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PubMed1999

A prospective randomized trial comparing low dose flutamide, finasteride, ketoconazole, and cyproterone acetate-estrogen regimens in the treatment of hirsutism.

Sixty-six hirsute women were randomized and treated with 1) flutamide (n = 15), 250 mg/day; 2) finasteride (n = 15), 5 mg/day; 3) ketoconazole (n = 16), 300 mg/day; and 4) ethinyl estradiol (EE)-cyproterone acetate (CPA; n = 20), 0.01 mg EE/day for the first week, 0.02 mg EE/day for the second week, and 0.01 mg EE/day for the third week, followed by a pause of 7 days, then 12.5 mg CPA/day added during the first 10 days of every month for 12 months. Hirsutism was evaluated by the Ferriman-Gallwey score, and hair diameter and hair growth rate were determined by a special image analysis processor in basal conditions and after 90, 180, 270, and 360 days of treatment. All treatments produced a significant decrease in the hirsutism score, hair diameter, and daily hair growth rate: flutamide, -55 +/- 13%, -21 +/- 14%, and -37 +/- 18%; finasteride, -44 +/- 13%, -16 +/- 12%, and -27 +/- 14%; ketoconazole, -53 +/- 18%, -14 +/- 12%, and -30 +/- 21%; and EE-CPA, -60 +/- 18%, -20 +/- 11%, and -28 +/- 21%. Some differences existed among treatments with regard to effectiveness; EE-CPA and flutamide seem to be the most efficacious in improving hirsutism. For the hirsutism score, a greater decrease was seen with EE-CPA (-60 +/- 18%) than with finasteride (-44 +/- 13%; P < 0.01) and a greater decrease was seen with flutamide (-58 +/- 18%) than with finasteride (-44 +/- 13%; P < 0.05). Flutamide is the fastest in decreasing hair diameter; EE-CPA is the fastest in slowing down hair growth, even though at the end of the treatment there was a significant difference between flutamide and finasteride only (-41 +/- 18% vs. -27 +/- 14%; P < 0.05). Flutamide, ketoconazole, and EE-CPA induced a significant decrease in total and free testosterone, 5alpha-dihydrotestosterone, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione plasma levels. During the EE-CPA treatment, gonadotropins were suppressed, and the sex hormone-binding globulin level increased. Finasteride induced a decrease in dehydroepiandrosterone sulfate and 5alpha-dihydrotestosterone and an increase in testosterone levels. Very few side-effects were observed during treatment with low doses of flutamide, EE-CPA, and particularly finasteride. Flutamide induced a decrease whereas EE-CPA induced an increase in triglycerides and cholesterol, showing higher values within the normal range. Ketoconazole induced several side-effects and complications, and several people dropped out of the study. Despite different modalities of action and significantly different effects on androgen levels, low doses of flutamide, finasteride, and EE-CPA constitute very satisfactory alternative therapeutic regimens in the treatment of hirsutism.

Adult↗
PubMed2002

[Sex-difference on flutamide metabolism in rat liver microsomal cytochrome P450 1A2].

AIM: To assess the sex-difference on flutamide metabolism in rat liver microsomes useing rat cytochrome P450, 1A2, inhibitory monoclonal antibody. METHODS: Liver microsomes were prepared from male or female rats. Protein concentration and total cytochrome P450 content were determined. Incubation mixture included liver microsomes (1.0 nmol.L-1), reduced form of nicotinamide adenine dinucleotide phosphate (NADPH, 0.1 nmol.L-1), CYP1A2 (1:400) and flutamide (2 mg.L-1). The incubation time was 30 min. The concentration of flutamide and its major metabolite 2-hydroxyflutamide were analyzed by reverse high-performance liquid chromatography. The mobile phase was a mixture of methanol-acetonitrile-water-diethylether (40:20:35:1) with methyltestosterone as internal standard. The detection wavelength was 234 nm. The reaction mixture was extracted with acetic ether 4 mL. Sex-difference on flutamide metabolism was expressed as the difference between the concentration ratio of 2-hydroxyflutamide to flutamide in male and female rat liver microsomes. RESULTS: The recoveries of flutamide and 2-hydroxyflutamide for the proposed method were more than 75%. The formation of 2-hydroxyflutamide from flutamide was inhibited by CYP1A2 antibodies (1:400) in male and female rat liver microsome for 30 min of incubation time, but the inhibition of flutamide metabolism in female rat was stronger than that in male. The concentration ratios of 2-hydroxyflutamide to flutamide were (1.5 +/- 0.6) and (0.9 +/- 0.4) in male and female rat liver microsomes, respectively (P < 0.01). CONCLUSION: The results indicate that the activity of male rat CYP1A2 is higher than that of the female rat. There is difference in sex-related rate of flutamide metabolism in rat liver microsomes.

