lechuga P, Baena-González V (2014). "Treatment of gynecomastia in patients with prostate cancer and androgen deprivation". Actas Urologicas EspañOlas. 38 (1): 34–40. doi:10.1016/j.acuro.2013.02.013. PMID 23850393. The frequency of occurrence of gynecomastia with the use of antiandrogens with gonadotrophin-releasing hormone agonists is about 15%, but the frequency of gynecomastia with antiandrogens in monotherapy is rather similar; thus, we found gynecomastia rates of around 43–76% with flutamide, 79% with nilutamide, and between 47 and 85% with bicalutamide.
  47. 1 2 Ricci F, Buzzatti G, Rubagotti A, Boccardo F (November 2014). "Safety of antiandrogen therapy for treating prostate cancer". Expert Opinion on Drug Safety. 13 (11): 1483–99. doi:10.1517/14740338.2014.966686. PMID 25270521. S2CID 207488100.
  48. 1 2 3 Dicker AP (2003). "The safety and tolerability of low-dose irradiation for the management of gynaecomastia caused by antiandrogen monotherapy". The Lancet Oncology. 4 (1): 30–6. doi:10.1016/s1470-2045(03)00958-6. PMID 12517537.
  49. 1 2 3 Iversen P, Melezinek I, Schmidt A (January 2001). "Nonsteroidal antiandrogens: a therapeutic option for patients with advanced prostate cancer who wish to retain sexual interest and function". BJU International. 87 (1): 47–56. doi:10.1046/j.1464-410x.2001.00988.x. PMID 11121992.
  50. 1 2 Blackledge GR (1996). "Clinical progress with a new antiandrogen, Casodex (bicalutamide)". European Urology. 29 Suppl 2 (2): 96–104. doi:10.1159/000473847. PMID 8717470. Casodex is associated with significantly less gastrointestinal effects (diarrhoea) than the nonsteroidal antiandrogen flutamide (Eulexin, Schering-Plough International). Casodex is not associated with alcohol intolerance, pneumonitis and ocular defects which have been seen with the antiandrogen nilutamide (Anandron, Roussel).
  51. 1 2 3 Fradet Y (February 2004). "Bicalutamide (Casodex) in the treatment of prostate cancer". Expert Review of Anticancer Therapy. 4 (1): 37–48. doi:10.1586/14737140.4.1.37. PMID 14748655. S2CID 34153031. In contrast, the incidence of diarrhea was comparable between the bicalutamide and placebo groups (6.3 vs. 6.4%, respectively) in the EPC program [71].
  52. 1 2 Chang C (22 March 2005). Prostate Cancer: Basic Mechanisms and Therapeutic Approaches. World Scientific. pp. 10–11. ISBN 978-981-4481-61-8. Archived from the original on 8 September 2017.
  53. ↑ Harris MG, Coleman SG, Faulds D, Chrisp P (1993). "Nilutamide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in prostate cancer". Drugs & Aging. 3 (1): 9–25. doi:10.2165/00002512-199303010-00002. PMID 8453188.
  54. ↑ Danseuse P, Snyder RR, Monks TJ, Jollow DJ, Sipes IG, Greim H, Gibson GG, Delaforge M (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. Archived from the original on 28 April 2016.
  55. 1 2 Ramon J, Denis L (5 June 2007). Prostate Cancer. Springer Science & Business Media. pp. 256–. ISBN 978-3-540-40901-4. Archived from the original on 27 April 2016.
  56. ↑ Bennett CL, Raisch DW, Sartor O (October 2002). "Pneumonitis associated with nonsteroidal antiandrogens: presumptive evidence of a class effect". Annals of Internal Medicine. 137 (7): 625. doi:10.7326/0003-4819-137-7-200210010-00029. PMID 12353966. An estimated 0.77% of the 6,480 nilutamide-treated patients, 0.04% of the 41,700 flutamide-treated patients, and 0.01% of the 86,800 bicalutamide-treated patients developed pneumonitis during the study period.
