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PubMed1996

Recommended dose of flutamide with LH-RH agonist therapy in patients with advanced prostate cancer.

BACKGROUND: In a recent study by the Casodex Combination Study Group, USA, patients in a flutamide (750 mg/day) plus LH-RH agonist group showed a high treatment failure rate, mainly due to flutamide-induced diarrhea and hepatotoxicity. Our current study was conducted to determine the optimal dose of flutamide for use in this type of combination therapy. METHODS: In a randomized, multicenter study, 30 patients (hormone untreated; stage C or D) were divided into 2 groups: flutamide 250 mg (125 mg x 2; 14 patients) and flutamide 375 mg (125 mg x 3; 16 patients, and each dose combined with either goserelin acetate (3.6 mg every 4 weeks) or leuprolide acetate (3.75 mg every 4 weeks). Goserelin and leuprolide were administered to patients in a 1:1 ratio. Flutamide monotherapy at a daily dose of 375 mg was determined to be the optimal dose in Japan in our previous phase II study. The endpoints of this pilot study were the objective response and adverse events during the 12-week treatment. RESULTS: The objective response rate was 83.3% in the flutamide 250 mg group and 85.7% in the flutamide 175 mg group according to the Japanese response criteria for prostate cancer. Elevated PSA levels fell to within the normal range in 83.3% of the patients in the former group and in 93.3% of the patients in the latter group. One patient administered 250 mg of flutamide experienced diarrhea, while the serum GOT and/or GPT were elevated in 3 patients administered 250 mg of flutamide and 4 patients administered 375 mg of flutamide. CONCLUSIONS: Based on the findings of this pilot study of maximal androgen-depletion therapy for advanced prostate cancer, 375 mg/day of flutamide is recommended in combination with an LH-RH agonist. Assessment of the effects of our recommended regimen on longer term survival, quality of life and antiandrogen withdrawal syndrome of patients treated requires additional patients and time for follow-up.

Aged↗
PubMed2005

PGC-1 upregulation via estrogen receptors: a common mechanism of salutary effects of estrogen and flutamide on heart function after trauma-hemorrhage.

Flutamide, an androgen receptor antagonist, is thought to improve cardiovascular function by blocking the androgen receptor after trauma-hemorrhage (T-H). Although 17beta-estradiol (E2) and flutamide improve cardiac function after T-H, whether E2 and flutamide produce their salutary effect via the same or a different mechanism is unknown. We hypothesized that E2 and flutamide mediate their effects via estrogen receptor (ER)-mediated upregulation of peroxisome proliferator-activated receptor coactivator 1 (PGC-1). PGC-1, a key regulator of cardiac mitochondrial function, induces mitochondrial genes by activating transcription factors such as nuclear respiratory factor 2 (NRF-2), which regulates mitochondrial proteins [i.e., mitochondrial transcription factor A (Tfam), cytochrome-c oxidase subunit IV, and beta-ATP synthase]. Adult male rats underwent T-H [5-cm midline incision and hemorrhage (blood pressure = 40 mmHg for approximately 90 min)] and resuscitation. At the onset of resuscitation, rats received vehicle, flutamide (25 mg/kg), or E2 (50 microg/kg). Another group received the ER antagonist ICI-182780 (3 mg/kg) with or without flutamide. Flutamide or E2 administration after T-H restored depressed cardiac function. Moreover, E2 and flutamide normalized expression of cardiac PGC-1, NRF-2, Tfam, cytochrome-c oxidase subunit IV, and the mitochondrial DNA-encoded gene cytochrome-c oxidase subunit I and beta-ATP synthase, mitochondrial ATP, and cytochrome-c oxidase activity. However, if the ER antagonist ICI-182780 was administered with flutamide, flutamide-mediated PGC-1 upregulation was totally abolished. These results indicate that E2 and flutamide upregulate PGC-1 via the ER. Thus PGC-1 upregulation appears to be the common mechanism by which E2 and flutamide mediate their salutary effects on cardiac function after T-H.

Animals↗
PubMed2000

Efficacious chemoprevention of primary prostate cancer by flutamide in an autochthonous transgenic model.

Although the etiology of prostate cancer is still not clear, family history, hormones, and age are thought to play a role in its initiation and progression. There is no cure for the advanced disease. Because prostate cancer initially develops as an androgen-dependent tumor, agents with antiandrogen activity have become the focus for chemoprevention of this disease. A pilot study was undertaken to test the efficacy of flutamide (an antiandrogen) in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model of prostate cancer. Three groups of mice received s.c. implantation of slow-release flutamide pellets: (a) low-dose flutamide group (6.6 mg/kg); (b) high-dose flutamide group (33 mg/kg); and (c) control placebo group. Efficacy was measured by the absence of palpable tumor formation. Prostate tissues/tumors were harvested for evaluation by molecular and histology techniques. The low-dose flutamide group did not differ significantly from the placebo group, in which palpable tumors initially presented at 17 weeks of age, and by 33 weeks, all of the animals developed palpable tumors. In the high-dose flutamide group, however, tumors did not appear until 24 weeks, a lag of 7 weeks, and by 34 weeks, 42% of the animals were still tumor free. The period of time at which 50% of the animals had tumors was 33 weeks in the high-dose flutamide group, 24.5 weeks in the low-dose flutamide group, and 24.5 weeks in the placebo group. The difference between the placebo and high-dose flutamide groups was statistically significant (log rank, P = 0.0036; Wilcoxon's statistical analysis, P = 0.0060). Tumors from high-dose flutamide-treated animals were more differentiated and retained much of the normal glandular architecture compared with those of the placebo group, whose tumors consisted of sheets of poorly differentiated cells. The expression of T antigen in the prostate tissues of flutamide-treated animals (at 10 weeks age) was lower than that in the comparable placebo-treated group. Flutamide had the ability to suppress T antigen-driven carcinogenesis, resulting in a significant decrease in the incidence of prostate cancer and an increase in the latency period of prostate cancer in TRAMP mice.