Androgen Antagonists↗
PubMedDate not supplied

Flutamide administration at 500 mg daily has similar effects on serum testosterone to 750 mg daily.

A prior comparison of 750 mg flutamide daily to 500 mg daily with an LHRH analog or orchiectomy showed no difference in effect on prostate specific antigen (PSA). However, any difference was likely masked by hypogonadism from concomitant LHRH analog or orchiectomy. We sought to evaluate different flutamide dosing schedules without this confounding factor. We recruited 50 men with advanced prostate cancer who elected to receive hormonal therapy to be randomized to 1 of 3 flutamide treatment groups: 1) 250 mg once daily, 2) 250 mg twice daily, or 3) 250 mg 3 times daily for 3 months, after which the therapy of their choice was instituted. Serum samples at the initiation of therapy and at the 1- and 3-month time point were assessed for PSA, testosterone, liver function tests, hematology, and renal function. Prostate volume, androgen deficiency symptoms, and a compliance diary were also recorded. Testosterone and PSA levels show a dose-dependent response to flutamide monotherapy. Loss of libido and erectile dysfunction occurred in all 3 treatment groups, with a trend toward worsening sexual function with higher flutamide dosing, but this trend did not reach statistical significance. Prostate volumes decreased by an average of 34.3% in the patients receiving 250 mg flutamide 3 times daily, 27.8% in patients receiving 250 mg flutamide twice daily, and 19.2% in those receiving a once daily dose of 250 mg flutamide. There was a significant difference between the once daily group and the 3 times daily group (P =.047). Flutamide at 500 mg did not result in significant changes in testosterone, PSA, prostate volume, or androgen deficiency symptoms compared to 750 mg daily after 3 months.

Aged↗
PubMed1990

Similarities and differences in progesterone and androgens in modulation of LH, FSH and PRL release: unexpected properties of flutamide.

The purpose of this study was to determine if the similarity of effect of progesterone and androgens on antagonism of estrogen-induced prolactin release also applied to the regulation of LH and FSH release. An additional objective was to examine the effect of the antiandrogen, flutamide, upon the ability of progesterone to induce gonadotropin secretion. Using the ovariectomized estrogen-primed immature rat, testosterone propionate suppressed LH and FSH secretion, whereas dihydrotestosterone only suppressed serum LH levels. In contrast, progesterone significantly elevated both serum LH and FSH levels. Thus, with respect to regulation of gonadotropin secretion, the effects of androgens and progesterone were dissimilar. In the estrogen-primed ovariectomized immature rat, flutamide was found to suppress LH, FSH and PRL secretion. Progesterone (0.8 mg/kg body wt) was incapable of overcoming this suppressive effect of flutamide. The effect of flutamide on gonadotropin secretion required estrogen priming. The effect of flutamide in suppressing LH, FSH and PRL release was not through suppression of an adrenal steroid as shown by adrenalectomy or the use of RU486. In the PMSG primed immature rat, flutamide had no effect on basal gonadotropin levels or ovulation. However, flutamide antagonized progesterone and triamcinolone acetonide-induced gonadotropin surges and blocked their ability to facilitate ovulation. These studies demonstrate that in the ovariectomized estrogen-primed immature rat flutamide has potent neuroendocrine regulatory ability leading to suppression of LH, FSH and PRL release. Flutamide also blocked progesterone and triamcinolone acetonide induced gonadotropin surges and ovulation in PMSG-primed immature female rats.

