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Bicalutamide

Bicalutamide, sold under the brand name Casodex among others, is an antiandrogen medication that is primarily used to treat prostate cancer. It is typically used together with a gonadotropin-releasing hormone (GnRH) analogue or surgical removal of the testicles to treat metastatic prostate cancer (mPC). To a lesser extent, it is used at high doses for locally advanced prostate cancer (LAPC) as a monotherapy without castration. Bicalutamide was also previously used as monotherapy to treat localized prostate cancer (LPC), but authorization for this use was withdrawn following unfavorable trial findings. Besides prostate cancer, bicalutamide is limitedly used in the treatment of excessive hair growth and scalp hair loss in women, as a puberty blocker and component of feminizing hormone therapy for transgender girls and women, to treat gonadotropin-independent early puberty in boys, and to prevent overly long-lasting erections in men. It is taken by mouth.

Common side effects of bicalutamide in men include breast growth, breast tenderness, and hot flashes. Other side effects in men include feminization and sexual dysfunction. Some side effects like breast changes and feminization are minimal when combined with castration. While the medication appears to produce few side effects in women, its use in women is not explicitly approved by the Food and Drug Administration (FDA) at this time. Use during pregnancy may harm the baby. In men with early prostate cancer, bicalutamide monotherapy has been found to increase the likelihood of death from causes other than prostate cancer. Bicalutamide produces abnormal liver changes necessitating discontinuation in around 1% of people. Rarely, it has been associated with cases of serious liver damage, serious lung toxicity, and sensitivity to light. Although the risk of adverse liver changes is small, monitoring of liver function is recommended during treatment.

Bicalutamide is a member of the nonsteroidal antiandrogen (NSAA) group of medications. It works by selectively blocking the androgen receptor (AR), the biological target of the androgen sex hormones testosterone and dihydrotestosterone (DHT). It does not lower androgen levels. The medication can have some estrogen-like effects in men when used as a monotherapy due to increased estradiol levels. Bicalutamide is well-absorbed, and its absorption is not affected by food. The elimination half-life of the medication is around one week. It shows peripheral selectivity in animals, but crosses the blood–brain barrier and affects both the body and brain in humans.

Bicalutamide was patented in 1982 and approved for medical use in 1995. It is on the World Health Organization's List of Essential Medicines. Bicalutamide is available as a generic medication. The drug is sold in more than 80 countries, including most developed countries. It was at one time the most widely used antiandrogen in the treatment of prostate cancer, with millions of men with the disease having been prescribed it. Although bicalutamide is also used for other indications besides prostate cancer, the vast majority of prescriptions appear to be for treatment of prostate cancer.

Medical uses
Bicalutamide is approved for and mainly used in the following indications:

 * Metastatic prostate cancer (mPC) in men in combination with a gonadotropin-releasing hormone (GnRH) analogue or surgical castration at 50 mg/day
 * Locally advanced prostate cancer (LAPC) in men as a monotherapy at 150 mg/day (not approved for this use in the United States)

In Japan, bicalutamide is uniquely used at a dosage of 80 mg/day both in combination with castration and as a monotherapy in the treatment of prostate cancer.

Bicalutamide is also employed for the following off-label (non-approved) indications:

 * To reduce the effects of the testosterone flare at the initiation of GnRH agonist therapy in men
 * Androgen-dependent skin and hair conditions such as acne, seborrhea, excessive hair growth, and scalp hair loss in women as well as high testosterone levels due to polycystic ovary syndrome (PCOS) in women, at 25 to 50 mg/day generally in combination with a birth control pill
 * Feminizing hormone therapy for transgender women in combination with an estrogen usually at 50 mg/day
 * Peripheral precocious puberty in boys at 12.5 to 100 mg/day in combination with an aromatase inhibitor like anastrozole, especially for familial male-limited precocious puberty (testotoxicosis)
 * Overly long-lasting erections in men at 50 mg per week to 50 mg every other day

The medication has been suggested for but has uncertain effectiveness in the following indication:

 * Hypersexuality and paraphilias, particularly in combination with chemical castration

For more information on these uses, see the medical uses of bicalutamide article.

Available forms
Bicalutamide is available for the treatment of prostate cancer in most developed countries, including over 80 countries worldwide. It is available in 50 mg, 80 mg (in Japan), and 150 mg tablets for oral administration. The drug is registered for use as a 150 mg/day monotherapy for the treatment of LAPC in at least 55 countries, with the U.S. being a notable exception where it is registered only for use at a dosage of 50 mg/day in combination with castration. No other formulations or routes of administration are available or used. All formulations of bicalutamide are specifically indicated for the treatment of prostate cancer alone or in combination with surgical or medication castration. Due to the low water solubility of bicalutamide, bicalutamide in oral bicalutamide tablets is micronized to ensure small and consistent particle sizes and optimize oral bioavailability.

A combined formulation of bicalutamide and the GnRH agonist goserelin in which goserelin is provided as a subcutaneous implant for injection and bicalutamide is included as 50 mg tablets for oral ingestion is marketed in Australia and New Zealand under the brand name ZolaCos CP (Zoladex–Cosudex Combination Pack).

Contraindications
Bicalutamide is pregnancy category X, or "contraindicated in pregnancy", in the U.S., and pregnancy category D, the second most restricted rating, in Australia. As such, it is contraindicated in women during pregnancy, and women who are sexually active and who can or may become pregnant are strongly recommended to take bicalutamide only in combination with adequate contraception. It is unknown whether bicalutamide is excreted in breast milk, but many drugs are excreted in breast milk, and for this reason, bicalutamide treatment is similarly not recommended while breastfeeding.

In individuals with severe, though not mild-to-moderate hepatic impairment, there is evidence that the elimination of bicalutamide is slowed, and hence, caution may be warranted in these patients as circulating levels of bicalutamide may be increased. In severe hepatic impairment, the elimination half-life of the active (R)-enantiomer of bicalutamide is increased by about 1.75-fold (76% increase; elimination half-life of 5.9 and 10.4 days for normal and impaired patients, respectively). The elimination half-life of bicalutamide is unchanged in renal impairment.

Side effects
The side effect profile of bicalutamide is highly dependent on sex; that is, on whether the person is male or female. In men, due to androgen deprivation, a variety of side effects of varying severity may occur during bicalutamide treatment, with breast pain/tenderness and gynecomastia (breast development/enlargement) being the most common. Gynecomastia occurs in up to 80% of men treated with bicalutamide monotherapy, and is of mild-to-moderate severity in more than 90% of affected men. In addition to breast changes, physical feminization and demasculinization in general, including reduced body hair growth, decreased muscle mass and strength, feminine changes in fat mass and distribution, reduced penile length, and decreased semen/ejaculate volume, may occur in men. Other side effects that have been observed in men and that are similarly related to androgen deprivation include hot flashes, sexual dysfunction (e.g., loss of libido, erectile dysfunction), depression, fatigue, weakness, and anemia. However, most men have preserved sexual function with bicalutamide monotherapy. In females, due to the minimal biological importance of androgens in this sex, the side effects of pure antiandrogens or NSAAs are few, and bicalutamide has been found to be very well tolerated. However, bicalutamide has been found to increase levels of total and LDL cholesterol in women. The non-pharmacological side-effect profile of bicalutamide (i.e., side effects not related to its antiandrogenic activity) is said to be similar to that with placebo. In any case, general side effects of bicalutamide that might occur in either sex include diarrhea, constipation, abdominal pain, nausea, dry skin, itching, and rash. The drug is well-tolerated at higher dosages than 50 mg/day, up to 600mg/day, with rare additional side effects.

Bicalutamide has been associated with abnormal liver function tests such as elevated liver enzymes. In the Early Prostate Cancer (EPC) clinical programme of bicalutamide for LPC and LAPC, the rate of abnormal liver function tests with bicalutamide monotherapy was 3.4% relative to 1.9% for placebo. However, higher rates, up to 11%, have been seen in other studies. Hepatic changes that have necessitated discontinuation of bicalutamide, such as marked increases in liver enzymes or hepatitis, have occurred in 0.3 to 1.5% of men in clinical trials, or approximately 1% overall. Elevated liver enzymes with bicalutamide usually occur within the first 3 to 6 months of treatment. Monitoring of liver function during treatment is recommended, particularly in the first few months. In men with early prostate cancer, bicalutamide monotherapy has been found to increase non-prostate cancer mortality. The reasons for the increase in mortality with bicalutamide in these men are unknown, but possible factors could include androgen deprivation or drug-related toxicity of bicalutamide.

There are 10 published case reports of liver toxicity associated with bicalutamide as of 2022. Death occurred in 2 of these cases. Hundreds of additional cases of liver complications in people taking bicalutamide exist in the FDA Adverse Event Reporting System (FAERS) database. In all of the published case reports of liver toxicity with bicalutamide, the onset of symptoms was within the first 6 months of treatment. Symptoms that may indicate liver dysfunction include nausea, vomiting, abdominal pain, fatigue, anorexia, "flu-like" symptoms, dark urine, and jaundice. There are also published case reports of interstitial pneumonitis and eosinophilic lung disease associated with bicalutamide. along with hundreds of additional instances in the FAERS database as well. Interstitial pneumonitis can potentially progress to pulmonary fibrosis and may be fatal. Symptoms that may indicate lung dysfunction include dyspnea (difficult breathing or shortness of breath), cough, and pharyngitis (inflammation of the pharynx, resulting in sore throat). The exact incidence of liver toxicity and interstitial pneumonitis with bicalutamide are unknown, but both are said to be very rare events. A few cases of photosensitivity have been reported with bicalutamide. Hypersensitivity reactions (drug allergy) like angioedema and hives have also uncommonly been reported in association with bicalutamide.

