Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of flutamide on cortisol metabolism was studied in eight patients with prostate cancer. Flutamide markedly decreased the formation of 3 alpha, 17,21-trihydroxypregnane-11,20-dione (THF), and the 11-oxy-17-ketosteroid metabolites by 72%, 50%, and 46% respectively; however, 3 alpha, 11 beta, 17,21-tetrahydroxy-5 alpha- pregnan-20-one was increased by 46%. The 24-h mean plasma cortisol concentration was not altered. The cortisol production rate decreased by an average of 53% (from 32.7 to 15.5 mg/24 h). The effect of the drug on plasma cortisol kinetics was studied in three patients. This showed that flutamide increased the t1/2 (from 80 to 108 min) but decreased the distribution volume (from 17.8 to 13.8 liters) and the MCR (from 222 to 130 liters/24 h). The changes in THE and THF formation and in the t1/2 and MCR of [C]cortisol are similar to the effects observed in patients with intrahepatic cholestasis. It is suggested that in the case of flutamide these changes were also due to a cholestasis-producing effect of the drug on the liver. As the clinical response to the drug did not correlate with the cortisol metabolic changes, its therapeutic effect was probably not mediated by its effects on cortisol metabolism.
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PMID:Effect of flutamide on cortisol metabolism. 26 25

Flutamide, a nonsteroidal antiandrogen, was given to 11 men with prostate cancer, in doses of 750 to 1500 mg daily for 0.5--7 months. Four patients had a clinical remission and seven showed no response. All the patients showed a profound change in the peripheral metabolism of testosterone: markedly increased conversion to androsterone (A) and correspondingly decreased conversion to etiocholanolone (E); the A/E ratio rose to levels never before observed consistently in any group of healthy or diseased humans. This change was probably due to alteration by flutamide of the relative activities of steroid 5alpha and 5beta reductase in favor of the former. 24-Hour mean plasma testosterone was increased in five of the six patients studied for this parameter, for the group as a whole, testosterone rose from 279 ng/dl to 484 ng/dl (P less than .05). 24-Hour mean values for plasma dihydrotestosterone, dehydroisoandrosterone, LH and FSH showed no significant change, for the group as a whole, in the same six patients. Since flutamide did not change the metabolic clearance rate or volume of distribution of testosterone tracers, the increased plasma levels of the hormone were probably due to increased production.
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PMID:The effect of flutamide on testosterone metabolism and the plasma levels of androgens and gonadotropins. 59 17

A 66-year-old man with metastatic prostate cancer was treated with bilateral orchiectomy and 750 mg. flutamide per day. Near fatal liver dysfunction developed 10 weeks later. Flutamide was discontinued and 8 weeks later liver enzymes had returned to normal.
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PMID:Near fatal liver dysfunction secondary to administration of flutamide for prostate cancer. 143 40

Flutamide is a non-steroidal anti-androgen which has been used to treat prostate cancer. Results to date indicate that flutamide is as effective as other conventional therapy. It has only moderate activity in patients in whom conventional hormonal therapy has previously failed, but appears to be beneficial when combined with an LHRH agonist.
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PMID:A rationale for the use of non-steroidal anti-androgens in the management of prostate cancer. 157 63

Flutamide (250 mg. orally 3 times daily) yielded a subjective response in 5 of 25 fully evaluable patients with hormone-resistant prostatic cancer. Four additional patients had early progression. A 40% or greater decrease in the pre-treatment prostate specific antigen level was observed in 7 of 24 patients and this finding was correlated with improved survival. Toxicity was mainly gastrointestinal and resulted in permanent discontinuation of flutamide in 5 patients. Flutamide or similar antiandrogens may have a role in the management of hormone-resistant prostatic cancer when relief of subjective symptoms should be an important treatment goal together with improvement of survival. However, before the drug should be used routinely in the management of hormone-resistant prostatic cancer phase 3 studies must confirm its effectiveness, especially in comparison to less expensive drugs.
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PMID:Flutamide in hormone-resistant prostatic cancer. 170 Jan 54

Flutamide, a nonsteroidal antiandrogenic drug devoid of hormonal agonist activity, is used in the treatment of advanced prostate cancer. In previously untreated patients, flutamide 750 mg daily given alone is of comparable efficacy to diethylstilbestrol (stilboestrol) 1 or 3 mg daily and estramustine 560 or 840 mg daily, but has the potential advantages of fewer cardiovascular effects and maintenance of some sexual potency. Its greatest therapeutic potential is as a component of combination androgen blockade, where administration with an agonist analogue of gonadotrophin-releasing hormone (GnRH) [luteinising hormone-releasing hormone (LH-RH)] in both initial uncontrolled and randomised studies increased survival time relative to GnRH agonist monotherapy or orchidectomy. Subsequent multicentre trials, however, have been unable to confirm an improvement in survival time. Thus, while there seems to be little doubt that flutamide prevents the initial disease flare caused by GnRH agonists, an improvement in remission rate and survival remains contentious. Flutamide is generally well tolerated and is suitable monotherapy in patients with previously untreated advanced prostatic cancer who wish to preserve sexual potency. However, full assessment of the role of combination androgen blockade awaits publication of the final results of ongoing multicentre trials.
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PMID:Flutamide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in advanced prostatic cancer. 179 8