  57. ↑ "Casodex Product Monograph" (PDF). Retrieved 24 September 2018.
  58. ↑ "NU-Bicalutamide Product Monograph" (PDF). Retrieved 24 September 2018.
  59. ↑ Blackledge GR (1996). "Clinical progress with a new antiandrogen, Casodex (bicalutamide)". Eur. Urol. 29 Suppl 2: 96–104. doi:10.1159/000473847. PMID 8717470.
  60. 1 2 3 Rathkopf D, Scher HI (2013). "Androgen receptor antagonists in castration-resistant prostate cancer". Cancer Journal. 19 (1): 43–9. doi:10.1097/PPO.0b013e318282635a. PMC 3788593. PMID 23337756.
  61. 1 2 3 Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, Wongvipat J, Smith-Jones PM, Yoo D, Kwon A, Wasielewska T, Welsbie D, Chen CD, Higano CS, Beer TM, Hung DT, Scher HI, Jung ME, Sawyers CL (May 2009). "Development of a second-generation antiandrogen for treatment of advanced prostate cancer". Science. 324 (5928): 787–90. Bibcode:2009Sci...324..787T. doi:10.1126/science.1168175. PMC 2981508. PMID 19359544.
  62. ↑ Rodriguez-Vida A, Galazi M, Rudman S, Chowdhury S, Sternberg CN (2015). "Enzalutamide for the treatment of metastatic castration-resistant prostate cancer". Drug Design, Development and Therapy. 9: 3325–39. doi:10.2147/DDDT.S69433. PMC 4492664. PMID 26170619.
  63. ↑ Annual Reports in Medicinal Chemistry. Elsevier Science. 13 September 2013. pp. 498–. ISBN 978-0-12-417151-0. Archived from the original on 8 September 2017.
  64. ↑ Balaj K (25 April 2016). Managing Metastatic Prostate Cancer In Your Urological Oncology Practice. Springer. pp. 24–25. ISBN 978-3-319-31341-2. Archived from the original on 8 September 2017.
  65. ↑ Antonarakis ES (June 2013). "Enzalutamide: The emperor of all anti-androgens". Translational Andrology and Urology. 2 (2): 119–120. doi:10.3978/j.issn.2223-4683.2012.09.04. PMC 3785324. PMID 24076589.
  66. ↑ Joseph JD, Lu N, Qian J, Sensintaffar J, Shao G, Brigham D, Moon M, Maneval EC, Chen I, Darimont B, Hager JH (September 2013). "A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509". Cancer Discovery. 3 (9): 1020–9. doi:10.1158/2159-8290.CD-13-0226. PMID 23779130.
  67. 1 2 Litt JZ (25 January 2013). Litt's Drug Eruptions and Reactions Manual, 19th Edition. CRC Press. pp. 148–. ISBN 978-1-84214-599-9. Archived from the original on 22 May 2016.
  68. 1 2 Tombal B, Borre M, Rathenborg P, Werbrouck P, Van Poppel H, Heidenreich A, Iversen P, Braeckman J, Heracek J, Baskin-Bey E, Ouatas T, Perabo F, Phung D, Hirmand M, Smith MR (May 2014). "Enzalutamide monotherapy in hormone-naive prostate cancer: primary analysis of an open-label, single-arm, phase 2 study". The Lancet Oncology. 15 (6): 592–600. doi:10.1016/S1470-2045(14)70129-9. PMID 24739897.
  69. ↑ Tombal B, Borre M, Rathenborg P, Werbrouck P, Van Poppel H, Heidenreich A, Iversen P, Braeckman J, Heracek J, Baskin-Bey E, Ouatas T, Perabo F, Phung D, Baron B, Hirmand M, Smith MR (November 2015). "Long-term Efficacy and Safety of Enzalutamide Monotherapy in Hormone-naïve Prostate Cancer: 1- and 2-Year Open-label Follow-up Results". European Urology. 68 (5): 787–94. doi:10.1016/j.eururo.2015.01.027. PMID 25687533.