Adrenalectomy↗
PubMed1996

Flutamide-induced liver toxicity including fatal hepatic necrosis.

PURPOSE: To describe hepatic injuries in three patients who received flutamide prior to and during radiation treatment to make radiation oncologists aware of the need for careful monitoring of liver function during use of this drug. METHODS AND MATERIALS: The records of three patients who developed abnormal liver function tests while undergoing total androgen suppression (TAS), as well as the literature concerning flutamide toxicity were reviewed and summarized. RESULTS: Three of 34 patients treated with a TAS regimen incorporating flutamide developed significant hepatic abnormalities: elevated transaminases [2] and fatal hepatic necrosis [1]. Following the discontinuation of flutamide, two patients recovered fully. Unfortunately, the third patient's hepatic function continued to deteriorate, which culminated in his death. Transient elevations in serum transaminases, which do not exceed four times the upper limits of normal, are common and apparently without clinical significance. Unfortunately, idiosyncratic serious and/or fatal liver damage can occur. Significant liver toxicity may be obviated by monitoring of liver function tests (LFT) early in the course of flutamide therapy. CONCLUSION: The incidence of hepatic toxicity associated with flutamide may be higher than previously suggested. To prevent the development of serious hepatic dysfunction, all patients receiving flutamide should be monitored clinically for signs and symptoms referable to hepatic injury and with serial LFT. We recommend baseline LFT followed by serial LFT at weeks 2, 4, 6, and 8 from the start of treatment with flutamide. Flutamide should be stopped promptly if significant liver abnormalities are detected.

Adenocarcinoma↗
PubMed1996

Combined finasteride and flutamide therapy in men with advanced prostate cancer.

OBJECTIVES: To evaluate the efficacy of combined finasteride and flutamide therapy in men with advanced prostate cancer by determining (1) the short-term tolerability of finasteride monotherapy and its effect on serum prostate-specific antigen (PSA) and hormone (testosterone, dihydrotestosterone) levels, and (2) the effects of the addition of flutamide on tolerability and on serum PSA and hormone levels. METHODS: Thirteen hormone-naive men with advanced prostate cancer (4 with Stage D2, 1 with Stage D1, 1 with Stage D0, and 7 with rising PSA levels after radical prostatectomy [n = 2] or definitive radiation therapy [n = 5]) were initially treated with 5 mg finasteride daily. Flutamide (250 mg three times a day) was added after serum PSA levels stabilized. RESULTS: Finasteride alone (median 5 weeks) had no significant effect on serum PSA levels (P > 0.05). Combined finasteride and flutamide resulted in a mean 91% reduction in serum PSA levels, with 85% of men achieving a nadir serum PSA level of less than 4.0 ng/mL and 46% achieving undetectable levels (0.2 ng/mL or less). Finasteride alone had no significant effect on serum testosterone levels (P > 0.05) but did result in a mean 74% reduction in serum dihydrotestosterone levels. Combined finasteride and flutamide resulted in a mean 56% increase in serum testosterone levels but had no additional effect on serum dihydrotestosterone levels (P > 0.05). Side effects occurred in 85% (gynecomastia or breast tenderness in 62% [8 of 13] and diarrhea in 23% [3 of 13]) of men on combined therapy. Potency was preserved in 66%. Combined finasteride and flutamide therapy was withdrawn from 15% (2 of 13) because of flutamide-induced diarrhea and from 23% (3 of 13) because of disease progression. All remaining patients (8 of 13) have serum PSA levels below 4.0 ng/mL and 4 of these 8 have undetectable levels. These men have received combined finasteride and flutamide for a median 11 months (range 6 to 19). CONCLUSIONS: Finasteride monotherapy is inadequate therapy for advanced prostate cancer, but combined finasteride and flutamide may be a reasonable alternative for men with advanced prostate cancer who refuse conventional hormone therapy.

Aged↗
PubMed1999

Pharmacokinetics of flutamide in patients with renal insufficiency.