Adenocarcinoma↗
PubMed1996

Characterization of patients with androgen-independent prostatic carcinoma whose serum prostate specific antigen decreased following flutamide withdrawal.

PURPOSE: We confirmed the reported rate of prostate specific antigen (PSA) suppression after flutamide withdrawal in patients with metastatic prostatic carcinoma, increasing serum PSA and tumor progression following treatment with total androgen blockade (castration and flutamide). The value of clinical variables in predicting the rate of PSA decrease after flutamide withdrawal was assessed and adrenal androgen metabolism was correlated with the rate of PSA suppression following flutamide withdrawal. MATERIALS AND METHODS: A total of 41 consecutive patients with metastatic prostatic adenocarcinoma and an increasing serum PSA while effectively castrated (plasma testosterone level less than 50 ng./ml.) who were receiving 250 mg. flutamide 3 times daily was evaluated prospectively before cessation of the flutamide. Responses were determined at 6 weeks. Only 2 of the 41 study patients (3%) had stable disease at 6 weeks, that is they had not met objective criteria for response or progression at analysis. RESULTS: Of 39 patients studied 11 (28.2%, 95% confidence internal 14 to 45%) had a PSA decrease (more than 50% from baseline) following flutamide withdrawal and they were treated with initial complete androgen blockade. Median duration of PSA decrease was only 13 weeks (range 7 to 52), and 3 of the 11 patients had continued suppression of serum PSA concentrations at 12+, 13+ and 20+ weeks. The serum PSA decrease was associated with improved clinical symptoms, although objective regression of the disease was found in only 1 to 2 patients with measurable disease. No statistical correlation between endocrine studies or serum bombesin secretion and PSA decrease was found, although patients with a PSA decrease after flutamide withdrawal tended to have a lower dehydroepiandrosterone concentration than those with PSA progression. No correlation between known prognostic variables and decreased serum PSA after flutamide withdrawal was detected. CONCLUSIONS: We confirmed the existence of the reported paradoxical PSA decrease in patients with androgen-independent carcinoma of the prostate, and that the delivery of simultaneous initial flutamide with castration predicts for PSA decrease. Individual patients appear to benefit from flutamide withdrawal although the overall impact was slight. The differences in frequency compared to those reported by others may be accounted for by patient selection and the number of patients receiving sequential castration therapy followed by flutamide.

Adenocarcinoma↗
PubMed1996

A dose-response study of the effect of flutamide on benign prostatic hyperplasia: results of a multicenter study.