  70. ↑ Foster WR, Car BD, Shi H, Levesque PC, Obermeier MT, Gan J, Arezzo JC, Powlin SS, Dinchuk JE, Balog A, Salvati ME, Attar RM, Gottardis MM (April 2011). "Drug safety is a barrier to the discovery and development of new androgen receptor antagonists". The Prostate. 71 (5): 480–8. doi:10.1002/pros.21263. PMID 20878947. S2CID 24620044.
  71. ↑ Keating GM (March 2015). "Enzalutamide: a review of its use in chemotherapy-naïve metastatic castration-resistant prostate cancer". Drugs & Aging. 32 (3): 243–9. doi:10.1007/s40266-015-0248-y. PMID 25711765. S2CID 29563345.
  72. ↑ Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, Iversen P, Bhattacharya S, Carles J, Chowdhury S, Davis ID, de Bono JS, Evans CP, Fizazi K, Joshua AM, Kim CS, Kimura G, Mainwaring P, Mansbach H, Miller K, Noonberg SB, Perabo F, Phung D, Saad F, Scher HI, Taplin ME, Venner PM, Tombal B (July 2014). "Enzalutamide in metastatic prostate cancer before chemotherapy". The New England Journal of Medicine. 371 (5): 424–33. doi:10.1056/NEJMoa1405095. PMC 4418931. PMID 24881730.
  73. ↑ Richard J., Editor in Chief Hamilton FAAEM FACMT (4 December 2013). Tarascon Pocket Pharmacopoeia 2014 Deluxe Lab-Coat Edition. Jones & Bartlett Publishers. pp. 336–. ISBN 978-1-284-05399-9. Archived from the original on 17 June 2016. {{cite book}}: |author= has generic name (help)
  74. ↑ McCutcheon SB (2013). "Enzalutamide: a new agent for the prostate cancer treatment armamentarium". Journal of the Advanced Practitioner in Oncology. 4 (3): 182–5. doi:10.6004/jadpro.2013.4.3.7. PMC 4093421. PMID 25031999.
  75. 1 2 3 4 Wellington K, Keam SJ (2006). "Bicalutamide 150mg: a review of its use in the treatment of locally advanced prostate cancer" (PDF). Drugs. 66 (6): 837–50. doi:10.2165/00003495-200666060-00007. PMID 16706554. S2CID 46966712. Archived from the original (PDF) on 28 August 2016. Retrieved 20 November 2017.
  76. 1 2 Advances in Clinical Chemistry. Academic Press. 11 October 2000. pp. 111–. ISBN 978-0-08-052230-2. Archived from the original on 15 February 2017.
  77. 1 2 Thomas JA (12 March 1997). Endocrine Toxicology, Second Edition. CRC Press. pp. 152–. ISBN 978-1-4398-1048-4. Archived from the original on 8 September 2017.
  78. 1 2 3 4 5 6 Figg W, Chau CH, Small EJ (14 September 2010). Drug Management of Prostate Cancer. Springer Science & Business Media. pp. 56, 71–72, 75, 93. ISBN 978-1-60327-829-4.
  79. 1 2 3 4 5 6 7 8 9 Singh SM, Gauthier S, Labrie F (February 2000). "Androgen receptor antagonists (antiandrogens): structure-activity relationships". Current Medicinal Chemistry. 7 (2): 211–47. doi:10.2174/0929867003375371. PMID 10637363.
  80. 1 2 3 4 5 Poyet P, Labrie F (October 1985). "Comparison of the antiandrogenic/androgenic activities of flutamide, cyproterone acetate and megestrol acetate". Molecular and Cellular Endocrinology. 42 (3): 283–8. doi:10.1016/0303-7207(85)90059-0. PMID 3930312. S2CID 24746807.