AIMS: The aim of this study was to determine the pharmacokinetic parameters of flutamide, a nonsteroidal antiandrogenic compound, and its pharmacologically active metabolite, hydroxyflutamide, in renal insufficiency. Haemodialysis (HD) clearance of flutamide and hydroxyflutamide was also determined. METHODS: Pharmacokinetic parameters were assessed for flutamide and hydroxyflutamide in 26 male subjects with normal renal function (creatinine clearance by 24 h urine collection, CLcr, greater than 80 ml min(-1) 1.73 m(-2); n=6) or reduced renal function; CLcr=50-80 (n=7), 30-49 (n=3), 5-29 (n=4), and <5 ml min(-1) 1.73 m(-2)-HD (n=6), following a single, oral 250 mg flutamide dose. Subjects undergoing HD received a second 250 mg dose of flutamide 4 h prior to HD; blood and dialysate were collected during HD to determine dialysability of flutamide and hydroxyflutamide. RESULTS: Cmax, tmax, AUC, t1/2, and renal clearance of flutamide and hydroxyflutamide did not differ between groups. Less than 1% of the dose appeared in dialysate as hydroxyflutamide. No serious adverse events were observed. CONCLUSIONS: Renal function did not affect flutamide nor hydroxyflutamide disposition. HD did not alter hydroxyflutamide pharmacokinetics. Dosing adjustments for renal impairment or HD are not indicated for flutamide.

Androgen Antagonists↗
PubMed1978

Flutamide therapy for carcinoma of the prostate.

In our three-year experience with the use of flutamide for the treatment of carcinoma of the prostate, 20 patients with previously untreated stage D carcinoma of the prostate were enrolled in a 12-week double-blind study. Seven patients received 1.5 gm of flutamide daily, seven patients received 0.75 gm of flutamide daily, and six patients received 1.0 mg of diethylstilbestrol daily. Two patients receiving flutamide did not complete the 12-week study. Six patients receiving flutamide and three patients receiving diethylstilbestrol had objective evidence of improvement. Of the patients receiving flutamide, 50% were alive at one year, and 43% were alive at two years. Three of the original 14 patients started on flutamide are alive at 36, 33, and 24 months. In addition, we continued clinical evaluation of flutamide as an open study, enrolling six other patients (four with stage D and two with stage C carcinoma of the prostate). All except one of these patients had received previous hormonal therapy. At present, four are still being followed up at 13, 15, 20 and 24 months, demonstrating that flutamide can give positive results to some patients whose condition is deteriorating despite diethylstilbestrol therapy.

Aged↗
PubMed2005

Flutamide restores cardiac function after trauma-hemorrhage via an estrogen-dependent pathway through upregulation of PGC-1.

Although previous studies have shown that flutamide improves cardiovascular function after trauma-hemorrhage, the mechanisms responsible for the salutary effect remain unknown. We hypothesized that flutamide mediates its beneficial effects via an estrogen-dependent pathway through upregulation of peroxisome proliferator-activated receptor-gamma coactivator 1 (PGC-1). PGC-1, a key regulator of cardiac mitochondrial ATP production, induces mitochondrial DNA (mtDNA)-encoded genes such as cytochrome-c oxidase (COX) subunit I, II, and III (COX I, COX II, and COX III), which regulates mitochondrial oxidative phosphorylation. To test this hypothesis, male rats underwent trauma-hemorrhage (mean arterial pressure of 35-40 mmHg for approximately 90 min) followed by resuscitation. At the onset of resuscitation, rats received vehicle, flutamide (25 mg/kg body wt), flutamide in combination with estrogen receptor (ER) antagonist ICI-182,780 (3 mg/kg body wt), or ICI-182,780 alone. Flutamide administration after trauma-hemorrhage restored the depressed cardiac function and increased cardiac testosterone, estrogen levels, and aromatase activity. These increases were accompanied by normalized cardiac ER-alpha and ER-beta protein levels, PGC-1, and COX I mRNA expression, mitochondrial COX activity, and ATP contents. However, cardiac dihydrotestosterone, 5alpha-reductase II, androgen receptor protein levels, and mtDNA-encoded genes COX II and COX III were unaffected by flutamide treatment. The flutamide-mediated restoration of cardiac function, the increases in aromatase activity and estrogen levels, ER-alpha, ER-beta, PGC-1, COX I, COX activity, and ATP contents were, however, abolished when ER antagonist ICI-182,780 was administrated along with flutamide. These findings suggest that the salutary effect of flutamide on cardiac function after trauma-hemorrhage is mediated via an estrogen-dependent pathway through upregulation of PGC-1.