Because it is an antiandrogen, bicalutamide has a theoretical risk of birth defects like ambiguous genitalia in male fetuses. Due to its teratogenic capacity, contraception should be used in women taking bicalutamide who are fertile and sexually active.

Comparison
The side effect profile of bicalutamide in men and women differs from that of other antiandrogens and is considered favorable in comparison. Relative to GnRH analogues and the steroidal antiandrogen (SAA) cyproterone acetate (CPA), bicalutamide monotherapy has a much lower incidence and severity of hot flashes and sexual dysfunction. In addition, unlike GnRH analogues and CPA, bicalutamide monotherapy is not associated with decreased bone mineral density or osteoporosis. Conversely, bicalutamide monotherapy is associated with much higher rates of breast tenderness, gynecomastia, and feminization in men than GnRH analogues and CPA. However, gynecomastia with bicalutamide is rarely severe and discontinuation rates due to this side effect are fairly low. These differences in side effects between bicalutamide monotherapy, GnRH analogues, and CPA are attributed to the fact that whereas GnRH analogues and CPA suppress estrogen production, bicalutamide monotherapy does not lower estrogen levels and in fact actually increases them.

Bicalutamide does not share the risk of neuropsychiatric side effects like fatigue as well as cardiovascular side effects like coagulation changes, blood clots, fluid retention, ischemic cardiomyopathy, and adverse serum lipid changes that CPA has been associated with. It has a much lower risk of hepatotoxicity than flutamide and CPA and of interstitial pneumonitis than nilutamide. The drug also does not share the unique risks of diarrhea with flutamide and nausea, vomiting, visual disturbances, and alcohol intolerance with nilutamide. Unlike enzalutamide, bicalutamide is not associated with seizures or related central side effects like anxiety and insomnia. However, although the risk of adverse liver changes with bicalutamide is low, enzalutamide differs from bicalutamide in having no known risk of elevated liver enzymes or hepatotoxicity. In contrast to the SAA spironolactone, bicalutamide does not have antimineralocorticoid effects, and hence is not associated with hyperkalemia, urinary frequency, dehydration, hypotension, or other related side effects. In women, unlike CPA and spironolactone, bicalutamide does not produce menstrual irregularity or amenorrhea and does not interfere with ovulation or fertility.

Overdose
A single oral dose of bicalutamide in humans that results in symptoms of overdose or that is considered to be life-threatening has not been established. Dosages of up to 600 mg/day have been well tolerated in clinical trials, and it is notable that there is a saturation of absorption with bicalutamide such that circulating levels of its active (R)-enantiomer do not further increase above a dosage of 300 mg/day. Overdose is considered unlikely to be life-threatening with bicalutamide or other first-generation NSAAs (i.e., flutamide and nilutamide). A massive overdose of nilutamide (13 grams, or 43 times the normal maximum 300 mg/day clinical dosage) in a 79-year-old man was uneventful, producing no clinical signs, symptoms, or toxicity. There is no specific antidote for bicalutamide or NSAA overdose, and treatment should be based on symptoms, if any are present.

Interactions
Bicalutamide is almost exclusively metabolized by CYP3A4. As such, its levels in the body may be altered by inhibitors and inducers of CYP3A4. (For a list of CYP3A4 inhibitors and inducers, see here.) However, in spite of the fact bicalutamide is metabolized by CYP3A4, there is no evidence of clinically significant drug interactions when bicalutamide at a dosage of 150 mg/day or less is co-administered with drugs that inhibit or induce cytochrome P450 enzyme activity.

In-vitro studies suggest that bicalutamide may be able to inhibit CYP3A4 and, to a lesser extent, CYP2C9, CYP2C19, and CYP2D6. Conversely, animal studies suggest that bicalutamide may induce cytochrome P450 enzymes. In a clinical study, bicalutamide co-administered with the CYP3A4 substrate midazolam caused only a small and statistically non-significant increase in midazolam levels (+27%) presumably due to CYP3A4 inhibition. However, this was well below increases in midazolam exposure with potent CYP3A4 inhibitors like ketoconazole (+1500%), itraconazole (+1000%), and erythromycin (+350%), and is considered to not be clinically important. There is no indication of clinically significant enzyme inhibition or induction with bicalutamide at doses of 150mg/day or below.

Because bicalutamide circulates at relatively high concentrations and is highly protein-bound, it has the potential to displace other highly protein-bound drugs like warfarin, phenytoin, theophylline, and aspirin from plasma binding proteins. This could, in turn, result in increased free concentrations of such drugs and increased effects and/or side effects, potentially necessitating dosage adjustments. Bicalutamide has specifically been found to displace coumarin anticoagulants like warfarin from their plasma binding proteins (namely albumin) in vitro, potentially resulting in an increased anticoagulant effect, and for this reason, close monitoring of prothrombin time and dosage adjustment as necessary is recommended when bicalutamide is used in combination with these drugs. However, in spite of this, no conclusive evidence of an interaction between bicalutamide and other drugs was found in clinical trials of nearly 3,000 patients.

Antiandrogenic activity
Bicalutamide acts as a highly selective competitive silent antagonist of the AR (IC50 = 159–243 nM), the major biological target of the androgen sex hormones testosterone and DHT, and hence is an antiandrogen. The activity of bicalutamide lies in the (R)-isomer. Due to its selectivity for the AR, bicalutamide does not interact importantly with other steroid hormone receptors and hence has no clinically relevant off-target hormonal activity (e.g., progestogenic, estrogenic, glucocorticoid, antimineralocorticoid). However, it has been reported that bicalutamide has weak affinity for the progesterone receptor (PR), where it is an antagonist, and hence it could have some antiprogestogenic activity. Bicalutamide does not inhibit 5α-reductase nor is known to inhibit other enzymes involved in androgen steroidogenesis (e.g., CYP17A1). Although it does not bind to the estrogen receptors (ERs), bicalutamide can increase estrogen levels secondarily to AR blockade when used as a monotherapy in males, and hence can have some indirect estrogenic effects in males. Bicalutamide neither suppresses nor inhibits androgen production in the body (i.e., it does not act as an antigonadotropin or androgen steroidogenesis inhibitor or lower androgen levels) and hence exclusively mediates its antiandrogenic effects by antagonizing the AR. In addition to the classical nuclear AR, bicalutamide has been assessed at the membrane androgen receptors (mARs) and found to act as a potent antagonist of ZIP9 (IC50 = 66.3 nM), whereas it does not appear to interact with GPRC6A.

The affinity of bicalutamide for the AR is relatively low as it is approximately 30 to 100 times lower than that of DHT, which is 2.5- to 10-fold as potent as an AR agonist as testosterone in bioassays and is the main endogenous ligand of the receptor in the prostate gland. However, typical clinical dosages of bicalutamide result in circulating levels of the drug that are thousands of times higher than those of testosterone and DHT, allowing it to powerfully prevent them from binding to and activating the receptor. This is especially true in the case of surgical or medical castration, in which testosterone levels in the circulation are approximately 95% reduced and DHT levels in the prostate gland are about 50 to 60% reduced. In women, levels of testosterone are substantially lower (20- to 40-fold) than in men, so much smaller doses of bicalutamide (e.g., 25 mg/day in the hirsutism studies) are necessary.

Blockade of the AR by bicalutamide in the pituitary gland and hypothalamus results in prevention of the negative feedback of androgens on the hypothalamic–pituitary–gonadal axis (HPG axis) in males and consequent disinhibition of pituitary luteinizing hormone (LH) secretion. This, in turn, results in an increase in circulating LH levels and activation of the gonadal production of testosterone and by extension production of estradiol. Levels of testosterone have been found to increase 1.5- to 2-fold (59–97% increase) and levels of estradiol about 1.5- to 2.5-fold (65–146% increase) in men treated with 150 mg/day bicalutamide monotherapy. In addition to testosterone and estradiol, there are smaller increases in concentrations of DHT, sex hormone-binding globulin, and prolactin. Estradiol levels with bicalutamide monotherapy are similar to those in the low-normal premenopausal female range while testosterone levels generally remain in the high end of the normal male range. Testosterone concentrations do not typically exceed the normal male range due to negative feedback on the HPG axis by the increased concentrations of estradiol. Bicalutamide influences the HPG axis and increases hormone levels only in men and not also in women. This is due to the much lower levels of androgens in women and their lack of basal suppression of the HPG axis in this sex. As evidenced by its effectiveness in the treatment of prostate cancer and other androgen-dependent conditions, the antiandrogenic actions of bicalutamide considerably exceed any impact of the increased levels of testosterone it results in. However, the elevated levels of estradiol remain unopposed by bicalutamide and are responsible for the gynecomastia and feminizing side effects it causes in men. Although bicalutamide monotherapy increases gonadotropin and sex hormone levels in men, this will not occur if bicalutamide is combined with an antigonadotropin such as a GnRH analogue, estrogen, or progestogen, as these medications maintain negative feedback on the HPG axis.