OBJECTIVES: The objective of this study was to evaluate efficacy, safety, and dose-response profiles of four dosing schemes of flutamide over 24 weeks. METHODS: Patients were randomized to receive one of the following five treatment regimens for a period of 24 weeks: placebo capsule, flutamide capsules 125 mg twice daily, 250 mg once daily, 250 mg twice daily, and 250 mg three times daily. Patients were then evaluated at baseline (0 weeks) and at 4, 6, 12, 18, and 24 weeks after the start of treatment, and 8 weeks after the end of treatment (32 weeks). Evaluation of efficacy was performed by noting changes in urine flow rate, residual urine volume, symptom score, prostate volume, and prostate-specific antigen level. A total of 372 patients were enrolled into the study at 32 centers (14 centers in the United States and 18 international centers). RESULTS: Baseline peak urinary flow rate and percent change from baseline in maximum flow rate showed a dose-related increase at 4 and 6 weeks; this increase was significant in the 250 mg three times daily group. At later time points, no significant differences between the flutamide and placebo groups were observed, largely because of the decreasing number of evaluable patients. At 4 and 6 weeks, 25% of patients in the 250 mg three times daily group had more than 3 cc/s increase in uroflow compared to about 10% of placebo patients (P < 0.05). All flutamide-treated groups had a significant decrease in prostate volume from baseline to the last treatment visit compared to placebo and this reduction was dose related (in comparison to placebo: P < 0.05 for 125 mg twice daily and P < 0.001 for all other treatment arms). Median decrease for the flutamide-treated groups ranged from 6% to 23% at 12 weeks and from 14% to 29% at 24 weeks. All treatment groups showed a subsequent increase in prostate volume after treatment was stopped. Furthermore, there was a significant reduction in residual urine volume at 24 weeks only in the 250 mg three times daily group. It increased following cessation of therapy. Urinary symptoms at 6, 12, 18, and 24 weeks did not show any significant difference between placebo and any flutamide dose group. The most common adverse events were nipple and breast tenderness (42% to 52%), diarrhea (29% to 34%), and gynecomastia (14% to 19%). Each of these adverse events had a significantly higher incidence in all flutamide dose groups compared with placebo, but none appeared to occur in a dose-related fashion. Sixteen percent of patients in the placebo group and 25% to 39% of patients in flutamide groups were discontinued due to diarrhea (12% to 17%) or nipple and breast tenderness (4% to 8%). A total of 1% to 3% of patients in various treatment arms discontinued due to deranged liver enzymes (1% for placebo); and 1% to 4% due to impotence (1% for placebo). CONCLUSIONS: Flutamide reduced the prostate volume in a dose-related fashion and resulted in an increase in peak flow rate at 4 weeks (3% for 250 mg three times daily, P value < 0.05), but the early positive effects did not maintain statistical significance due to an increasing number of dropouts due to adverse events. Effect on postvoid residual volume was observed only at the highest dose and at 24 weeks (median reduction, 23 mL, P < 0.05). Despite volume reduction and early improvement in peak flow rate, there were no significant differences in urinary symptoms among the placebo and flutamide groups. Higher incidences of diarrhea, breast tenderness, and gynecomastia, however, were the main limiting factors in this study and until these problems are overcome, the role of flutamide in the management of benign prostatic hyperplasia remains investigational.

Aged↗
PubMed1995

Clinical efficacy and safety of low-dose flutamide alone and combined with an oral contraceptive for the treatment of idiopathic hirsutism.

BACKGROUND AND OBJECTIVE: High doses of flutamide, which is the only antiandrogen that specifically blocks the androgen receptor, have recently been used with good clinical results in women with hirsutism. Since regression of hair growth requires long-term therapy, clinical and economic considerations are important. The use of the lowest efficacious dosage could reduce costs. This study was undertaken to compare safety and efficacy of a low dose of flutamide (125 mg twice daily) alone and in combination with a triphasic oral contraceptive (OC) in women with idiopathic hirsutism. PATIENTS: Flutamide was administered orally in a low dose of 125 mg twice daily for 12 months alone in women with no risk of pregnancy or during the use of an oral contraceptive. MEASUREMENTS: Women were seen every 3 months and were evaluated for hirsutism score, hormone and lipid measurements. DESIGN: The study, which was conducted as a prospective open trial, was proposed to patients with idiopathic hirsutism, that is, with serum androgen levels in normal range and LH/FSH ratio less than 2. RESULTS: A statistically significant decrease in hirsutism score as compared to baseline was observed after only 3 months with either treatment, flutamide alone (16.9 +/- 1.6 vs 14.2 +/- 1.7, P < 0.0001) or the combination of flutamide with OC (15.6 +/- 0.8 vs 11.9 +/- 0.8, P < 0.001). Three months after cessation of treatment a statistically significant decrease from baseline was observed in the two groups. Nevertheless, at 6 months post-treatment this decrease was still significant only in the group who took flutamide in combination with an oral contraceptive. Flutamide alone does not appear to modify the levels of lipoproteins. The association of flutamide with a triphasic formulation significantly increased the HDL-C levels. CONCLUSIONS: This study shows beneficial effects of a low dose of flutamide in women with idiopathic hirsutism. The addition of an oral contraceptive is judicious to prevent pregnancy and reduce recurrence of hirsutism after cessation of flutamide. Peripheral androgenic blockage does not modify lipid profiles and it might reduce the negative effect of oral contraceptive on HDL-C levels. The addition of electrolysis delays the recurrence of hirsutism after cessation of flutamide.

Adult↗
PubMed2000

Prostate-specific antigen levels and clinical response to flutamide as the second hormone therapy for hormone-refractory prostate carcinoma.

BACKGROUND: Some authors have recently reported that maximum androgen block (MAB), in which the nonsteroidal anti-androgen, flutamide, is used together with conventional hormone therapy such as castration or luteinizing hormone-releasing hormone analogue, is more effective for prostate cancer than conventional methods. However, others have reported that the effect of MAB on survival is minimal, and definite conclusions concerning MAB remain unclear. Conversely, using flutamide as a second-line hormone therapy after recurrence is also considered, but few authors have reported whether this therapeutic option is effective or for which patients it is effective. MATERIALS AND METHODS: 124 patients with prostate cancer were diagnosed and followed at Kobe City General Hospital between 1995 and 1997. Twenty-two of these cases developed recurrence during first-line hormone therapy, and flutamide was prescribed in these cases. The prognostic value and effectiveness of flutamide were evaluated by measurement of serum prostate-specific antigen (PSA) at diagnosis, posttreatment nadir PSA level, PSA at the time of flutamide use, histological grade, recurrence-free time after firstline hormone therapy and age at the time of diagnosis. RESULTS: Six of 9 cases whose post-treatment nadir PSA levels after initial hormone therapy were within the normal limit (<4 ng/ml) achieved complete remission (CR) with flutamide use, but no patient whose post-treatment nadir PSA level remained elevated achieved CR. PSA at diagnosis and PSA at the start of flutamide use were significantly lower for patients with CR. However, the results of multivariate logistic regression analysis demonstrated that only the post-treatment nadir PSA level was significantly correlated with prognosis of flutamide use. CONCLUSIONS: Flutamide use as second-line hormone therapy should be limited to cases in which first-line hormone therapy has been highly effective and for whom the post-treatment nadir PSA level was within normal limits, and other patients should undergo other therapies. By limiting flutamide use to patients in whom the effect of flutamide is considered to be maximal, the incidence of complications and medication costs can be decreased.