Abdominal Injuries↗
PubMed1996

Double-blind, randomized study of primary hormonal treatment of stage D2 prostate carcinoma: flutamide versus diethylstilbestrol.

PURPOSE: Patients with stage D2 prostate carcinoma are often treated initially with hormones to decrease endogenous testosterone. Therapy with diethylstilbestrol (DES), leuprolide, or bilateral orchiectomy has been reported to be equivalent. DES is the cheapest preparation, but has the potential for serious cardiovascular or thromboembolic complications. Flutamide is a novel antiandrogen with fewer side effects. PATIENTS AND METHODS: The Eastern Cooperative Oncology Group (ECOG) conducted a double-blind, randomized study to compare the efficacy of flutamide (250 mg three times daily) to DES (1 mg three times daily) as the primary hormonal therapy for patients with stage D2 prostate cancer. Patients were stratified by performance status, disease sites, and history of cardiovascular disease at randomization. RESULTS: Forty-eight patients received DES and 44 flutamide. Patient characteristics were evenly distributed between the two treatments. The overall response rate was similar (DES, 62%; flutamide, 50%). Grade III or worse cardiovascular or thromboembolic toxicity developed in 33.3% of patients on DES and in 17.6% on flutamide (P = .051). Other toxicities were similar between the two treatment arms. However, DES produced significantly longer time to treatment failure (26.4 v 9.7 months, P = .016) and longer survival than flutamide (43.2 v 28.5 months, P = .040). CONCLUSION: As the primary hormonal therapy for stage D2 prostate cancer, DES caused more serious cardiovascular or thromboembolic complications than flutamide. Despite this, flutamide was not as active an initial agent as DES. However, the effectiveness of flutamide in conjunction with other agents compared with DES remains undetermined, and the optimal initial hormone therapy of stage D2 prostate cancer requires further studies.

Administration, Oral↗
PubMed2001

Flutamide versus prednisone in patients with prostate cancer symptomatically progressing after androgen-ablative therapy: a phase III study of the European organization for research and treatment of cancer genitourinary group.

PURPOSE: Time to progression (TTP), overall survival, and quality of life (QL) were compared in patients with hormone-resistant prostate cancer (HRPC) treated with prednisone (5 mg orally, four times a day) or flutamide (250 mg orally, three times a day). PATIENTS AND METHODS: Symptomatic patients were randomized to receive either prednisone (101 patients) or flutamide (100 patients). Subjective response was assessed based on performance status, the use of analgesics, and the need to apply alternative palliative treatment. Prostate-specific antigen (PSA)-based biochemical response (>or= 50% reduction of baseline PSA) was recorded. At baseline and at 6-week intervals during follow-up, patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C-30. RESULTS: There was no difference between the groups in median TTP (prednisone, 3.4 months; flutamide, 2.3 months) or overall survival (prednisone, 10.6 months; flutamide, 11.2 months). In the prednisone group, 56% of the patients experienced a subjective response, compared with 45% in the flutamide group (P: = .18). The median response duration was 4.8 months for prednisone and 4.2 months for flutamide. A biochemical response was observed in 21% and 23% of the prednisone and flutamide groups, respectively. Gastrointestinal toxicity was the reason for trial discontinuation in seven patients receiving flutamide and two patients receiving prednisone. The QL assessment parameters favored the use of prednisone with statistically significant differences in pain, fatigue, role functioning, appetite loss, gastrointestinal distress, and overall QL. CONCLUSION: In symptomatic HRPC, treatment with prednisone or flutamide leads to similar rates of TTP and overall survival and no difference in subjective or biochemical response. The QL results favor the use of low-cost prednisone in patients with HRPC.