NSAA monotherapy, including with bicalutamide, shows a number of tolerability differences from methods of androgen deprivation therapy that incorporate surgical or medical castration. For example, the rates of hot flashes, depression, fatigue, and sexual dysfunction are all much higher with GnRH analogues than with NSAA monotherapy. It is thought that this is because GnRH analogues suppress estrogen production in addition to androgen production, resulting in estrogen deficiency. In contrast, NSAA monotherapy does not decrease estrogen levels and in fact increases them, resulting in an excess of estrogens that compensates for androgen deficiency and allows for a preservation of mood, energy, and sexual function. Neurosteroids that are produced from testosterone like 3α-androstanediol and 3β-androstanediol, which are ERβ agonists and the former a potent GABAA receptor positive allosteric modulator, may also be involved. In the specific case of sexual dysfunction, an additional possibility for the difference is that without concomitant suppression of androgen production, blockade of the AR by the bicalutamide in the brain is incomplete and insufficient to markedly influence sexual function.

Under normal circumstances, bicalutamide has no capacity to activate the AR. However, in prostate cancer, mutations and overexpression of the AR can accumulate in prostate gland cells which can convert bicalutamide from an antagonist of the AR into an agonist. This can result in paradoxical stimulation of prostate cancer growth with bicalutamide and is responsible for the phenomenon of the antiandrogen withdrawal syndrome, where antiandrogen discontinuation paradoxically slows the rate of prostate cancer growth.

In transgender women, breast development is a desired effect of antiandrogen or estrogen treatment. Breast development and gynecomastia induced by bicalutamide is thought to be mediated by increased activation of the ER secondary to blockade of the AR (resulting in disinhibition of the ER in breast tissue) and increased levels of estradiol. In addition to fat deposition, connective tissue growth, and ductal development, bicalutamide has been found to produce moderate lobuloalveolar development of the breasts. However, full lobuloalveolar maturation necessary for lactation and breastfeeding will not occur without progestogen treatment.

Bicalutamide monotherapy seems to have minimal effect on testicular spermatogenesis, testicular ultrastructure, and certain aspects of male fertility. This seems to be because testosterone levels in the testes (where ~95% of testosterone in males is produced) are extremely high (up to 200-fold higher than circulating levels) and only a small fraction (less than 10%) of the normal levels of testosterone in the testes are actually necessary to maintain spermatogenesis. As a result, bicalutamide appears to not be able to compete with testosterone in this sole part of the body to an extent sufficient to considerably interfere with androgen signaling and function. However, while bicalutamide does not seem to be able to adversely influence testicular spermatogenesis, it may interfere with AR-dependent sperm maturation and transport outside of the testes in the epididymides and vas deferens where androgen levels are far lower, and hence may still be able to impair male fertility. In addition, the combination of bicalutamide with other medications, such as estrogens, progestogens, and GnRH analogues, can compromise spermatogenesis due to their own adverse effects on male fertility. These medications are able to strongly suppress gonadal androgen production, which can severely impair or abolish testicular spermatogenesis, and estrogens also appear to have direct and potentially long-lasting cytotoxic effects in the testes at sufficiently high concentrations.

Other activities
Bicalutamide has been found to act as an inhibitor or inducer of certain cytochrome P450 enzymes including CYP3A4, CYP2C9, CYP2C19, and CYP2D6 in preclinical research, but no evidence of this has been found in humans treated with up to 150 mg/day. It has also been identified in vitro as a strong inhibitor of CYP27A1 (cholesterol 27-hydroxylase) and as an inhibitor of CYP46A1 (cholesterol 24-hydroxylase), but this has yet to be assessed or confirmed in vivo or in humans and the clinical significance remains unknown. Bicalutamide has been found to be a P-glycoprotein (ABCB1) inhibitor. Like other first-generation NSAAs and enzalutamide, it has been found to act as a weak non-competitive inhibitor of GABAA receptor-mediated currents in vitro (IC50 = 5.2 μM). However, unlike enzalutamide, bicalutamide has not been found to be associated with seizures or other related adverse central effects, so the clinical relevance of this finding is uncertain.

Pharmacokinetics
Though its absolute bioavailability in humans is unknown, bicalutamide is known to be extensively and well-absorbed. Its absorption is not affected by food. The absorption of bicalutamide is linear at doses up to 150 mg/day and is saturable at doses above this, with no further increases in steady-state levels of bicalutamide occurring at doses above 300 mg/day. Whereas absorption of (R)-bicalutamide is slow, with levels peaking at 31 to 39 hours after a dose, (S)-bicalutamide is much more rapidly absorbed. Steady-state concentrations of the drug are reached after 4 to 12 weeks of treatment independently of dosage, with a 10- to 20-fold progressive accumulation in levels of (R)-bicalutamide. The long time to steady-state levels is the result of bicalutamide's very long elimination half-life. There is wide interindividual variability in (R)-bicalutamide levels (up to 16-fold) with bicalutamide regardless of dosage.

The tissue distribution of bicalutamide is not well-characterized. The amount of bicalutamide in semen that could potentially be transferred to a female partner during sexual intercourse is low and is not thought to be important. Based on animal studies with rats and dogs it was thought that bicalutamide could not cross the blood–brain barrier and hence could not enter the brain. As such, it was initially thought to be a peripherally selective antiandrogen. However, subsequent clinical studies found that this was not also the case for humans, indicating species differences; bicalutamide crosses into the human brain and, in accordance, produces effects and side effects consistent with central antiandrogenic action. In any case, there is indication that bicalutamide might have at least some peripheral selectivity in humans. Bicalutamide is highly plasma protein bound (96.1% for racemic bicalutamide, 99.6% for (R)-bicalutamide) and is bound mainly to albumin, with negligible binding to SHBG and corticosteroid-binding globulin.

Bicalutamide is metabolized in the liver. (R)-Bicalutamide is metabolized slowly and almost exclusively via hydroxylation by CYP3A4 into (R)-hydroxybicalutamide. This metabolite is then glucuronidated by UGT1A9. In contrast to (R)-bicalutamide, (S)-bicalutamide is metabolized rapidly and mainly by glucuronidation (without hydroxylation). None of the metabolites of bicalutamide are known to be active and levels of the metabolites are low in plasma, where unchanged biclautamide predominates. Due to the stereoselective metabolism of bicalutamide, (R)-bicalutamide has a far longer terminal half-life than (S)-bicalutamide and its levels are about 10- to 20-fold higher in comparison following a single dose and 100-fold higher at steady-state. (R)-Bicalutamide has a relatively long elimination half-life of 5.8 days with a single dose and 7 to 10 days following repeated administration.

Bicalutamide is eliminated in similar proportions in feces (43%) and urine (34%), while its metabolites are eliminated roughly equally in urine and bile. The drug is excreted to a substantial extent in unmetabolized form, and both bicalutamide and its metabolites are eliminated mainly as glucuronide conjugates. The glucuronide conjugates of bicalutamide and its metabolites are eliminated from the circulation rapidly, unlike unconjugated bicalutamide.

The pharmacokinetics of bicalutamide are not affected by consumption of food, a person's age or body weight, renal impairment, or mild-to-moderate hepatic impairment. However, steady-state levels of bicalutamide are higher in Japanese individuals than in white people.

Chemistry
Bicalutamide is a racemic mixture consisting of equal proportions of enantiomers (R)-bicalutamide (dextrorotatory) and (S)-bicalutamide (levorotatory). Its systematic name (IUPAC) is (RS)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide. The compound has a chemical formula of C18H14F4N2O4S, a molecular weight of 430.373 g/mol, and is a fine white to off-white powder.

The acid dissociation constant (pKa') of bicalutamide is approximately 12. It is a highly lipophilic compound (log P = 2.92). At 37 °C (98.6 °F), or normal human body temperature, bicalutamide is practically insoluble in water (4.6 mg/L), acid (4.6 mg/L at pH 1), and alkali (3.7 mg/L at pH 8). In organic solvents, it is slightly soluble in chloroform and absolute ethanol, sparingly soluble in methanol, and freely soluble in acetone and tetrahydrofuran.

Bicalutamide is a synthetic and nonsteroidal compound which was derived from flutamide. It is a bicyclic compound (has two rings) and can be classified as and has variously been referred to as an anilide (N-phenylamide) or aniline, a diarylpropionamide, and a toluidide.

Analogues
First-generation NSAAs including bicalutamide, flutamide, and nilutamide are all synthetic, nonsteroidal anilide derivatives and structural analogues of each other. Bicalutamide is a diarylpropionamide while flutamide is a monoarylpropionamide and nilutamide is a hydantoin. Bicalutamide and flutamide, though not nilutamide, can also be classified as toluidides. All three of the compounds share a common 3-trifluoromethylaniline moiety. Bicalutamide is a modification of flutamide in which a 4-fluorophenylsulfonyl moiety has been added and the nitro group on the original phenyl ring has been replaced with a cyano group. Topilutamide, also known as fluridil, is another NSAA that is closely related structurally to the first-generation NSAAs, but, in contrast to them, is not used in the treatment of prostate cancer and is instead used exclusively as a topical antiandrogen in the treatment of pattern hair loss.