Aged↗
PubMed1985

Effect of a nonsteroidal antiandrogen, flutamide, on androgen receptor dynamics and ornithine decarboxylase gene expression in mouse kidney.

The mechanisms by which nonsteroidal antiandrogens such as flutamide (alpha, alpha, alpha-trifluoro-2-methyl-4'-nitro-m-propionotoluidide) influence androgen receptor distribution and androgen-regulated gene expression are poorly understood. Therefore, we studied acute and long-term effects of flutamide, administered alone or in combination with testosterone, on androgen receptor dynamics in mouse kidney. Nuclear androgen receptors were measured using 5 mM pyridoxal 5'-phosphate extracts of renal nuclei isolated with the hexylene glycol method. Androgen-regulated ornithine decarboxylase (ODC) and ODC-messenger RNA were used as biological markers for hormone action. A single dose of flutamide increased the measurable concentration of renal nuclear androgen receptors in a dose-dependent manner by 1 h after treatment, although to a lesser extent than a comparable dose of testosterone. When 5 mg flutamide was given concomitantly with a submaximal dose of testosterone (0.1 mg), nuclear androgen receptor concentration was similar to that achieved with flutamide alone; this inhibitory effect of the antiandrogen was reversed by a 10-fold higher dose of testosterone. The influence of flutamide on the steady-state receptor levels in renal nuclei achieved by continuous androgen administration was investigated by giving a single dose of this compound to mice with testosterone-releasing implants. In these animals, flutamide administration decreased nuclear androgen receptor concentration with an initial half-life of about 3.3 h. This half-life was similar to that after cycloheximide administration, but significantly longer than that measured (1.3 h) upon removal of the implant. During treatment of female mice for 8 days with testosterone-releasing implants (40 micrograms/day), both the immunoreactive and catalytically active ODC concentration increased about 300-fold. In contrast, there was no stimulation of ODC during the prolonged administration of flutamide, although this treatment resulted in a dose-dependent increase in the nuclear androgen receptor concentration. However, flutamide (up to 650 micrograms/day) given concomitantly with testosterone (40 micrograms/day) almost completely abolished the testosterone-induced increase in ODC. The changes in ODC-messenger RNA concentration, as measured by hybridization to a complementary DNA probe, paralleled those of the enzyme protein suggesting that flutamide action involves inhibition of transcription of androgen-regulated gene(s). We conclude that 1) nuclear androgen receptor turnover in mouse kidney is a relatively rapid process and 2) nonsteroidal antiandrogens such as flutamide have an intrinsic ability to form

Anilides↗
PubMed2002

Flutamide decreases cortisol clearance in patients with congenital adrenal hyperplasia.

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency is characterized by a defect in cortisol and aldosterone secretion and adrenal hyperandrogenism. Current treatment is to provide adequate glucocorticoid and mineralocorticoid substitution to prevent adrenal crises and to suppress excess adrenal androgen secretion. Satisfactory adrenocortical suppression often requires supraphysiological doses of hydrocortisone, which may produce an unacceptable degree of hypercortisolism. A new four-drug treatment regimen of flutamide, testolactone, reduced hydrocortisone dose, and 9alpha-fludrocortisone has been shown to achieve normal growth and development after 2 yr of therapy and may, therefore, represent a potential alternative approach to the treatment of children with classic congenital adrenal hyperplasia. We investigated the effect of flutamide and testolactone, and flutamide alone, on cortisol clearance by performing clearance studies twice in 13 children (6 males and 7 females; age range, 7.0-14.5 yr) with classic 21-hydroxylase deficiency. All studies were conducted at least 3 months after institution of the four-drug treatment regimen. In eight patients (group 1), the first cortisol clearance study was performed on the four-drug regimen, and the second study was performed after a 48-h washout period off flutamide and testolactone. In five patients (group 2), the first study was conducted 1 wk after discontinuation of testolactone and while patients were receiving flutamide, hydrocortisone and 9alpha-fludrocortisone, and the second study was performed after a 48-h washout period off flutamide. Oral hydrocortisone was held on the day of the clearance studies, and all patients received a continuous infusion of hydrocortisone (0.6 mg/m(2).h) from 1800 h to 0200 h, with cortisol concentrations measured once hourly. In addition, an in vitro study was conducted to exclude the possibility of an analytical interference of flutamide, 2-hydroxyflutamide, and testolactone with the serum cortisol immunoassay. Total body cortisol clearance was significantly lower during treatment with the four-drug regimen than during treatment with hydrocortisone and 9alpha-fludrocortisone (153.5 +/- 26.8 vs.355.4 +/- 65.8 ml/min; P = 0.001). Similar results were obtained comparing flutamide, hydrocortisone, and 9alpha-fludrocortisone therapy to hydrocortisone and 9alpha-fludrocortisone therapy (155.8 +/- 26.5 vs. 281.8 +/- 96.2 ml/min; P = 0.037). The in vitro study indicated that an interference with the serum cortisol immunoassay was unlikely. These findings indicate that the addition of flutamide and testolactone to the treatment regimen of hydrocortisone and 9alpha-fludrocortisone decreases cortisol clearance in patients with classic 21-hydroxylase deficiency, and this effect seems to be due to flutamide. Glucocorticoid replacement doses should be reduced when flutamide is added to the treatment regimen of patients receiving hydrocortisone.