  81. ↑ Ettner R, Monastery S, Eyler AE (1 February 2013). Principles of Transgender Medicine and Surgery. Routledge. pp. 76–. ISBN 978-1-136-76566-7. Archived from the original on 15 February 2017.
  82. 1 2 3 4 Mydlo JH, Godec CJ (29 September 2015). Prostate Cancer: Science and Clinical Practice. Elsevier Science. pp. 516–521, 534–540. ISBN 978-0-12-800592-7. Archived from the original on 8 September 2017.
  83. ↑ Haber RS, Stough DB (2006). Hair Transplantation. Elsevier Health Sciences. pp. 6–7. ISBN 978-1-4160-3104-8. Archived from the original on 4 July 2014. Retrieved 28 May 2012.
  84. ↑ Goroll AH, Mulley AG (27 January 2009). Primary Care Medicine: Office Evaluation and Management of the Adult Patient. Lippincott Williams & Wilkins. p. 1264. ISBN 978-0-7817-7513-7. Archived from the original on 4 July 2014. Retrieved 28 May 2012.
  85. ↑ Grigoriou O, Papadias C, Konidaris S, Antoniou G, Karakitsos P, Giannikos L (April 1996). "Comparison of flutamide and cyproterone acetate in the treatment of hirsutism: a randomized controlled trial". Gynecological Endocrinology. 10 (2): 119–23. doi:10.3109/09513599609097901. PMID 8701785.
  86. ↑ Pratt WB (1994). The Anticancer Drugs. Oxford University Press. pp. 219–220. ISBN 978-0-19-506739-2. Archived from the original on 8 September 2017.
  87. ↑ Diamanti-Kandarakis E, Nestler JE, Pandas D, Pasquale R (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. Archived from the original on 19 May 2016.
  88. 1 2 3 Sugiono M, Winkler MH, Okeke AA, Benney M, Gillatt DA (2005). "Bicalutamide vs cyproterone acetate in preventing flare with LHRH analogue therapy for prostate cancer—a pilot study". Prostate Cancer and Prostatic Diseases. 8 (1): 91–4. doi:10.1038/sj.pcan.4500784. PMID 15711607.
  89. ↑ James VH, Pasqualini JR (22 October 2013). Hormonal Steroids: Proceedings of the Sixth International Congress on Hormonal Steroids. Elsevier Science. pp. 391–. ISBN 978-1-4831-9067-9. Archived from the original on 19 August 2017.
  90. 1 2 Luthy IA, Begin DJ, Labrie F (1988). "Androgenic activity of synthetic progestins and spironolactone in androgen-sensitive mouse mammary carcinoma (Shionogi) cells in culture". Journal of Steroid Biochemistry. 31 (5): 845–52. doi:10.1016/0022-4731(88)90295-6. PMID 2462135.
  91. 1 2 Müller E (18 September 2003). Peptides and Non Peptides of Oncologic and Neuroendocrine Relevance: From Basic to Clinical Research. Springer Science & Business Media. pp. 171–. ISBN 978-88-470-0295-1. Archived from the original on 8 September 2017. [CPA] induces relevant effects on the coagulative system. A recent meta-analysis relating to total androgenic blockade has shown that cyproterone acetate when combined with castration reduces the long-term efficacy of androgen-suppressive treatments. In fact, it causes an increase in treatment-related mortality, mainly due to cardiovascular complications (No authors, 2000).
  92. ↑ Sundar S, Dickinson PD (2012). "Spironolactone, a possible selective androgen receptor modulator, should be used with caution in patients with metastatic carcinoma of the prostate". BMJ Case Reports. 2012: bcr1120115238. doi:10.1136/bcr.11.2011.5238. PMC 3291010. PMID 22665559.
  93. ↑ Flynn T, Guancial EA, Kilari M, Kilari D (2016). "Case Report: Spironolactone Withdrawal Associated With a Dramatic Response in a Patient With Metastatic Castrate-Resistant Prostate Cancer". Clin Genitourin Cancer. 15 (1): e95–e97. doi:10.1016/j.clgc.2016.08.006. PMID 27641657. S2CID 38441469.
