In advanced/metastatic prostate cancer, a standard treatment is androgen deprivation therapy, either by surgical castration/LH-RH agonist monotherapy or by combined androgen blockade (CAB) with an antiandrogen. Clinical improvement and survival after CAB with an antiandrogen (instead of monotherapy) has been investigated for 20 years in many randomized clinical trials conducted primarily in Europe and America. However, there were both positive and negative results regarding the efficacy of CAB therapy. Therefore, CAB has neither been recommended as, nor has it become, a common therapy. But, in 2000, a meta-analysis-conducted Prostate Cancer Trialists Collaborative Group (PCTCG)showed the survival benefits of CAB with nonsteroidal antiandrogen (nilutamide and flutamide). Moreover, the J-Cap phase III trial in Japan suggested that CAB with bicalutamide significantly prolongs survival, which has led to the placement of CAB as the treatment of choice for advanced/metastatic prostate cancer. Neverthless, the benefit of CAB compared to monotherapy remains controversial because of the many issues involving survival, safety profiles, QOL, and cost-effectiveness. In this article, we discuss the feasibility of CAB for advanced/metastatic prostate cancer by reviewing the results of RCT, and introduce novel treatment modalities involving androgen and the androgen receptor, which are still under development.
Male, castrated male, or flutamide-treated rats (25 mg/kg subcutaneously after resuscitation) were subjected to a laparotomy (trauma), mesenteric lymph duct cannulation, and 90 minutes of shock (35 mm Hg) or trauma sham-shock. Mesenteric lymph was collected preshock, during shock, and postshock. Gut injury was determined at 6 hours postshock using ex vivo ileal permeability with fluorescein dextran. Postshock mesenteric lymph was assayed for biological activity in vivo by injection into mice and measuring lung permeability, neutrophil activation, and red blood cell deformability. In vitro neutrophil priming capacity of the lymph was also tested.
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To compare the effects of flutamide at 250 mg/d and 500 mg/d in the treatment of hirsutism.
The various clinical trials suggest that the qualitative and quantitative responses of patients with Stage D prostatic carcinoma to antiandrogens are similar to those achieved with conventional endocrine therapy. These antiandrogens appear generally safe and many avoid the increased risks of cardiovascular or thromboembolic complications seen with estrogen therapy. Further, flutamide appears to have a lesser adverse effect on libido and sexual potency than do alternative therapies. Antiandrogens offer an alternative mode of therapy for previously untreated patients with advanced prostatic cancer but have produced no convincing benefits in hormonally refractory patients.
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Prostate function is critical for male fertility; nevertheless, prostate was so far overlooked in reproductive toxicity assays. Within the EU project ReProTect, the human prostate cell line LNCaP was utilized to identify molecules targeting prostate function by the integrated assessment of cell viability (MTS assay) and prostate-specific antigen (PSA) secretion as specific marker; a training set - five (anti)androgenic chemicals - and a ReProTect feasibility set - ten chemicals - were used. Several compounds reduced PSA only at cytotoxic concentrations. Androgens (DHT, MT) markedly increased PSA as did the herbicide glufosinate ammonium, not known as androgen agonist. Anti-androgens (2OH-flutamide, linuron, vinclozolin, di-n-butyl phthalate) also increased PSA, but the effect of magnitude was much lower than for androgens. The ER-binder bisphenol A reduced PSA, while increasing cell viability. At this stage, the approach can identify chemicals able to interfere with prostate function: further refinements may allow to include prostate effects in reproductive toxicity in vitro testing.
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Of 80 overweight-obese women with PCOS, 76 completed the study.
We describe the case of a 26-year-old girl with amenorrhea and severe hirsutism who was treated with flutamide 250 mg/day and developed liver toxicity during therapy.
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A study was carried out in 146 common rats to assess the effects of 4'-nitro-3'-trifluoromethylisobutyranilide (Sch 13521) on the hypertrophied prostate gland. The hypertrophy was induced in castrated, sexually immature males by s.c. implantation of a pill of testosterone-propionate. After 20 days of administration of Sch 13521 in oral doses of 5, 10 and 25 mg/kg, the dimensions and weight of the hypertrophied prostate gland were reduced by 1.5 to 2 times. After 2 months of administration of the preparation in doses of 10 and 25 mg/kg a reduction of the hypertrophied prostate gland to the dimensions of the intact control was observed. Morphological studies confirmed the efficacy of the therapeutic action of Sch 13521.
Flutamide, but not hydroxyflutamide, successfully suppressed the transcription of all of the mutant androgen receptors examined in this study and also showed suppressive effects on PSA secretion by LNCaP cells treated with dihydrotestosterone. These inhibitory effects were probably not the result of competitive inhibition by flutamide given its low affinity to the androgen receptor constructs.