A few radiolabeled derivatives of bicalutamide have been developed for potential use as radiotracers in medical imaging. They include [18F]bicalutamide, 4-[76Br]bromobicalutamide, and [76Br]bromo-thiobicalutamide. The latter two were found to have substantially increased affinity for the AR relative to that of bicautamide. However, none of these agents have been evaluated in humans.

5N-Bicalutamide, or 5-azabicalutamide, is a minor structural modification of bicalutamide which acts as a reversible covalent antagonist of the AR and has approximately 150-fold higher affinity for the AR and about 20-fold greater functional inhibition of the AR relative to bicalutamide. It is among the most potent AR antagonists to have been developed and is being researched for potential use in the treatment of antiandrogen-resistant prostate cancer.

Synthesis
A number of chemical syntheses of bicalutamide have been published in the literature. The procedure of the first published synthesis of bicalutamide can be seen below.

History
Bicalutamide as well as all of the other currently marketed NSAAs were derived from structural modification of flutamide, which itself was originally synthesized as a bacteriostatic agent in 1967 at Schering Plough Corporation and was subsequently and serendipitously found to possess antiandrogenic activity. Bicalutamide was discovered by Tucker and colleagues at Imperial Chemical Industries (ICI) in the 1980s and was selected for development from a group of over 2,000 synthesized compounds. It was first patented in 1982 and was first reported in the scientific literature in June 1987.

Bicalutamide was first studied in a phase I clinical trial in 1987 and the results of the first phase II clinical trial in prostate cancer were published in 1990. The pharmaceutical division of ICI was split out into an independent company called Zeneca in 1993, and in April and May 1995, Zeneca (now AstraZeneca, after merging with Astra AB in 1999) began pre-approval marketing of bicalutamide for the treatment of prostate cancer in the U.S.. It was first launched in the U.K. in May 1995, and was subsequently approved by the U.S. FDA on 4 October 1995, for the treatment of prostate cancer at a dosage of 50 mg/day in combination with a GnRH analogue.

Following its introduction for use in combination with a GnRH analogue, bicalutamide was developed as a monotherapy at a dosage of 150 mg/day for the treatment of prostate cancer, and was approved for this indication in Europe, Canada, and a number of other countries in the late 1990s and early 2000s. This application of bicalutamide was also under review by the FDA in the U.S. in 2002, but ultimately was not approved in this country. In Japan, bicalutamide is licensed at a dosage of 80 mg/day alone or in combination with a GnRH analogue for prostate cancer. The unique 80 mg dosage of bicalutamide used in Japan was selected for development in this country on the basis of observed pharmacokinetic differences with bicalutamide in Japanese men.

Subsequent to negative findings of bicalutamide monotherapy for LPC in the EPC clinical programme, approval of bicalutamide for use specifically in the treatment of LPC was withdrawn in a number of countries including the U.K. (in October or November 2003) and several other European countries and Canada (in August 2003). In addition, the U.S. and Canada explicitly recommended against the use of 150 mg/day bicalutamide for this indication. The drug is effective for, remains approved for, and continues to be used in the treatment of LAPC and mPC, on the other hand.

The patent protection of bicalutamide expired in the U.S. in March 2009 and the drug has subsequently been available as a generic, at greatly reduced cost.

Bicalutamide was the fourth antiandrogen (and the third NSAA) to be introduced for the treatment of prostate cancer, following the SAA CPA in 1973 and the NSAAs flutamide in 1983 (1989 in the U.S.) and nilutamide in 1989 (1996 in the U.S.). It has been followed by abiraterone acetate in 2011, enzalutamide in 2012, apalutamide in 2018, and darolutamide in 2019, and may also be followed by in-development drugs such as proxalutamide and seviteronel.

Generic names
Bicalutamide is the generic name of the drug in English and French and its INN, USAN, USP, BAN, DCF, AAN, and JAN. It is also referred to as bicalutamidum in Latin, bicalutamida in Spanish and Portuguese, bicalutamid in German, and bikalutamid in Russian and other Slavic languages. The "bica-" prefix corresponds to the fact that bicalutamide is a bicyclic compound, while the "-lutamide" suffix is the standard suffix for NSAAs. Bicalutamide is also known by its former developmental code name ICI-176,334.

Brand names
Bicalutamide is marketed by AstraZeneca in oral tablet form under the brand names Casodex, Cosudex, Calutide, Calumid, and Kalumid in many countries. It is also marketed under the brand names Bicadex, Bical, Bicalox, Bicamide, Bicatlon, Bicusan, Binabic, Bypro, Calutol, and Ormandyl among others in various countries. The drug is sold under a large number of generic trade names such as Apo-Bicalutamide, Bicalutamide Accord, Bicalutamide Actavis, Bicalutamide Bluefish, Bicalutamide Kabi, Bicalutamide Sandoz, and Bicalutamide Teva as well. A combination formulation of bicalutamide and goserelin is marketed by AstraZeneca in Australia and New Zealand under the brand name ZolaCos-CP.

Cost and generics
Bicalutamide is off-patent and available as a generic. Unlike bicalutamide, the newer NSAA enzalutamide is still on-patent, and for this reason, is considerably more expensive in comparison.

The patent protection of all three of the first-generation NSAAs has expired and flutamide and bicalutamide are both available as low-cost generics. Nilutamide, on the other hand, has always been a poor third competitor to flutamide and bicalutamide and, in relation to this fact, has not been developed as a generic and is only available as brand name Nilandron, at least in the U.S.

Bicalutamide is considerably less costly than GnRH analogues, which, in spite of some having been off-patent many years, have been reported (in 2013) to typically cost US$10,000–$15,000 per year (or about US$1,000 per month) of treatment.

Sales and usage
Sales of bicalutamide (as Casodex) worldwide peaked at US$1.3 billion in 2007, and it has been described as a "billion-dollar-a-year" drug prior to losing its patent protection starting in 2007. In 2014, despite the introduction of abiraterone acetate in 2011 and enzalutamide in 2012, bicalutamide was still the most commonly prescribed drug in the treatment of metastatic castration-resistant prostate cancer (mCRPC). Moreover, in spite of being off-patent, bicalutamide was said to still generate a few hundred million dollars in sales per year for AstraZeneca. Total worldwide sales of brand name Casodex were approximately US$13.4 billion as of the end of 2018.

Between January 2007 and December 2009 (a period of three years), 1,232,143 prescriptions of bicalutamide were dispensed in the U.S., or about 400,000 prescriptions per year. During that time, bicalutamide accounted for about 87.2% of the NSAA market, while flutamide accounted for 10.5% of it and nilutamide for 2.3% of it. Approximately 96% of bicalutamide prescriptions were written for diagnosis codes that clearly indicated neoplasm. About 1,200, or 0.1% of bicalutamide prescriptions were dispensed to pediatric patients (age 0–16).

Regulation
Bicalutamide is a prescription drug. It is not specifically a controlled substance in any country and therefore is not an illegal drug. However, the manufacture, sale, distribution, and possession of prescription drugs are all still subject to legal regulation throughout the world.

Research
Bicalutamide has been studied in combination with the 5α-reductase inhibitors finasteride and dutasteride in prostate cancer. It has also been studied in combination with raloxifene, a selective estrogen receptor modulator (SERM), for the treatment of prostate cancer. Bicalutamide has been tested for the treatment of AR-positive ER/PR-negative locally advanced and metastatic breast cancer in women in a phase II study for this indication. Enzalutamide is also being investigated for this type of cancer. Bicalutamide has also been studied in a phase II clinical trial for ovarian cancer in women.

Bicalutamide has been studied in the treatment of benign prostatic hyperplasia (BPH) in a 24-week trial of 15 patients at a dosage of 50 mg/day. Prostate volume decreased by 26% in patients taking bicalutamide and urinary irritative symptom scores significantly decreased. Conversely, peak urine flow rates and urine pressure flow examinations were not significantly different between bicalutamide and placebo. The decrease in prostate volume achieved with bicalutamide was comparable to that observed with the 5α-reductase inhibitor finasteride, which is approved for the treatment of BPH. Breast tenderness (93%), gynecomastia (54%), and sexual dysfunction (60%) were all reported as side effects of bicalutamide at the dosage used in the study, although no treatment discontinuations due to adverse effects occurred and sexual functioning was maintained in 75% of patients.

A phase III clinical trial of bicalutamide in combination with an ethinylestradiol-containing combined oral contraceptive for the treatment of severe hirsutism in women with PCOS was completed in Italy in 2017 under supervision of the Italian Agency for Drugs (AIFA).

Antiandrogens have been suggested for treating COVID-19 in men and as of May 2020 high-dose bicalutamide is in a phase II clinical trial for this purpose.