Aged↗
PubMed1989

Flutamide. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in advanced prostatic cancer.

Flutamide is a non-steroidal antiandrogenic drug devoid of hormonal agonist activity. Flutamide appears to be a specific antiandrogen only at androgen-dependent accessory genital organs. Its pharmacological activity is due substantially to the principal metabolite, 2-hydroxyflutamide. In comparative trials involving small numbers of patients with previously untreated advanced prostatic cancer, flutamide 750mg daily is comparable with stilboestrol 1 or 3mg daily and with estramustine 560 or 840mg daily. Treatment of newly diagnosed advanced prostatic cancer with flutamide plus a luteinising hormone releasing hormone (LHRH) agonist has produced very promising results, and appears to prolong survival relative to that achieved with leuprolide alone. However, these results require confirmation in suitably designed prospective studies. In previously treated patients refractory to castration, flutamide 750mg daily appears comparable in efficacy to estramustine phosphate 600 mg/m2 daily. Apart from a high incidence (34 to 100%) of gynaecomastia flutamide monotherapy is usually well tolerated, and has the advantage of preserving libido and sexual potency in at least 80% of patients. Gynaecomastia is infrequent, however, when flutamide is used in conjunction with surgical castration or an LHRH agonist. Thus, flutamide is a suitable alternative to other systemic treatment in patients with advanced prostatic cancer who wish to preserve sexual potency. In combination with an LHRH agonist flutamide may become a first-line agent for previously untreated patients with cancer of the prostate.

Anilides↗
PubMed1994

Comparison of the efficacy of spironolactone versus flutamide in the treatment of hirsutism.

OBJECTIVE: To compare the efficacy of two antiandrogens, spironolactone and flutamide, in the treatment of hirsutism. PATIENTS, PARTICIPANTS: Twenty women with idiopathic hirsutism were randomized to receive either flutamide or spironolactone. DESIGN: Twenty hirsute women were recruited from patients presenting to the hirsutism clinic in Marmara University, Istanbul. Each patient underwent a complete medical and gynecological examination as well as endocrine profile, hematologic, hepatic, and renal function analyses. Hirsutism scores were determined according to the Ferriman-Gallwey scoring system. These tests were then repeated at 3, 6, and 9 months of therapy. Ten patients received 250 mg of flutamide two times per day, and 10 patients received 100 mg of spironolactone for 9 months. RESULTS: Ferriman-Gallwey scores were decreased significantly in both groups at the end of 9 months. The percent of change in hirsutism scores in flutamide and spironolactone group were as follows: 26.4% and 20.9% at 3 months; 39.5% and 32.9% at 6 months; and 46.4% and 39.6% at 9 months, respectively. There was a trend toward a better response with flutamide that did not achieve significance. None of the hormonal parameters changed significantly during this period of time. Irregular bleeding was observed in five patients (50%) of the spironolactone group, whereas none of the patients in the flutamide group experienced menstrual irregularity. Conversely, dry skin and increased appetite were experienced by two patients (20%) in the flutamide group but not in the spironolactone group. CONCLUSION: These data suggest that both spironolactone and flutamide were similarly effective in treatment of hirsutism, and the pure antiandrogen flutamide is a safe and effective alternative in treatment.

Adolescent↗
PubMed1998

Flutamide-induced acute hepatitis: investigation on the role of immunoallergic mechanisms.

Flutamide is a nonsteroidal antiandrogen drug used in the treatment of prostatic cancer. Hepatotoxic reactions due to flutamide have been reported with an incidence ranging from 1% to 5%. These reactions are usually reversible upon withdrawal of the drug but can occasionally be life-threatening. The mechanism of flutamide-associated hepatotoxicity is not well established. We report a case of a 69-year-old man with prostatic carcinoma in whom flutamide induced an acute hepatitis which resolved completely soon after drug withdrawal. In this patient, we have studied the possible involvement of an immunological mechanism in causing flutamide hepatitis by investigating the presence of circulating antibodies directed against reactive metabolites of flutamide bound to liver proteins with enzyme-linked immunosorbent assay technique. Although, in the present case, we have failed to detect IgG reacting with rat liver microsomes incubated in vitro with flutamide, this does not completely rule out the possibility of an immunological involvement in flutamide hepatotoxicity. The possibility of severe flutamide-related injury, independently of the underlying pathogenic mechanism, strongly suggests the need for careful monitoring of liver enzymes in patients taking this drug.