  94. 1 2 Miyamoto H, Messing EM, Chang C (2004). "Androgen deprivation therapy for prostate cancer: current status and future prospects". The Prostate. 61 (4): 332–53. doi:10.1002/pros.20115. PMID 15389811. S2CID 22300358.
  95. ↑ Jameson JL, de Kretser DM, Marshall JC, De Groot LJ (7 May 2013). Endocrinology Adult and Pediatric: Reproductive Endocrinology. Elsevier Health Sciences. ISBN 978-0-323-22152-8. Archived from the original on 25 July 2014. Nonsteroidal antiandrogens (e.g., flutamide and nilutamide) are also used, but they increase gonadotropin secretion, causing increased secretion of testosterone and estradiol.119 The latter is desirable in this context, as it has feminizing effects.
  96. ↑ Caubet JF, Tosteson TD, Dong EW, Naylon EM, Whiting GW, Ernstoff MS, Ross SD (1997). "Maximum androgen blockade in advanced prostate cancer: a meta-analysis of published randomized controlled trials using nonsteroidal antiandrogens". Urology. 49 (1): 71–8. doi:10.1016/S0090-4295(96)00325-1. PMID 9000189. Because steroidal antiandrogens such as cyproterone acetate have intrinsic androgenic activity and lower antiandrogenic activity than the NSAAs such as flutamide and nilutamide,39–43 it is not surprising that the two classes of antiandrogens may have different efficacies.
  97. 1 2 3 4 5 6 Furr BJ, Tucker H (January 1996). "The preclinical development of bicalutamide: pharmacodynamics and mechanism of action". Urology. 47 (1A Suppl): 13–25, discussion 29–32. doi:10.1016/S0090-4295(96)80003-3. PMID 8560673.
  98. ↑ Terrence Priestman (26 May 2012). Cancer Chemotherapy in Clinical Practice. Springer Science & Business Media. pp. 97–. ISBN 978-0-85729-727-3.
  99. ↑ Migliari R, Muscas G, Murru M, Verdacchi T, De Benedetto G, De Angelis M (1999). "Antiandrogens: a summary review of pharmacodynamic properties and tolerability in prostate cancer therapy". Archivio Italiano di Urologia e Andrologia. 71 (5): 293–302. PMID 10673793. The only advantage of cyproterone acetate on pure antiandrogens seems to be the low incidence of hot flushes; [...] However, hepatotoxicity associated with long term daily doses of 300 mg daily and the unacceptably high incidence of cardiovascular side effects (10%) should restrict its use to patients who are intolerant of pure antiandrogen compound. In contrast to steroidal compound nonsteroidal compounds let sexual potency to be retained, [...]
  100. ↑ Mahler C, Verhelst J, Denis L (May 1998). "Clinical pharmacokinetics of the antiandrogens and their efficacy in prostate cancer". Clinical Pharmacokinetics. 34 (5): 405–17. doi:10.2165/00003088-199834050-00005. PMID 9592622. S2CID 25200595.
  101. ↑ Han M, Nelson JB (2000). "Non-steroidal anti-androgens in prostate cancer—current treatment practice". Expert Opinion on Pharmacotherapy. 1 (3): 443–9. doi:10.1517/14656566.1.3.443. PMID 11249529. S2CID 25535097.
  102. ↑ Savidou I, Deutsch M, Soultati AS, Koudouras D, Kafiri G, Dourakis SP (2006). "Hepatotoxicity induced by cyproterone acetate: a report of three cases". World Journal of Gastroenterology. 12 (46): 7551–5. doi:10.3748/wjg.v12.i46.7551. PMC 4087608. PMID 17167851.
  103. ↑ Thole Z, Manso G, Salgueiro E, Revuelta P, Hidalgo A (2004). "Hepatotoxicity induced by antiandrogens: a review of the literature". Urologia Internationalis. 73 (4): 289–95. doi:10.1159/000081585. PMID 15604569. S2CID 24799765.