Veterinary use
Bicalutamide may be used to treat hyperandrogenism and associated benign prostatic hyperplasia secondary to hyperadrenocorticism (caused by excessive adrenal androgens) in male ferrets. However, it has not been formally assessed in controlled studies for this purpose.

title: Bicalutamide


text:
Samantha Mumba

Samantha Tamania Anne Cecilia Mumba (born 18 January 1983) is an Irish singer-songwriter, dancer, actress, fashion model and TV presenter. In 2000, at the age of 17, she shot to fame with the release of her debut single "Gotta Tell You", which reached the top five in Ireland, United Kingdom and the United States. It has since been listed in Billboard's 100 Greatest Choruses of the 21st Century. Her album of the same name was released later that year and reached number four in Ireland and number nine in the UK. She has had seven top five hits in Ireland and six top ten hits in the United Kingdom.

Mumba has also pursued an acting career, making her film debut in the 2002 film The Time Machine, as well as appearing in a number of Irish independent films. She returned to music in 2013, and announced plans to release a second album in 2019; however this never came to fruition. Mumba released the singles "Cool" and "Process" in 2020 and further single "The Lie" in 2023.

Early life and education
Mumba was born in Dublin, Ireland. Her father, Peter Mumba (died March 2020 ) was from Zambia and was formerly an aircraft engineer; her mother is Irish.

When Mumba was 15 she was discovered on a Raidió Teilifís Éireann (RTÉ–Radio Television Ireland) talent show Let Me Entertain You by Irish music executive Louis Walsh (manager of Boyzone and Westlife). Walsh was impressed by her talent and she was signed to Polydor Records.

Mumba subsequently spent several months moving between Denmark, Sweden, UK, and Ireland, where she co-wrote and recorded her debut album, Gotta Tell You. She eventually dropped out of school to focus on her music career, explaining that it was becoming difficult to stay in school and work on her music.

Career
Mumba sings contralto. Her first single, "Gotta Tell You", was released in 2000 and peaked at number one in Ireland and New Zealand, number two in the UK, number three in Australia, and number four in the US, as well as reaching the top twenty in several countries across Europe. "Gotta Tell You" has since been listed in Billboard's 100 Catchiest Choruses of the 21st Century

At the age of 17 Mumba released her debut album, Gotta Tell You, in late 2000. The album reached the top ten in both Ireland and the UK, and number 67 on the Billboard 200. Following the success of Gotta Tell You, she was chosen to play Mara in The Time Machine. Directed by Simon Wells, H.G.Wells' great-grandson, Samantha co-starred with Guy Pearce and her real-life brother, Omero. At the Teen Choice Awards in 2001 and 2002, she was nominated for Choice Music: Best Breakout Artist and Choice Movie: Best Breakout Actress for the film The Time Machine, respectively.

Mumba and fellow teen star Aaron Carter performed a concert at Disney MGM Studios for the Disney Channel titled Aaron Carter and Samantha Mumba in Concert, which was then released on DVD. A year later, she and Carter also appeared on an episode of All That.

In 2001, Mumba contributed to the track "You Raise Me Up" by the Celtic Tenors. An EP titled Samantha Sings Christmas was released at Christmas 2001, which included covers of "White Christmas" and "All I Want for Christmas Is You". Samantha Sings Christmas was also included as a bonus disc on some editions of Gotta Tell You.

In 2002, Mumba released a new single "I'm Right Here". The video features Damian Marley, son of Bob Marley. The single became Mumba's fifth UK and Irish top five single. Rumours circulated that Mumba was getting ready to release a second album, Woman and that due to the poor sales of the lead single "I'm Right Here" in the US and a short lived time on the UK chart, she was dropped from her label. However, Mumba has since confirmed she was unable to release any new material anyway, due to contract restrictions following the restructure of Polydor Records, which resulted in her being dropped. In 2007, she stated on the Late Late Show that there never was a second album, and the tracks leaked on the internet were attempts by her to find a new sound.

Mumba's second venture into films was in 2003, where she appeared in the film Spin the Bottle. In October 2006, a compilation album, The Collection, was released. The album features songs from Gotta Tell You, B-sides and two new tracks including her single "I'm Right Here".

In June 2013, Mumba confirmed her musical comeback on Twitter. On 16 August 2013 she appeared on the RTÉ television show The Hit to compete for a spot in the show's final. The song selected for chart battle was "Somebody Like Me" which was released on iTunes immediately afterwards and competed against "Thinking of You" by Irish band Republic of Loose. The song peaked at number five on the Irish Singles Chart, marking her first hit single in 11 years.

On 25 June 2015, Mumba played a gig as part of the Dublin Pride Festival, which was described as "fierce glam altogether". In early 2017, she participated in a celebrity version of MasterChef Ireland and went on to fill in as co-host on The 6 O'Clock Show while Lucy Kennedy took maternity leave. In 2018, she made her comeback onto British television, firstly as a guest and then a panellist on Loose Women and has confirmed her return to music, sharing pictures of herself in the studio with the likes of Wanya Morris and MNEK. In January 2019 she confirmed that she hoped to release a second album before the end of the year, but this did not happen.

On 27 November 2020, Mumba released the single "Cool", the lead single from her upcoming album, which Mumba has described as "sexy", "different" and "more adult". She followed this with the release of single "Process", a song she had written after the death of her father.

In May 2023, Mumba performed at Birmingham Pride. In June 2023, Mumba performed at the Mighty Hoopla music festival in London, where she previewed new song "Run Boy Run"; on 3 June 2023, Mumba released the single "The Lie".

Modelling
Shortly after the success of Gotta Tell You, Mumba became the face of Reebok appearing in print advertising in the UK and Ireland for the Quest range.

Around the same time, Mumba was also seen as the face of the fashion designer Louise Kennedy's spring/summer collection.

In 2004, she was chosen to model the World's Most Expensive Dress. A£5m diamond cobweb dress, created by Scott Henshall, which was showcased at the London premiere for Spider-Man 2.

Shortly after, she became the face of Dior ambassador and launched the Dior Watch Collection in Ireland.

In 2005, Mumba modelled for the Ultimo Per Amore range, available exclusively at the Irish main-street chain Dunnes Stores.

Personal life
Mumba dated R&B singer Sisqó from 2004 to 2005.

Mumba became engaged to Los Angeles police officer Torray Scales in June 2011. The couple married in Los Angeles on 24 February 2012. In September 2014, she announced that she was pregnant with her first child. In February 2015, she escaped uninjured from a three car pile-up in Los Angeles just weeks before her due date. On 3 March 2015, she gave birth to a baby daughter, whom Mumba and her husband named Sage.

Discography

 * Gotta Tell You (2000)

Films

 * The Time Machine (2002)
 * Spin the Bottle (2003)
 * Boy Eats Girl (2005)
 * Nailed (2006)
 * Johnny Was (2006)
 * 3 Crosses (2007)
 * Shifter (2007)
 * Loftus Hall (2011)
 * Home (2016)

Television

 * Billboard Music Awards (2000)
 * Top of the Pops (2000, 2001, 2002)
 * Friday Night with Jonathan Ross (2001)
 * Royal Variety Performance (2001)
 * MOBO Awards (2001)
 * Brit Awards (2001, 2002)
 * An Audience With Lulu (2002)
 * V Graham Norton (2002)
 * The Kumars at No. 42 (2003)
 * Meteor Ireland Music Awards (2001–2006)
 * Get Your Act Together with Harvey Goldsmith (2007)
 * Dancing on Ice (2008)
 * Celebrity Masterchef Ireland 2017 (2017)
 * The 6 O'Clock Show (2017)
 * Loose Women (2008, 2018–)
 * Last Singer Standing (2021)
 * Harry Wild (2023-)

Awards and nominations

 * BMI Pop Awards
 * 2002, Award-Winning Song, "Gotta Tell You" (Won)
 * BT Digital Music Awards
 * 2002, People's Choice Award (Nominated)
 * Billboard Music Video Awards
 * 2001, Best Pop Video of the Year – New Artist, "Gotta Tell You" (Nominated)
 * Meteor Music Awards
 * 2001, Best Selling Irish Single – Female Artist, "Gotta Tell You" (Won)
 * 2002, Best Female Singer (Won)
 * MOBO Awards
 * 2001, Best Album, Gotta Tell You (Nominated)
 * 2000, Best Video, "Gotta Tell You" (Nominated)
 * Smash Hits Poll Winners Party
 * 2000, Best New Female (Won)
 * 2000, Most Fanciable Female (Nominated)
 * 2000, Best Dressed Female (Nominated)
 * 2000, Best Dancer in Pop (Nominated)
 * 2002, Best Female Solo (Nominated)
 * Teen Choice Awards
 * 2001, Choice Music: Breakout Artist (Nominated)
 * 2002, Choice Movie: Breakout Actress, The Time Machine (Nominated)
 * The Record of the Year
 * 2000, Record of the Year, "Gotta Tell You" (Nominated)

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: Samantha Mumba


text:
King colobus

The king colobus (Colobus polykomos), also known as the western black-and-white colobus, is a species of Old World monkey, found in lowland and mountain rainforests in a region stretching from Senegal, through Guinea-Bissau, Guinea, Sierra Leone and Liberia to the Ivory Coast. One of five members of the genus Colobus, the black-and-white colobuses, the king colobus is the westernmost species of the group on the continent of Africa. It eats mainly leaves, but also fruits and flowers. Though it is arboreal, it eats primarily on the ground. It lives in small groups consisting of 3 to 4 females and 1 to 3 males, plus their young. These groups maintain distance from one another through territorial calling.

