zanoterone and Prostatic-Hyperplasia

Zanoterone (100 to 800 mg.) versus placebo was studied in 463 patients with benign prostatic hyperplasia.. Study end points were maximum urinary flow rate, American Urological Association symptom index, prostate volume, prostate specific antigen and sex steroid concentrations after 6 months of treatment.. Mean increases in maximum urinary flow rate were 2 to 3-fold over placebo, although only the 200 mg. group had significant results (1.7 ml. per second, p = 0.026). There were no statistically significant differences between the zanoterone and placebo groups in symptom index or prostate volume. Estradiol and testosterone concentrations, and the incidence of breast pain and gynecomastia increased significantly with zanoterone compared with placebo. Prostate specific antigen levels decreased significantly.. Zanoterone did not demonstrate a favorable risk-to-benefit profile for the treatment of benign prostatic hyperplasia.

Topics: Aged; Androgen Antagonists; Estradiol; Gynecomastia; Humans; Male; Middle Aged; Pregnanes; Prostate; Prostate-Specific Antigen; Prostatic Hyperplasia; Pyrazoles; Testosterone; Urodynamics

The effects of the steroidal androgen receptor antagonist Win 49,596 on steroid-induced prostatic growth, histomorphology, and secretory function were studied in the castrate male beagle dog. At oral doses ranging from 0.625 to 40 mg/kg/day for 12 weeks, Win 49,596 inhibited prostatic growth in terms of both weight and total DNA in a dose-dependent manner. In addition, both the incidence and severity of diffuse glandular hyperplasia/hypertrophy were dose-dependently inhibited by Win 49,596, resulting in diffuse glandular atrophy. Prostatic secretory function was also inhibited by Win 49,596 treatment. The effects of Win 49,596 at a dosage of 40 mg/kg/day were similar to that observed for the nonsteroidal androgen receptor antagonist flutamide at 10 mg/kg/day. Oral administration of Win 49,596 to castrate dogs at a dosage of 40 mg/kg/day for 12 weeks failed to produce any evidence of agonist activity. These results demonstrate that Win 49,596 prevented the experimental induction of benign prostatic hyperplasia in dogs and suggest that on further evaluation this compound may be efficacious in the treatment of the human disease.

Topics: Androgen Antagonists; Androgens; Animals; DNA; Dogs; Male; Orchiectomy; Organ Size; Pregnanes; Prostate; Prostatic Hyperplasia; Pyrazoles; Ultrasonography

The effect of the steroidal androgen receptor antagonist Win 49,596 on the prostate and testis was studied in beagle dogs and was compared to the effects of the nonsteroidal androgen receptor antagonist ICI 176,334 and the steroidal 5 alpha-reductase inhibitor MK-906. Win 49,596 was shown to bind to the androgen receptor from normal canine prostate with a Ki of 2.2 microM. After 16 weeks of treatment, prostate size, as estimated by transrectal ultrasonography, was unchanged in intact controls and was 26% of the initial size in castrate controls. Oral doses of Win 49,596 from 0.625-40 mg/kg.day for 16 weeks caused dose-dependent prostatic regression and a dose-related increase in both the incidence and severity of glandular atrophy of the prostate. Prostatic secretory function was also inhibited by Win 49,596 treatment. The effects of Win 49,596 at 40 mg/kg.day on prostatic weight, total DNA, histomorphology, and secretory function were similar to those of castration, while the effects of Win 49,596 at 10 mg/kg.day were similar to those of ICI 176,334 at 0.25 mg/kg.day and MK-906 at 1.0 mg/kg.day. No effects on testicular weight, daily sperm production, or spermatogenesis were observed; however, mild Leydig cell hyperplasia was observed in two dogs treated with 40 mg/kg.day Win 49,596. In addition, at 10 and 40 mg/kg.day Win 49,596, moderate but variable increases in serum testosterone levels were observed. In summary, Win 49,596 caused regression of the hypertrophic canine prostate without effects on spermatogenesis and/or sexual function, supporting its possible use in the treatment of human benign prostatic hypertrophy/hyperplasia.

Topics: 5-alpha Reductase Inhibitors; Androgen Antagonists; Androstenes; Anilides; Animals; Azasteroids; DNA; Dogs; Finasteride; Hypertrophy; Male; Nitriles; Orchiectomy; Organ Size; Pregnanes; Prostate; Prostatic Hyperplasia; Pyrazoles; Receptors, Androgen; Semen; Spermatogenesis; Testis; Testosterone; Tosyl Compounds; Ultrasonography