  104. ↑ Manso G, Thole Z, Salgueiro E, Revuelta P, Hidalgo A (April 2006). "Spontaneous reporting of hepatotoxicity associated with antiandrogens: data from the Spanish pharmacovigilance system". Pharmacoepidemiology and Drug Safety. 15 (4): 253–9. doi:10.1002/pds.1168. PMID 16294367. S2CID 24515447.
  105. ↑ Blume-Peytavi U, Whiting DA, Trüeb RM (26 June 2008). Hair Growth and Disorders. Springer Science & Business Media. pp. 161–162, 181. ISBN 978-3-540-46911-7.
  106. ↑ James Barrett (2007). Transsexual and Other Disorders of Gender Identity: A Practical Guide to Management. Radcliffe Publishing. p. 174. ISBN 978-1-85775-719-4. Archived from the original on 20 July 2014.
  107. ↑ Barth JH, Cherry CA, Wojnarowska F, Dawber RP (July 1991). "Cyproterone acetate for severe hirsutism: results of a double-blind dose-ranging study". Clinical Endocrinology. 35 (1): 5–10. doi:10.1111/j.1365-2265.1991.tb03489.x. PMID 1832346. S2CID 27293697.
  108. ↑ Rushton DH (July 2002). "Nutritional factors and hair loss". Clinical and Experimental Dermatology. 27 (5): 396–404. doi:10.1046/j.1365-2230.2002.01076.x. PMID 12190640. S2CID 39327815.
  109. ↑ Neumann F, Kalmus J (1991). "Cyproterone acetate in the treatment of sexual disorders: pharmacological base and clinical experience". Experimental and Clinical Endocrinology. 98 (2): 71–80. doi:10.1055/s-0029-1211103. PMID 1838080.
  110. ↑ Side Effects of Drugs Annual: A worldwide yearly survey of new data in adverse drug reactions. Elsevier Science. 1 December 2014. pp. 629–. ISBN 978-0-444-63391-0.
  111. ↑ Furr BJ (June 1995). "Casodex: preclinical studies and controversies". Annals of the New York Academy of Sciences. 761 (1): 79–96. Bibcode:1995NYASA.761...79F. doi:10.1111/j.1749-6632.1995.tb31371.x. PMID 7625752. S2CID 37242269.
  112. ↑ Aronson JK (2 March 2009). Meyler's Side Effects of Cardiovascular Drugs. Elsevier. pp. 253–258. ISBN 978-0-08-093289-7.
  113. ↑ Lenz AM, Shulman D, Eugster EA, Rahhal S, Fuqua JS, Pescovitz OH, Lewis KA (September 2010). "Bicalutamide and third-generation aromatase inhibitors in testotoxicosis". Pediatrics. 126 (3): e728–33. doi:10.1542/peds.2010-0596. PMC 4096839. PMID 20713483.
  114. ↑ Greenblatt DJ, Koch-Weser J (July 1973). "Adverse reactions to spironolactone. A report from the Boston Collaborative Drug Surveillance Program". JAMA. 225 (1): 40–3. doi:10.1001/jama.1973.03220280028007. PMID 4740303.
  115. ↑ Munoz R, da Cruz E, Vetterly CG, et al. (26 June 2014). Handbook of Pediatric Cardiovascular Drugs. Springer. pp. 224–. ISBN 978-1-4471-2464-1.
  116. ↑ Katsambas A, Lotti T, Dessinioti C, D'Erme AM (28 April 2015). European Handbook of Dermatological Treatments. Springer. pp. 1460–. ISBN 978-3-662-45139-7. Archived from the original on 15 February 2017.
  117. ↑ Erem C (2013). "Update on idiopathic hirsutism: diagnosis and treatment". Acta Clinica Belgica. 68 (4): 268–74. doi:10.2143/ACB.3267. PMID 24455796. S2CID 39120534.