Little is known about the efficacy of flutamide monotherapy in previously untreated patients with prostatic carcinoma. In this study, 40 patients with advanced disease were treated with 250 mg flutamide, three times daily. The mean follow-up was 7 months. After 3 months, 35 patients were evaluable for efficacy; 17 showed a partial response and 18 showed no change. Tumor response after 6 months was evaluated in 22 patients; 10 had a partial response, nine had stable disease, and three had progression. The level of prostate-specific antigen was reduced markedly following 6 months' treatment with flutamide. Levels of testosterone increased slightly but significantly, and were still elevated not significant after a follow-up period of 1 year. Follicle-stimulating hormone did not change markedly, whereas luteinizing hormone rose significantly. Eighteen patients experienced mild gynecomastia and eight suffered diarrhea. In two patients, flutamide was discontinued for 2 weeks due to serious diarrhea. One patient was withdrawn after 6 weeks because of cholestatic hepatitis. Sexual potency was evaluated in 15 patients, 10 of whom remained sexually active during treatment. Flutamide monotherapy was concluded to be relatively safe and effective in patients with advanced prostatic cancer.
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PMID:Flutamide monotherapy as primary treatment in advanced prostatic carcinoma. 194 17

While the elimination of androgens of testicular origin can be easily achieved by orchiectomy or medical castration with LHRH agonists, the action of adrenal androgen precursors which are converted into the active androgen 5 alpha-dihydrotestosterone (DHT) in the prostatic tissue itself can be partially neutralized by antiandrogens which compete with DHT for binding to the androgen receptor. In order to increase the efficiency of androgen blockade, we have used 4-MA, an inhibitor of 5 alpha-reductase, the enzyme which converts testosterone into DHT, to reduce intracellular DHT concentrations and thus facilitate the action of the antiandrogen Flutamide. The present data show that the inhibitory effects of 4-MA (17 beta, N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one) and of the antiandrogen Flutamide are additive on prostatic growth and on androgen-sensitive prostatic binding protein mRNA levels in the rat, thus clearly suggesting that such a combination could provide the basis for a further improvement in the therapy of prostate cancer.
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PMID:Combination of an antiandrogen and a 5 alpha-reductase inhibitor: a further step towards total androgen blockade? 205 5

The effect of nonsteroid antiandrogen flutamide on 3H-testosterone (3H-T) metabolism in vitro was studied in Wistar male rat prostatic and hepatic homogenates. Flutamide was administered per os in a dose of 25 mg/kg daily for 3, 10 or 30 consecutive days. Following 30 days 5 alpha-dihydrotestosterone (DHT) formation in the prostate was reduced by 50%. In castrated animals antiandrogen abolished the recovering action of testosterone propionate (TP) on 5 alpha-reductase activity. When added to incubation medium flutamide proved ineffective, while hydroxyflutamide appeared to decrease DHT formation. The metabolic utilization of 3H-T in the liver of rats receiving flutamide for 30 days was found to be 3 times lower. The formation of DHT, androsterone, ethiocholanolone and androstenedione was substantially suppressed. In castrated rats, both treated and nontreated with TP, flutamide also inhibited the formation of steroid metabolites of 3H-T. Synergism to flutamide and TP action on androgen metabolism in the liver is suggested to be related to antiandrogen ability of interaction with an unusual estrogen-binding protein of rat liver. The decrease in DHT formation induced by flutamide may play a role in the mechanism of its therapeutic action in prostatic cancer patients.
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PMID:Nonsteroid antiandrogen inhibiting effect on testosterone metabolism in rat prostate and liver. 209 78

Three antiandrogens are or will soon be available for clinical use. Only Flutamide has been studied in monotherapy of prostatic cancer patients. The use of Flutamide is associated with significant side effects. However, previously potent patients usually remain potent under Flutamide monotherapy. The mechanism of retained potency is poorly understood. In phase II studies parameters which are usually used for determining response of prostatic cancer to endocrine treatment react favourably to Flutamide monotherapy. Since the long-term elevation of plasma testosterone may have an impact on stimulation of prostatic cancer cells, long-term results of studies are mandatory. Such results, unfortunately, are not available in the literature. The use of "pure" antiandrogens as monotherapy and their long-term effectiveness is therefore uncertain. If effectiveness could be proven, especially in comparison to other standard forms of endocrine treatment, the use of a "pure" antiandrogen, especially of a substance with very few side effects, may provide a better quality of life than standard treatment and may therefore be preferable.
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PMID:Pure antiandrogens as monotherapy in prospective studies of prostatic carcinoma. 214 60


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