Acute Disease↗
PubMed1995

Antitumor activity of suramin in hormone-refractory prostate cancer controlling for hydrocortisone treatment and flutamide withdrawal as potentially confounding variables.

BACKGROUND: A prospective Phase II clinical trial was conducted to assess the clinical activity of a pharmacokinetically guided suramin regimen in patients who had documented progression of metastatic prostate cancer after hydrocortisone plus antecedent or simultaneous withdrawal of flutamide. METHODS: Fifty-four patients whose disease had progressed after castration and flutamide administration were enrolled on this trial. The study was divided into two parts. Initially, 52 patients received hydrocortisone (30 mg/day) and for those patients receiving flutamide, at study entry (34 patients) flutamide was simultaneously discontinued. Forty-three patients whose disease progressed on hydrocortisone received suramin for 6-8 weeks. Six patients who progressed on hydrocortisone became ineligible for suramin due to clinical deterioration, four patients are still responding to hydrocortisone at more than 1 year, and one patient elected to postpone initiation of suramin. Suramin was given as intermittent infusions at fixed doses on days 1-5 and thereafter dosing was guided by adaptive control with feedback to maintain plasma suramin concentrations between 300-175 micrograms/ml. Antitumor activity was assessed by prostate specific antigen (PSA) decline and soft-tissue disease response. RESULTS: Ten patients (19%; 95% CI, 9.6%-32.5%) responded to hydrocortisone therapy with either a 50% or greater PSA decline for at least 4 weeks (9 patients) and/or a partial response of measurable soft-tissue disease (2 patients). Five of these patients (10%) demonstrated a 80% or greater PSA decline. All responders to hydrocortisone had simultaneous flutamide withdrawal, and had been receiving flutamide as part of initial combined androgen blockade. Seven of 37 evaluable patients (19%; 95% CI, 8.0%-35.2%) responded to suramin with a 50% or greater decline in PSA for 4 weeks or longer. One patient (3%) had a 80% or greater decline in PSA. There were no soft-tissue disease responses to suramin. The median time to progression was 1.9 months for hydrocortisone therapy and 2.6 months for suramin therapy. The median survival for all patients was 14.6 months. CONCLUSION: Suramin has antitumor activity in metastatic prostate carcinoma independent of the therapeutic effect of hydrocortisone administration or flutamide withdrawal. The role of prior flutamide withdrawal and hydrocortisone replacement should be taken into account in future studies of suramin.

Aged↗
PubMed1991

Testis and epididymis of the Indian wall lizard (Hemidactylus flaviviridis): effects of flutamide on FSH and testosterone influenced spermatogenesis, Leydig cell, and epididymis.

To determine the separate spermatogenic actions of FSH and testosterone, adult male lizards Hemidactylus flaviviridis with recrudescent testes were administered the non-steroidal antiandrogen flutamide either alone or in combination with FSH or testosterone, and the histology and histochemistry of the testes and ductus epididymides were studied. Flutamide-treated animals displayed a marked hypertrophy of Leydig cells. A few spermatids were also seen in testis of more than half the animals treated with flutamide. Flutamide also produced a significant increase of primary spermatocytes; no spermatids were observed in controls. A significant inhibition of spermatogenesis was noted in lizards treated either with testosterone alone or in combination with flutamide. Ovine FSH treatment caused a significant stimulation of spermatogenesis, as indicated by the increase of primary and secondary spermatocytes and the transformation of secondary spermatocytes into spermatids or, in a few cases, into spermatozoa. A considerable depletion of sudanophilic lipid and moderate delta 5-3 beta-hydroxysteroid dehydrogenase activity was noted in the Leydig cells of FSH-treated animals indicating enhanced steroidogenesis. Similar results were obtained when lizards were treated with flutamide + FSH. The effects of simultaneous treatment of flutamide with FSH or testosterone on ductus epididymidis revealed that flutamide markedly inhibited the epithelial cell height and lumen diameter with a loss of luminal content when compared to FSH or testosterone-treated lizards.