  118. ↑ Bahceci M, Tuzcu A, Canoruc N, Tuzun Y, Kidir V, Aslan C (2004). "Serum C-reactive protein (CRP) levels and insulin resistance in non-obese women with polycystic ovarian syndrome, and effect of bicalutamide on hirsutism, CRP levels and insulin resistance". Hormone Research. 62 (6): 283–7. doi:10.1159/000081973. PMID 15542929. S2CID 46261843.
  119. ↑ Cassel CK, Leipzig R, Cohen HJ, Larson EB, Meier DE (29 May 2006). Geriatric Medicine: An Evidence-Based Approach. Springer Science & Business Media. pp. 460–. ISBN 978-0-387-22621-7.
  120. 1 2 Strauss III JF, Barbieri RL (28 August 2013). Yen & Jaffe's Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management. Elsevier Health Sciences. pp. 688–. ISBN 978-1-4557-5972-9. Bone density improves in men receiving bicalutamide, most likely secondary to the 146% increase in estradiol and the fact that estradiol is the major mediator of bone density in men.
  121. ↑ d'Ancona FC, Debruyne FM (2005). "Endocrine approaches in the therapy of prostate carcinoma". Hum. Reprod. Update. 11 (3): 309–17. doi:10.1093/humupd/dmi004. PMID 15790600.
  122. 1 2 3 4 5 Kunath F, Grobe HR, Rücker G, Motschall E, Antes G, Dahm P, Wullich B, Meerpohl JJ (2015). "Non-steroidal antiandrogen monotherapy compared with luteinizing hormone-releasing hormone agonists or surgical castration monotherapy for advanced prostate cancer: a Cochrane systematic review". BJU Int. 116 (1): 30–6. doi:10.1111/bju.13026. PMID 25523493. S2CID 26204957.
  123. ↑ Wibowo E, Schellhammer P, Wassersug RJ (January 2011). "Role of estrogen in normal male function: clinical implications for patients with prostate cancer on androgen deprivation therapy". The Journal of Urology. 185 (1): 17–23. doi:10.1016/j.juro.2010.08.094. PMID 21074215.
  124. ↑ Motofei IG, Rowland DL, Popa F, Kreienkamp D, Paunica S (July 2011). "Preliminary study with bicalutamide in heterosexual and homosexual patients with prostate cancer: a possible implication of androgens in male homosexual arousal". BJU International. 108 (1): 110–5. doi:10.1111/j.1464-410X.2010.09764.x. PMID 20955264. S2CID 45482984.
  125. ↑ McLeod DG, Iversen P, See WA, Morris T, Armstrong J, Wirth MP (February 2006). "Bicalutamide 150 mg plus standard care vs standard care alone for early prostate cancer". BJU International. 97 (2): 247–54. doi:10.1111/j.1464-410X.2005.06051.x. PMID 16430622.
  126. ↑ Iversen P, Johansson JE, Lodding P, Lukkarinen O, Lundmo P, Klarskov P, Tammela TL, Tasdemir I, Morris T, Carroll K (November 2004). "Bicalutamide (150 mg) versus placebo as immediate therapy alone or as adjuvant to therapy with curative intent for early nonmetastatic prostate cancer: 5.3-year median followup from the Scandinavian Prostate Cancer Group Study Number 6". The Journal of Urology. 172 (5 Pt 1): 1871–6. doi:10.1097/01.ju.0000139719.99825.54. PMID 15540741.
  127. ↑ Orwell ES, Bilezikian JP, Vanderschueren D (30 November 2009). Osteoporosis in Men: The Effects of Gender on Skeletal Health. Academic Press. pp. 324–. ISBN 978-0-08-092346-8.
  128. ↑ Hanna L, Crosby T, Macbeth F (19 November 2015). Practical Clinical Oncology. Cambridge University Press. pp. 37–. ISBN 978-1-107-68362-4.
This article is issued from Offline. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.