Etymology
The word  'Colobus'  comes from the Greek word for 'mutilated', as all colobus monkeys only have a short stump where the thumb would be. The word  'poly'  comes from the Greek word for 'many.' The word  'komos'  comes from the Greek celebration of unrestrained singing. A possible subspecies known as C. p. dollmani can be found but is most likely a hybrid with C. vellerosus.

Characteristics
The male king colobus grows to a head-and-body length of 67 cm, with a tail of between 63 and 90 cm. The female is slightly smaller. Males weigh an average of 9.9 kg and females weigh an average of 8.3 kg.

The body is black, the limbs and fingers are long and the tail is white. There is a fringe of silvery hair around the face as well as long white "epaulettes" on its shoulders. The king colobus can be distinguished from other members of the Colobus genus by the placement of its white markings. The king colobus has white only on its whiskers, chest, and tail, and its tail is not covered by a tuft.

Distribution and habitat
The king colobus monkey is found in lowland and montane tropical rainforests. The region in which they inhabit is limited to a small range on the Ivory Coast up to Gambia. They can also be found in Senegal, through Guinea-Bissau, Guinea, Sierra Leone and Liberia. Much of the habitat of the king colobus has been destroyed by humans for farming and secondary forests have begun to fill in this area. The forest habitats experiences significant dry seasons and two rainfall peaks. This area is dominated by leguminous trees.

Behaviour and ecology
Diet consists mainly of arboreal leaves, but includes fruit and flowers depending on the season. It can be found foraging on the ground and typically stays within a foraging path of approximately 500 m.

It lives in small groups of less than 4 females and 1 to 3 males. Unlike males, females interact closely: males rarely interact and try to show dominance. Either males or both sexes will disperse from family groups.

The king colobus have an average home range of 22 hectares with some overlap between groups. Groups rarely encounter other groups of the same species but when they do, males engage in aggressive displays. Territorial calling is a common form of aggression but can also be a warning to the group of predators.

King colobus have been shown to live approximately 23.5 years in captivity and possibly around 30 years in the wild.

Reproduction

The king colobus live in a single male (polygynous) and multi-male (polygynandrous) mating system. Some groups have shown year round births while others have shown births in relation to the dry seasons. The average gestation period is 175 days and the females produce 1 offspring every 20 months. Both males and females reach sexual maturity at approximately 730 days or 2 years. Females provide the parental care by providing milk, grooming, protection and carry the newborns as they cannot walk immediately.

Status and conservation
The king colobus has a moderate-sized range; it used to be a common and widespread species but numbers have declined over the last few decades. The main cause for the decline is hunting which is threatening and fragmenting populations. In the 19th century the king colobus was hunted for its fur. There is also a continuing decline in the quality and quantity of the forested habitat where it lives; it seems to be largely restricted to primary forest and gallery forest, although it sometimes visits secondary forest. The International Union for Conservation of Nature has rated its conservation status as being endangered. Focus has been on managing the habitats to prevent further degradation and habitat destruction that could harm the species. The species is also maintained as part of an EAZA ex situ captive breeding programme by several European zoos.

title: King colobus


text:
Bierpinsel

The Bierpinsel (beer brush, in English) is the nickname of a 47-meter-high building built in 1976 and located on Schloßstraße in Steglitz, Berlin. The building is noted for its futuristic architecture. The building has been listed as a protected structure since January 2017.

History
The Steglitz Tower Restaurant, opened on October 13, 1976, and was in construction between 1972 and 1976, by architects Ralf Schüler and his wife Ursulina Schüler-Witte. The architecture is part of the pop art movement. There had been issues with the funding of the initial construction of the building, and it ran over budget more than once.

The building was an extension of the Joachim Tiburtius Bridge. The tower was created out of concrete, plastic cladding and paint. The exterior of the building was originally red around the top section.

The building's popular name, "Bierpinsel," ("beer brush") is a Berlinism coined during the construction period, related to the brush-like appearance of the building's vertical steel girders and its planned gastronomic purpose. A later owner took over the name officially in the company name Bierpinsel GmbH.

The building was sold in 2007 to a new owner who founded a company called Schlossturm GmbH (literally Castle Tower Ltd). That company was sold to the Immoma group in 2021.

The Immoma group wants to refurbish the building beginning in 2023.

Turmkunst 2010
Starting April 2010, several prominent graffiti artists painted the exterior of the structure over several weeks, as part of the Turmkunst 2010 (English: Tower Art 2010) project - an exhibition of street-art taking place both in and around the tower.

title: Bierpinsel


text:
Football Association of the Czech Republic

The Football Association of the Czech Republic (Fotbalová asociace České republiky; FAČR), or colloquially the Czech Football Association, is the governing body of association football in the Czech Republic based in Prague. It organizes the lower-level league competitions in the country (the professional Czech First League and Czech Second League are organized independently) and the Czech Cup.

History
First predecessor were established as Bohemian Football Union on 19 October 1901 in Austro-Hungarian constituency Kingdom of Bohemia. From 1922 to 1993, during the existence of Czechoslovakia, the association was known as the Czechoslovak Football Association (Československá asociace fotbalová; ČSAF) and controlled the Czechoslovakia national football team. After the partition of Czechoslovakia the association took the name Bohemian-Moravian Football Federation (Českomoravský fotbalový svaz; ČMFS) until June 2011.

Competitions

 * Czech First League
 * Czech Second League
 * Czech Women's First League
 * Czech Cup
 * Czech Supercup
 * Czech Women's Cup

Divisions

 * Czech Republic national football team
 * Czech Republic women's national football team
 * Czech Republic women's national under-19 football team
 * Czech Republic women's national under-17 football team
 * National under-21 football team
 * National under-19 football team
 * National under-18 football team
 * National under-17 football team


text:
Talk:Marriage counseling

Untitled
hello,

my wife and I split up about 5 months aga and have been devoriced for about 2 months. I now fell that we rushed into the devorice to fast. I was a butthead to her at first but now I see that i have made a mistake and want to give it another chance. Can someone give me any advise on how to convince her to give us another chance and work out our problmes and get her to forgive me for being a butthead??

If so please contact me at rsfoulk@yahoo.com

title: Talk:Marriage counseling


text:
Talk:Unreal Tournament 2004

older comments
You're an ass! (James wrote this) Does a commercial game like Unreal Tournament 2004 really need a Wikipedia article? What a waste of space! Look at the rules:

Please do not create an article to promote yourself, a website, a product, or a business (see Wikipedia:Policy).

 * Sure it needs one. There are many articles on commercial products and we're not as concerned about space the way paper encyclopedias are.  The policy cited is against promotion; it's not forbidding articles on those topics.  --Mrwojo 19:35, 12 Dec 2004 (UTC)
 * There's a lot of information here too, it's a very comprehensive article imo. Adding information about it's critical recieval could be interesting.I think that this article deserves better than a b rating, I've been playing the game online for 3 years and I've never found anything with half as much useful information in one place. Mark1512 11:50, 27 January 2007 (UTC)
 * The reason this article does not deserve anything better than B is because it goes well beyond the scope of Wikipedia. Ong elvin 15:17, 6 September 2007 (UTC)

Game Types:
You know what would rock here? A discussion of how over half the game is unavailable to single player users; most of the game modes are not even available with Bot play for SP gamers. ---some new user guy

I think you might've been posting in the wrong article. All game modes are available for single players, although bots aren't as fun to play against as human players. Retodon8
 * I think he meant that in the actual Single Player mode, where you get to own a team and play with them in the tournament ladder, not all gameplay modes are available. Instant Action however lets you play anything with the bots. --Tmandry 18:01, 2 October 2005 (UTC)

 * Something needs to be said about the essential lack of Single Player mode in this game, it's there, but it's a moot point- as all that turning up the bot difficulty does is improves their aim- thus rendering trying to emulate online play with bots doesn't quite work, it just makes things annoying. --Deltro 9:48 20 Dec 2005 (CST)
 * Its not just aim, also as Retodon8 said, its jumping and movement speed, but also evasion, ability at handling the weapons more, eg better at shock combos, better weapon choice ect...
 * Well, Epic often tells many people play the game offline instead of on, indicating they disagree. Something that also changes for the bots is their running speeds, not to mention their jumping capabilities, so it's not just their aim. Also the single player portion helps you get acquainted to the game before trying your luck online, especially with DM, something it wouldn't do if there weren't any bots, or if you couldn't even play offline/alone. We could argue the quality, but most games have worse bots as far as I know, and the article should keep a neutral tone, so I'm not sure it should be added. Retodon8 19:08, 20 December 2005 (UTC)

 * Hey at least the UT series has bots, unlike most popular fps games today. (and no I am not calling the UT series un-popular) - Lord Vipes 18:54, 23 November 2007 (UTC)~

 * Also, playing against higher skilled bots helps improve your aim among other skills. At least thats how i feel. Alcryt 10:03, 22 January 2007 (UTC)

---And what exactly is your point against them...? And over half of the game IS NOT available to the single player users. I play the real game, not the demo, over the internet, and about 90% of the time, I am downloading the map. This, I think, is true with all users.