Adrenal Hyperplasia, Congenital↗
PubMed2004

[Effectiveness of flutamide alone or combined with oral contraceptives in the treatment of hirsutism in women].

BACKGROUND: Flutamide is an antiandrogen devoid of other hormonal effects, except for a decrease in the secretion of adrenal androgens such as dehydroepidandrosterone sulphate (DHEA-s) and androstenedione. AIM: To assess the effectiveness of flutamide in the treatment of hirsutism, used as monotherapy or combined with oral contraceptives (OC). PATIENTS AND METHODS: Women with peripheral hirsutism (defined as the presence of normal serum androgen levels and normal ovulatory menstrual cycles) were assigned to receive flutamide alone (500 mg/day) or flutamide plus an OC (ethynylestradiol 0.03 mg and desogestrel 150 microg). Hirsute with hyperandrogenism (polycystic ovary syndrome) were assigned to receive flutamide plus an OC. The degree of hirsutism was assessed using a clinical score (Moncada) at three, six and twelve months of therapy. RESULTS: Twenty five women with peripheral hirsutism received flutamide alone and 18 receive flutamide plus the contraceptive. Eighteen women with polycystic ovary syndrome were studied. At three months, the reduction in hirsutism was 11.2, 15.9 and 24.7% in women with peripheral hirsutism receiving flutamide alone or flutamide plus OC and in hyperandrogenic women receiving flutamide plus OC, respectively. At twelve months, the figures were 57.2, 57.3 and 52.5% respectively. In hyperandrogenic women, at baseline and three months, serum testosterone levels were 0.96 and 0.42 ng/nl and serum DHEA-s levels were 2,980 and 1,490 ng/ml respectively. No collateral effects of treatment or elevations in serum transaminase levels were observed. CONCLUSIONS: Flutamide is effective in the treatment of hirsutism in women with normal or elevated androgen levels. Adding OC did not improve the efficacy of the drug.

Adolescent↗
PubMed2002

Flutamide induces relaxation in large and small blood vessels.

HYPOTHESIS: Flutamide, a testosterone receptor antagonist, produces various beneficial effects in male rats following hemorrhagic shock, possibly as a result of a direct vasodilating effect on large and small vessels in the rat. DESIGN, INTERVENTIONS, AND MAIN OUTCOME MEASURES: The aorta and the small intestine were isolated from normal male and female Sprague-Dawley rats. Isolated aortic rings were placed in the organ bath and constricted by 2 x 10(-7)M norepinephrine bitartrate (Sigma, St Louis, Mo). Flutamide-induced and testosterone-induced vascular relaxation dose-response curves were then determined. The dose-response curves of flutamide were also determined in the small blood vessels of the isolated small intestine under conditions of constant flow following preconstriction induced by 5 x 10(-6 )M norepinephrine bitartrate. The effects of prior incubation with testosterone (8 x 10(-5)M) and sex differences on flutamide-induced vascular relaxation were also examined in aortic rings and in the small intestine. Moreover, flutamide-induced relaxation in endothelium-denuded aortic rings and in aortic rings from animals subjected to trauma and hemorrhagic shock was examined. RESULTS: Flutamide induced significant relaxation in aortic rings and small intestinal blood vessels in healthy males. The flutamide-induced relaxation in vessels from normal males was partially attenuated by prior incubation with the male sex steroid testosterone, and was significantly lower in females. Flutamide-induced vascular relaxation in the aorta was partially attenuated by endothelium removal, but it was not significantly affected by trauma and hemorrhagic shock in male rats. CONCLUSIONS: Flutamide has a direct vasodilating effect on large and small vessels in rats, which involves sex-dependent mechanisms. Thus, the beneficial effects of flutamide on cardiovascular responses in males following trauma and hemorrhagic shock may be due to the direct vascular relaxation induced by this agent.

Androgen Antagonists↗
PubMed2003

Androgen receptor independent cardiovascular action of the antiandrogen flutamide.