Animals↗
PubMed1999

Disruption of androgen-regulated male reproductive development by di(n-butyl) phthalate during late gestation in rats is different from flutamide.

Gestational and lactational exposure to di(n-butyl) phthalate (DBP) at >/=250 mg/kg/day disrupts male rat reproductive development and function. Although this indicates an antiandrogenic mechanism, DBP and its biologically active metabolite do not interact with the androgen receptor (AR) in vitro. In the present study, we compared the effects of DBP and the antiandrogen flutamide using a shorter exposure during the prenatal period of male sexual differentiation in rats. Pregnant CD rats received DBP at 0, 100, 250, or 500 mg/kg/day po (n = 10) or flutamide at 100 mg/kg/day po (n = 5) from Gestation Days 12 to 21. In F1 males, DBP (500 mg/kg/day) and flutamide caused hypospadias; cryptorchidism; agenesis of the prostate, epididymis, and vas deferens; degeneration of the seminiferous epithelium; and interstitial cell hyperplasia of the testis. Flutamide and DBP (250 and 500 mg/kg/day) also produced retained thoracic nipples and decreased anogenital distance. Interstitial cell adenoma occurred at 500 mg DBP/kg/day in two males. The only effect seen at 100 mg DBP/kg/day was delayed preputial separation. In contrast to flutamide, DBP caused a low incidence of prostate agenesis and hypospadias with no vaginal pouch. The low incidence of DBP-induced intraabdominal testes contrasted with the high incidence of inguinal testes seen with flutamide. Thus prenatal male sexual differentiation is a sensitive period for the reproductive toxicity of DBP. A no observed adverse effect level was not established and the lowest observed (adverse) effect level was 100 mg/kg/day. Flutamide and DBP disrupted the androgen signaling necessary for male sexual differentiation but with a different pattern of antiandrogenic effects. DBP is an example of an environmental antiandrogen that disrupts androgen-regulated male sexual differentiation without interacting directly with the AR, as does flutamide.

Abnormalities, Drug-Induced↗
PubMed2006

Metabolism and hepatic toxicity of flutamide in cytochrome P450 1A2 knockout SV129 mice.

BACKGROUND: Flutamide, a nonsteroidal antiandrogen used for treatment of prostate cancer, causes a temporary increase in transaminase and in some cases severe liver dysfunction. It is dominantly metabolized by cytochrome P450 (CYP) 1A2 into 2-hydroxyflutamide (OH-flutamide), which has stronger antiandrogenic activity without obvious cytotoxicity to cultured hepatocytes. We hypothesized that another subsidiary metabolite might be responsible for induction of hepatotoxicity. METHODS: Flutamide was administered daily to CYP1A2 knockout mice and parental SV129 mice to compare pharmacokinetics and appearance of hepatic toxicity. RESULTS: In the CYP1A2 knockout mice, the plasma concentration of flutamide maintained at a high level and OH-flutamide stayed low; a higher amount of FLU-1, an alternative metabolite of flutamide, was detected in urine. Simple repetitive administration of 800 mg/kg of flutamide for 28 days to CYP1A2 knockout mice did not show abnormal elevation of plasma alanine aminotransferase (ALT). However, after the knockout mice were fed with an amino acid-deficient diet for 2 weeks, which reduced the glutathione (GSH) content to 27% of the initial, administration of 400 mg/kg of flutamide increased ALT to over 200 IU/l and histopathologically moderate hepatitis developed. Since FLU-1 itself did not show cytotoxicity or reduce GSH content in vitro, a further metabolized molecule must cause the hepatotoxicity. CONCLUSIONS: Blockade of CYP1A2 produced an unknown potential hepatotoxic molecule through FLU-1, and GSH might play an important role in diminishing the reactive hepatotoxic metabolite.

Alanine Transaminase↗