Then you didn't download the Bonus Packs, and Editor's Choice Packs and such. If you have to download after that, it's a custom map and no one has them until they are downloaded. It's pretty much the same as every other online FPS-style game. Also, I'm not sure where you got "Epic often tells many people play the game offline instead of on." I've never heard that, since it's far more exciting to play online. Mhoskins 21:06, 9 June 2006 (UTC)

 * Oh wow, I think what he means is that he's annoyed that there's too much user-generated content. So when he says "over half the game is not available for SP users" he means that he doesn't like the fact that not every UT2k4 map comes with the install. However, this isn't Epic's fault, since they don't even make most of the maps, so obviously they can't possibly include them in the game. darthsuo 05:23, 7 January 2007 (UTC)

SMP support?
i've found hints of this mentioned on the web, but does it have it? it would be one of the earliest games to support it if true. —The preceding unsigned comment was added by 75.30.78.7 (talk) 12:09, 19 March 2007 (UTC).

ROF for weapons
What do you think of including the rate of fire for all the weapons, since we already have damage? darthsuo 05:25, 7 January 2007 (UTC)

It is debatable if there's even a point to having a list of damage amounts. Anyone that doesn't play the game will not be interested in numbers, and anyone that does play the game will know other places to look these things up. 130.89.228.82 22:26, 7 February 2007 (UTC)

 * I don't play baseball, but they still have baseball stats on wikipedia that I don't care about. If you know the numbers and damage amounts, I think it's valid to include. Malamockq 15:42, 10 June 2007 (UTC)

Mister crow
Could someone who knows what Mister crow please merge it into this article? It should not have its own article. Thanks. Chick Bowen 16:34, 19 January 2006 (UTC)

 * Mister Crow is one of the characters you can play as in UT2003, UT2004, and Unreal Championship. He is not notable, so I made the page redirect to UT2004. (Chose the latest of the 3 games.) (Due to the announcer being VERY enthusiastic announcing him in UT2003's (and UC's?) character selection screen, he is sort of popular-ish. Although all other characters had their announcements dropped in UT2004, MC had his remain as sort of an Easter egg.) Retodon8 19:47, 19 January 2006 (UTC)
 * Thanks. I really had no way of knowing whether this character was significant or not. Chick Bowen 23:08, 19 January 2006 (UTC)
 * Mister Crow being the only announced character in UT2004 is an in-joke resulting from several barely comprehensible (and quite possibly never meant seriously) posts on the game's official boards. The posts have already been purged. 130.89.228.82 22:29, 7 February 2007 (UTC)

 * To the person who said Mr. Crow was popular... he isnt. Everyone over at Epic Games forum wants him dead, and so do I. - Lord Vipes 70.177.209.240 (talk) 18:53, 23 November 2007 (UTC)

Merging with UT2004
I'm in favor of this.

I'm for the merger. Describing a feature of a single game just dosn't seem like it needs an entire article. Perhaps if it described vehicles for multiple UT's (not possable yet) it might deserve it's own article, but for now, I vote nay. -DragonJTS

Im for the merge. ought to be, because its quite a defining feature of UT2004 - Me - Nineteenth of June, TwoThousandAndFour.

I just merged it. Ayavaron 00:43, 21 June 2006 (UTC)

 * I'm concerned about this merge. There was no notification on the talk page of the 'Vehicles' page. The supporters above are largely anonymous or making unique edits to this page only. I don't have a problem with that, but I think the new article is too long and would have liked the chance to say my bit before it happened. Naturenet | Talk 07:52, 21 June 2006 (UTC)

 * I'm sorry, I was just doing that Wikipedia guideline thing, being Bold. There was a little discussion in this talk page and everyone seemed to be in favor of it. I liked the idea so I did it. I figured that if the consensus was that this shouldn't be, then it'd be undone. The democratic nature of Wikipedia allows for that kind of thing and I assumed it'd be fine. Sorry it bothered you. Ayavaron 11:06, 30 June 2006 (UTC)

Separate article for vehicles
The section on vehicles seems too long. It contains good information, but should probably be spun off into its own article. Thoughts? Decrypt3 01:00, 17 August 2006 (UTC)

 * Good idea, vehicles is a large part of the unreal tournament article. On the dutch wikipedia, there already is a different vehicle article and a different ut2004 article. And nobody has complained about it so far. NeiNie 10:10, 17 August 2006 (UTC)

Last UT version that Digital Extremes and Atari involved themselves with
With UT2007 being officially published by Midway Games and solely produced by Epic, it should be mentioned that Atari and Digital Extremes have ended their long-time partnership with Epic in this franchise. Torinir  ( Ding my phone  My support calls   E-Support Options  ) 11:11, 14 September 2006 (UTC)
 * I think that would be better mentioned in the UT2007 article. Makron1n 21:06, 31 October 2006 (UTC)

Damage
I nuked the section on weapon damage. It doesn't seem appropriate for Wikipedia (details like that are much better suited for a gaming Wiki). The rest of the weapons needs to be cleaned up (the tone seems too informal for an encyclopedia). I'll do what I can.  superapathy man  03:40, 11 February 2007 (UTC)

And now, to get more information users need to go to an older version of the page, isn't the point of editing to add more quality information or edit previous information to make it more accurate or understandable, I believe the more information the better, as long as its relevent, and weapon stats certainly are. Ben 1220 (talk) 03:17, 10 July 2008 (UTC)

 * There's also such thing as notability and style to keep in mind. Is it really important enough to the subject to mandate a big section about it? --Draco 2k (talk) 03:43, 10 July 2008 (UTC)

Benefits
yeah, im a n00b, but i found this (http://www.rochester.edu/news/show.php?id=2764) and i love the game...and wanted to contribute.

So yell at me all u want but i wanted it there, so i but it there. —The preceding unsigned comment was added by Unreal Shock (talk • contribs) 09:40, 6 March 2007 (UTC).
 * Something like that would be better suited for an article like First-person shooter, since it applies to all action games, not UT2004 specifically  superapathy man  17:36, 6 March 2007 (UTC)
 * Hm, I reread the study, and I realized I missed the part where it says they chose the students who played Unreal Tournament. However, there is no evidence suggesting that it applies specifically to UT.  superapathy  man  17:54, 6 March 2007 (UTC)

can we still leave a link or something? just one line saying or refering something 2 it? Did you delete the link i provided in "external links"?
 * I missed it. Like I said, there is really no point in putting or linking to the benefits in the UT2004 article specifically.  This would be fine in a general article on video games or first person shooters.  One wouldn't list "the benefits of eating fiber" in Shredded Wheat.  superapathy  man  06:47, 8 March 2007 (UTC)

Good point, ok...i can be stuffed putting it in FPS wiki cuz i only like ut2004 :P...u can do it if u care that much. Only reason was 2 edit ut2004..cannt do it,,so meh.

Mods
I think that the list of mods should be pruned to only the most important ones. Any thoughts?  mi km  16:04, 27 March 2007 (UTC)

Agreed. I vapourised a section of "mods" the other day as it sounded like advertising for the mod, i.e. "its a lot of fun" sort of stuff. Prune the mods section down to only the most notable, e.g. jailbreak, Red Orchestra etc. Brophmeister 02:59, 29 May 2007 (UTC)

Restore the vehicle section
The seperate vehicle section was completely deleted for some ridiculous reason. The existing section on vehicles is very poor. Please restore this section to its former glory. Malamockq 05:07, 8 April 2007 (UTC)

I'm with Malamockq

Agreed, restore vehicles section to its former glory. Brophmeister 02:59, 29 May 2007 (UTC)

 * Done Malamockq 15:38, 10 June 2007 (UTC)

Fair use rationale for Image:SuperShieldPack2.Jpg
Image:SuperShieldPack2.Jpg is being used on this article. I notice the image page specifies that the image is being used under fair use but there is no explanation or rationale as to why its use in this Wikipedia article constitutes fair use. In addition to the boilerplate fair use template, you must also write out on the image description page a specific explanation or rationale for why using this image in each article is consistent with fair use.

Please go to the image description page and edit it to include a fair use rationale. Using one of the templates at Fair use rationale guideline is an easy way to insure that your image is in compliance with Wikipedia policy, but remember that you must complete the template. Do not simply insert a blank template on an image page.

If there is other fair use media, consider checking that you have specified the fair use rationale on the other images used on this page. Note that any fair use images uploaded after 4 May, 2006, and lacking such an explanation will be deleted one week after they have been uploaded, as described on criteria for speedy deletion. If you have any questions please ask them at the Media copyright questions page. Thank you.