We have previously shown that flutamide (specific antagonist of the androgen receptor) has antihypertensive effects. In the present study we examined the mechanisms of flutamide action in the vasculature. The vascular effects of flutamide were assayed in aortae isolated from male or female Sprague-Dawley rats and from rats or mice lacking a functional androgen receptor ( tfm, testicular feminization mutation). The effect of flutamide on coronary flow was tested in isolated hearts. In addition, male hypertensive rats with tfm mutation were treated with flutamide, and blood pressure was monitored. Flutamide induced a relaxation of rat aortae from all the strains used (maximum relaxation at 10 microM: 51.3+/-5.2% of phenylephrine contraction) and increased the coronary flow. The aortic relaxation to flutamide was abolished by endothelium removal, or by inhibition of nitric oxide synthase, guanylyl cyclase, and tyrosine kinase but not by calmodulin inhibition. Flutamide treatment attenuated the development of hypertension in mouse renin transgenic rats with the tfm mutation. Flutamide produces direct vasodilation by inducing release of NO from the endothelium and causes subsequent activation of soluble guanylyl cyclase in an active androgen receptor independent manner. This response may contribute to the observed antihypertensive actions of flutamide.

Androgen Antagonists↗
PubMed1987

Effect of flutamide on hepatic cytosolic methyltrienolone (R1881) binding kinetics and testosterone responsive hepatic drug and steroid metabolism in the adult male rat.

Flutamide was used to investigate the mechanism involved in androgen responsive hepatic microsomal drug and steroid metabolism. We compared the antiandrogenic action of flutamide on the prostate to its effect on testosterone responsive hepatic microsomal benzo[a]pyrene hydroxylase (BPH) and testosterone reductase (TR) activities. Male Wistar rats, castrated as adults, were treated with 5 mumoles.kg-1.day-1 of testosterone enanthate subcutaneously for 10 days. Co-administration of increasing doses of flutamide caused a dose-dependent reduction in prostate to body weight ratios and, in the same animals, caused significant alterations in adult male hepatic microsomal BPH and TR activities. These doses of flutamide did not affect the serum testosterone levels. To test the possibility that the action of flutamide on androgen responsive hepatic microsomal drug and steroid metabolism may be similar to that occurring in the prostate, a tissue which contains an androgen receptor, we also studied the effect of flutamide on the binding kinetics of the high affinity hepatic cytosolic [3H]R1881 binding protein in vivo. Scatchard analysis of [3H]R1881 binding data revealed a reduction in the binding capacity of the hepatic cytosolic androgen binding protein in castrated animals treated with a combination of flutamide and testosterone enanthate at doses capable of maximally altering hepatic microsomal drug and steroid metabolism. No alteration in binding affinity occurred in this treatment group. However, a decreased binding affinity was found when flutamide alone was given. The binding kinetics of the hepatic cytosolic androgen binding protein were not altered in the castrated adult male with or without testosterone treatment. When flutamide was injected daily into the intact adult female rat, no effect was observed on either hepatic microsomal BPH or TR activities. Taken together, these data indicate that flutamide reduces hepatic cytosolic R1881 binding in the adult male rat, and this may explain some of the effects of this antiandrogen on testosterone-sensitive hepatic microsomal drug and steroid metabolism.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2007

Effects of 17beta-estradiol and flutamide on splenic macrophages and splenocytes after trauma-hemorrhage.

Since splenic immune functions are depressed in metestrus females following trauma-hemorrhage, we hypothesized that administration of the androgen receptor antagonist flutamide at the onset of resuscitation will maintain the immune function of the spleen following trauma-hemorrhage. Female C57BL6/J mice (metestrus state, 8-12 weeks old), underwent laparotomy and hemorrhagic shock (35.0+/-5.0 mm Hg for 90 min) and received 17beta-estradiol (50 microg/25 g), flutamide (625 microg/25 g) or 17beta-estradiol+flutamide. Four hours after resuscitation, the in vitro productive capacity of different cytokines (TNF-alpha, IL-6, IL-10, and IFN-gamma) by splenic MPhi and splenocytes were determined by flow cytometry. A significantly decreased cytokine production by both splenocytes and splenic MPhi was observed following trauma-hemorrhage compared to shams. Administration of 17beta-estradiol, flutamide and 17beta-estradiol+flutamide following trauma-hemorrhage resulted in a significant increase in the in vitro IL-6 release by splenic MPhi. The TNF-alpha productive capacity, however, was only restored by 17beta-estradiol and 17beta-estradiol+flutamide administration following trauma-hemorrhage. No significant effect of either treatment was observed with regard to the suppressed splenic MPhi IL-10 release. Anti-CD3 stimulation, administration of 17beta-estradiol and 17beta-estradiol+flutamide, but not the administration of flutamide alone resulted in a significant increased release of TNF-alpha, IL-6 and IFN-gamma compared to vehicle-treated animals. No significant effect of either treatment was found on IL-10 productive capacity. These results collectively suggest that flutamide administration following trauma-hemorrhage in females has beneficial effects on splenic immune function. However, flutamide administration in combination with estrogen does not provide any significant, additional effects over 17beta-estradiol administration alone.