BetacommandBot 04:45, 3 July 2007 (UTC)

Cleanup
Hi there! I'm here to clean up random articles. This article seriously ignores WP:NOT, WP:NOT and WP:CVG/GL. I'll be fixing that. Cheers. Ong elvin 15:15, 6 September 2007 (UTC)
 * Well... after all that, there's not a lot of encyclopaedic information is there? If anyone objects to the changes, let me state that Wikipedia is not a game guide. Ong elvin 15:30, 6 September 2007 (UTC)

 * Please, keep the changes. This article was horrible, sloppy mess after it was edited. It had "game guide" written all over it. The UT3 page needs help as well. I don't have the time to do it myself, but if anyone wants to lend a hand it definently could use it. Metalhead0043 19:20, 10 September 2007 (UTC)

 * I agree with the previous user. Some major changes were long overdue. —Preceding unsigned comment added by 88.85.130.79 (talk) 06:05, 18 September 2007 (UTC)

Rewriting
I'm rewriting the article. It would be nice if anyone could chime in.

There's quite a lot of ground to be covered on gameplay, graphics, weapons, level design, technology, modding, soundtrack, competitive scene and overall notability for the industry and gaming itself for this game.

Adding at least a few of these sections would be nice, but in the meantime, there's still some cleaning up to be done. --Draco 2k (talk) 10:06, 22 June 2008 (UTC)

The plan so far is:

 * -Clean up development and release history sections of potential clutter.
 * -Find more references concerning critical and player reception.
 * -Add new subsections to Features section:
 * 1)Weapons section (Overview, describe interesting and notable examples)
 * 2)Gameplay (Overview, compare to other games in the series)
 * 3)Level design (One or two screenshots, outline general trends in visual and gameplay design)
 * 4)Soundtrack (list contributors, style, notability)
 * 5)Technology (Engine, Bots, VoIP, on-line features and matchmaking)
 * -Expand on notability of the game - references or direct comparison.
 * -Elaborate on competitive scene if any references are to be acquired.

To be edited depending on current progress. --Draco 2k (talk) 12:56, 22 June 2008 (UTC)

Wow, what a helpful redirect!
I type "deathball" into my search and am redirected here. Not what I'm looking for. So I Ctrl+F to find why I was thrown here. A single mention, way at the bottom, as only the name of a mod. Hooray, how helpful. Might want to think a little harder before creating redirects. --Buddy13 (talk) 23:30, 8 January 2009 (UTC)

A Plaque for The Pub With No Beer
There's a unique Assault map called "Outback" (included in the game, but not played normally in the single-player campaign) which consists of destroying adverts for a bland brew and returning the flow of the good stuff to "A Pub With No Beer". I say it's unique because it features an actual opening cinematic, with Slim Dusty's hit title playing in the background. Are there any design notes or author comments that can be added to this article about this map? predcon (talk) 16:03, 17 June 2011 (UTC)

You can find more info here:. It won the 3rd prize in the "Best Assault Level" category in Phase IV of the Make Something Unreal Contest. Love it. Hakken (talk) 18:31, 8 October 2014 (UTC)

Game install in FreeBSD
Minimal command set:
 * setenv UNAME_m i86
 * setenv SETUP_CDROM ~/directory
 * cd ~/directory
 * sh linux-installer.sh

"directory" = copy of all files and folders from "Editors Choice Edition" release DVD disc. — Preceding unsigned comment added by 46.134.130.235 (talk) 18:00, 1 June 2023 (UTC)

"Manta (Unreal Tournament)" listed at Redirects for discussion
The redirect [//en.wikipedia.org/w/index.php?title=Manta_(Unreal_Tournament)&redirect=no Manta (Unreal Tournament)] has been listed at redirects for discussion to determine whether its use and function meets the redirect guidelines. Readers of this page are welcome to comment on this redirect at  until a consensus is reached. Utopes (talk / cont) 06:17, 18 April 2024 (UTC)

title: Talk:Unreal Tournament 2004


text:
Mugby Junction

"Mugby Junction" is a set of short stories written in 1866 by Charles Dickens and collaborators Charles Collins, Amelia B. Edwards, Andrew Halliday, and Hesba Stretton. It was first published in a Christmas edition of the magazine All the Year Round. Dickens penned a majority of the issue, including the frame narrative in which "the Gentleman for Nowhere," who has spent his life cloistered in the firm Barbox Brothers & Co., makes use of his new-found freedom in retirement to explore the rail lines that connect with Mugby Junction. Dickens's collaborators each contributed an individual story to the collection.

Overview
Mugby Junction includes the famous ghost story "The Signal-Man" concerning a spectre seen beside a tunnel entrance. The signal-man of the title tells the narrator of a ghost that has been haunting him. Each spectral appearance precedes, and is a harbinger of, a tragic event on the railway on which the signalman works. The signalman's work is at a signalbox in a deep cutting near a tunnel entrance on a lonely stretch of the line, and he controls the movements of passing trains. When there is danger, his fellow signalmen alert him via telegraph and alarms. Three times, he receives phantom warnings of danger when his bell rings in a fashion that only he can hear. Each warning is followed by the appearance of the spectre, and then by a terrible accident.

The first accident involves a terrible collision between two trains in the tunnel. Dickens may have based this incident on the Clayton Tunnel rail crash that occurred in 1861, five years before he wrote the story. Readers in 1866 would have been familiar with this major disaster. The second warning involves the mysterious death of a young woman on a passing train. The final warning is a premonition of the signalman's own death.

Another story features, in a thinly disguised form, the town of Rugby in Warwickshire and the town's railway station. This was inspired by an incident in April 1866, when Charles Dickens was travelling from London to Liverpool. Dickens's train made an unscheduled stop at Rugby due to one of the carriages catching fire. While waiting for his journey to resume, he went into the refreshment room for a cup of coffee, and the proprietess, clearly not recognising the celebrity author, treated him rudely. Inspired by this, in chapter three of 'Mugby Junction' he made a scathing attack on railway refreshment rooms and their staff.

title: Mugby Junction


text:
Helmut Knochen

Helmut Herbert Christian Heinrich Knochen (March 14, 1910 – April 4, 2003) was the senior commander of the Sicherheitspolizei (Security Police) and Sicherheitsdienst in Paris during the Nazi occupation of France in World War II. He was sentenced to death first by a British military court in 1947, and then a French military court in 1954. After his sentences were commuted and reduced a few times, he was pardoned by President Charles de Gaulle and released in 1962.

Early life
He was born in Magdeburg, Germany. Before joining the Nazi Party in 1932, he worked as a teacher and editor.

Nazi career
Knochen joined the SS in 1936 and became involved in the SD. By 1940, he was the senior commander of security in Paris. In 1942, the jurisdiction under his control stretched from northern France to Belgium and he was promoted to the rank of Standartenführer. Knochen was involved in deporting French Jews to concentration camps and was responsible for the execution of thousands of Frenchmen. He was also responsible for the arrest and torture of SOE agents.

During the plot to assassinate Hitler of July 20, 1944, together with the top security man in Paris, SS-Gruppenführer Carl Oberg, he was arrested by Army troops under the command of Paris military governor, General Carl-Heinrich von Stülpnagel. He was released after the coup collapsed. Following the liberation of Paris, Knochen was transferred to the 1st SS Division Leibstandarte SS Adolf Hitler and he was degraded to the rank of SS-Grenadier.

Post-war trials, sentences, and reprieve
In March 1947, a British Military Court sentenced Knochen, alongside Hans Kieffer, to death for the murder of a number of British parachute troops on or around 9 August 1944. However, in 1947, he was extradited to France. There, in 1954, he was sentenced to death. The sentence was later commuted to life imprisonment. After he obtained a presidential pardon in 1958, Knochen was released on November 28, 1962, by President Charles de Gaulle, simultaneously with his former chief Carl Oberg. Back in Germany, he retired to Baden-Baden and died a free man in 2003.

In popular culture

 * The Eye of Vichy, a French documentary film directed by Claude Chabrol where Knochen himself appeared
 * Les Bienveillantes, a 2006 historical fiction novel written in French by Jonathan Littell, where Helmut Knochen is featured meeting the main character Maximilian Aue.
 * Field Gray, a 2010 fiction novel by Philip Kerr where Knochen featured.
 * 93 Rue Lauriston, a 2003 TV Film about French Gestapo.
 * The Great Arrangement, a 2007 TV Film about the collaborator Rene Bouquet.

title: Helmut Knochen


text:
Muckross Abbey

Muckross Abbey (Irish: Mainistir Locha Léin and Mainistir Mhucrois) is one of the major ecclesiastical sites, found in the Killarney National Park, County Kerry, Ireland. It was founded in 1448 as a Franciscan friary for the Observantine Franciscans by Donal McCarthy Mor.

It has had a violent history and has been damaged and reconstructed many times. The friars were often subjected to raids by marauding groups and were persecuted by Cromwellian forces under Lord Ludlow. Today the abbey is largely roofless but is otherwise generally quite well-preserved. Its most striking feature is a central courtyard, which contains a large yew tree and is surrounded by a vaulted cloister.

In the 17th and 18th centuries, it became the burial place for prominent County Kerry poets O'Donoghue, Ó Rathaille and Ó Súilleabháin, while Piaras Feiritéar is buried in the graveyard just outside.

title: Muckross Abbey