Animals↗
PubMed2005

Absence of hepatotoxicity after long-term, low-dose flutamide in hyperandrogenic girls and young women.

BACKGROUND: Flutamide is a pure non-steroidal anti-androgen that may be hepatotoxic, when given in high-dose (750 mg/d). Low- to ultralow-doses (250-62.5 mg/day) have been recently explored in patients with Polycystic Ovary Syndrome (PCOS), and these lower doses were found to confer benefit on multiple PCOS markers. There is a need for evidence on the potential hepatotoxicity of low- and ultralow-dose flutamide therapy. METHODS: We assessed circulating levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) as markers of hepatotoxicity in a total of 190 hyperandrogenic girls and young women receiving low- or ultralow-dose flutamide because of established (n = 150) or incipient (n = 40) PCOS without obesity. Assessments were performed before start of flutamide, after 3 months, and subsequently at least twice yearly. RESULTS: AST and ALT results were normal at baseline, and they remained so on flutamide treatment, including between 3 months and last assessment, which was after a mean time of 19 months on low- or ultralow-dose flutamide (range 3-54 months). None of the AST or ALT levels at any time during flutamide treatment was > or = 45 U/L. CONCLUSION: We found no evidence for hepatotoxicity in 190 hyperandrogenic girls or young women receiving low- or ultralow-dose flutamide for up to 54 months. These results may represent a first step in a long process whereby the status of low- and ultralow-dose flutamide may gradually evolve from 'absence of evidence on toxicity' towards 'evidence of absence of hepatic toxicity'. Ultralow-dose flutamide may become a key component within future therapies for hyperandrogenic states in girls and young women.

Adolescent↗
PubMed2006

The effect of flutamide on systemic and renal hemodynamics in Zucker diabetic rats: paradoxic renal vasodilator response to endothelin-1 and TXA2 receptor activation in female sex.

BACKGROUND: There is increasing evidence that endogenous sex hormones regulate vascular reactivity, and testosterone may contribute to the worse prognosis for renal disease in men. Male Zucker diabetic rats exhibit improved renal hemodynamic responses after castration. It is, however, unclear whether endogenous testosterone affects renal and systemic microcirculatory responses in the female sex, especially in type 2 diabetes. AIM: To test the hypothesis that endogenous testosterone in the female Zucker diabetic rat exerts a pathophysiologically relevant modulation of endothelial and renal microvascular function. METHODS: Female Zucker diabetic rats (FZDR) aged 5-6 weeks and from the same litter were divided into 2 groups (n = 6-8 each). The experimental group received the androgen receptor blocker flutamide, dissolved in alcohol and added to their drinking water (500 mL) at 20 mg/rat/week. The control FZDR received only the alcohol vehicle added to the same volume of drinking water. Both FZDR groups were treated for 3 months before undergoing the hemodynamic studies. A sex comparison control group of male Zucker diabetic rats (MZDR), also aged 5-6 weeks, was studied, following same protocol. Mean arterial pressure (MAP) and renal cortical blood flow (RCF) response to phenylephrine, acetylcholine, TXA2-mimetic U46619, endothelin-1 (ET-1), angiotensin II, and L-NG-nitro arginine methyl ester were studied. Furthermore, the role of protein kinase C in the responses was assessed using phorbol-12,13 dibutyrate 10(-4) M. The impact of flutamide on body weights and blood glucose of the rats were also determined. RESULTS: Flutamide-treated FZDR had a significant reduction in body weight/adiposity to 432 +/- 44 g, compared to controls at 553 +/- 37 g (P = 0.045), and random blood glucose concentration of 185 +/- 44 g/dL, compared to the control FZDR at 475 +/- 34 g/dL (P = 0.002). Vehicle-treated FZDR (n = 6-8), exhibited little or no systemic or renal response to any of the agonists. By contrast, flutamide treatment of FZDR (n = 5-7) caused a normalization of the dose-dependent MAP and RCF pressor response to phenylephrine [P < 0.005, analysis of variance (ANOVA)] and the vasodilator response to acetylcholine (P <. 0.01, ANOVA). Flutamide-treated FZDR showed enhanced pressor response to U46619 (P = 0.024, ANOVA), ET-1, and angiotensin II (P < 0.03, ANOVA). Surprisingly, the augmented systemic pressor action of U46619 and ET-1 was accompanied by a renal vasodilator action, with paradoxic RCF increases to U46619 (P < 0.003, ANOVA) and to ET-1 (P < 0.001, ANOVA) only in flutamide-treated FZDR. By contrast, flutamide-treated MZDR exhibited no significant change in body weight and an attenuation of the vasoconstrictor responses and enhanced nitric oxide-mediated dilatation compared with male controls. However, no specific effect on ET-1 or TXA2 receptor-mediated renal perfusion was discernible. Both L-NG-nitro arginine methyl ester and the protein kinase C agonist phorbol-12,13 dibutyrate [10(-4)M] significantly increased MAP and reduced RCF (P < 0.03) in the experimental FZDR compared with their controls. CONCLUSION: Flutamide administration to FZDR resulted in the reversal of abnormal systemic and renal alpha-1-mediated vasoconstriction and enhanced nitric oxide-mediated vasodilation. Flutamide caused a paradoxic but specific increase in renal perfusion during ET-1 and TXA2 receptor activation, which could be renoprotective in females. The salutary effects of flutamide on vascular reactivity in the FZDR may be mediated by a protein kinase C-dependent mechanism. These results are compatible with the notion that endogenous testosterone may regulate systemic and renal microcirculation in the female sex and in the type 2 diabetic state.

Animals↗
PubMed2006

Detection of a new N-oxidized metabolite of flutamide, N-[4-nitro-3-(trifluoromethyl)phenyl]hydroxylamine, in human liver microsomes and urine of prostate cancer patients.

Flutamide (2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide), a nonsteroidal antiandrogen, is used in the treatment of prostate cancer but is occasionally associated with hepatic dysfunction. In the present study, the metabolism of flutamide including the formation of the possible reactive toxic metabolites was investigated using human liver microsomes and 10 isoforms of recombinant human cytochrome P450 (P450). 2-Hydroxyflutamide (OH-flutamide) and 4-nitro-3-(trifluoromethyl)phenylamine (FLU-1) were the main products of flutamide metabolism in human liver microsomes. The formation of OH-flutamide was markedly inhibited by ellipticine, an inhibitor of CYP1A1/1A2, and was mainly catalyzed by the recombinant CYP1A2. FLU-1 was also produced from OH-flutamide, but its metabolic rate was much less than that from flutamide. An inhibitor of carboxylesterase, bis-(p-nitrophenyl)phosphoric acid, completely inhibited the formation of FLU-1 from flutamide in human liver microsomes. A new metabolite, N-[4-nitro-3-(trifluoromethyl)phenyl]hydroxylamine (FLU-1-N-OH), was detected as a product of the reaction of FLU-1 with human liver microsomes and identified by comparison with the synthetic standard. The formation of FLU-1-N-OH was markedly inhibited by the addition of miconazole, an inhibitor of CYP3A4, and was mediated by recombinant CYP3A4. Furthermore, FLU-1-N-OH was detected mostly as the conjugates (glucuronide/sulfate) in the urine of prostate cancer patients collected for 3 h after treatment with flutamide. The formation of FLU-1-N-OH, however, did not differ between patients with and without abnormalities of hepatic functions among a total of 29 patients. The lack of an apparent association of the urinary excretion of FLU-1-N-OH and hepatic disorder may suggest the involvement of an additional unknown factor in the mechanisms of flutamide hepatotoxicity.

Androgen Antagonists↗
PubMed2003

Long-term apoptotic cell death process with increased expression and activation of caspase-3 and -6 in adult rat germ cells exposed in utero to flutamide.

Although it is established that in utero exposure to antiandrogenic compounds such as flutamide induces hypospermatogenesis in adult male rat offspring, the cellular and molecular mechanisms remain to be investigated. By using adult rats exposed in utero to flutamide (0.4, 2, 10 mg/kg.d) as a model, we show that the hypospermatogenesis could be related to a chronic apoptotic cell death process associated with a long-term increase in caspase-3 and -6 expression and activation in germ cells. The number of apoptotic (terminal deoxynucleotidyl transferase-mediated deoxyuridine positive) adult germ cells was dependent on the dose of flutamide. The apoptotic germ cell death process could be related to an increased expression and activation of effector caspases-3 and -6. Procaspases-3 and -6 were immunodetected in germ cells from both untreated or flutamide-treated rats, whereas cleaved active caspase-3 was detected exclusively in germ cells from adult rat exposed in utero to flutamide. Exposure to the antiandrogen increased in a dose-dependent manner as caspase-3 and -6 mRNA (in RT-PCR approaches) as well as procaspase-3 and -6 protein (in Western blotting analyses) levels in the adult rat testis. Flutamide also activates procaspases. Indeed, whereas cleaved active caspase-3 and -6 proteins were absent in control animals, they were detected in adult rat testes exposed in utero to flutamide. Our results show that whereas the apoptotic germ cell death process associated with the increased caspase expression and activation in adult rat germ cells was chronic and nonreversible when exposure to flutamide occurred in utero, it was transient when such an exposure occurred during adulthood. Indeed, although an increase in caspase-3 and -6 mRNA and procaspase-3 and -6 protein levels was observed in germ cells after 3 d of exposure to flutamide, 1-2 wk after the cessation of the antiandrogen exposure, the caspase mRNA and procaspase protein levels were back to control. Active cleaved caspase-3 and -6 protein appeared following the exposure to the antiandrogen, whereas they disappeared at cessation of exposure to flutamide. In summary, the present findings indicate that in utero exposure to the antiandrogen induced in the adult rat testes a chronic apoptotic germ cell death associated with a long-term increase in the expression and activation in germ cells of caspases-3 and -6, two key components in the death machinery.

Age Factors↗