OBJECTIVE:To review the efficacy of the combination of the anti-androgen nilutamide (Anandron) plus orchidectomy in patients with stage D prostate cancer who had received no previous treatment.PATIENTS AND METHODS:The results of seven randomized double-blind trials were analysed. In these studies patients were followed up until progression of disease or withdrawal for other reasons. Bone pain, urinary symptoms, performance status, levels of prostatic acid phosphatase (PAP) and alkaline phosphatase (AP) were evaluated before treatment and after 1, 3, 6, 12 and 18 months of treatment. Bone scans and X-rays were taken every 6 months. The best objective response, the time of progression and the time of death were recorded. The changes from baseline in symptoms and levels of tumour markers at month six and the percentages of objective regressions in the two treatment groups were compared using the Cochran-Mantel-Haenszel test stratified by study. Peto's method was used for the analysis of time to progression and of survival.RESULTS:Of the 1191 patients enrolled in all the original trials, 1056 were eligible. In the group of patients treated with nilutamide 50% had complete or partial regression of disease compared with 33% of those who were given a placebo (P < 0.001); bone pain and levels of PAP and AP were improved or returned to normal significantly more frequently (P < 0.01); the odds of disease progression were significantly reduced (odds ratio 0.84, P = 0.05); the odds of death from cancer and from other causes were reduced but the difference was not statistically significant.CONCLUSIONS:The combination of nilutamide and orchidectomy has a beneficial effect on pain of metastatic origin, levels of tumour markers, the objective response of disease and the time to disease progression. This treatment combination might also improve survival.

We performed a metaanalysis of all double-blind studies that compared orchiectomy plus Anandron (Roussel Uclaf, Romainville, France) with orchiectomy plus placebo in stage D prostate cancer patients who had received no previous hormonal treatment. Our goal was to obtain a reliable assessment of the efficacy of the added antiandrogen.

Gonadotropin-releasing hormone (GnRH) analogues administered for the treatment of advanced prostatic cancer induce a transient increase in plasma testosterone levels during the first week of treatment, often with a secondary rise in plasma levels of prostatic acid phosphatase and a flareup of disease. To determine whether the antiandrogen nilutamide (Anandron) blocks these effects, we carried out a multicenter, placebo-controlled study of nilutamide in men with prostatic cancer treated with the GnRH analogue buserelin. Thirty-six men with disseminated prostatic cancer and elevated plasma levels of prostatic acid phosphatase were randomly assigned to two groups. Group 1 included 17 men who received buserelin (500 micrograms daily subcutaneously) and nilutamide (300 mg daily by mouth); group 2 included 19 men treated with buserelin and placebo. Symptoms were assessed, and plasma was collected before treatment, daily for 14 days, and on days 18, 22, and 29 after the initiation of treatment. Bone pain appeared or worsened in 5 of the 17 men in group 1 and in 12 of the 19 men in group 2 (P less than 0.05). Acute urinary obstruction occurred in one man in group 2. Despite similar changes in the plasma testosterone levels in both groups, the median concentration of plasma prostatic acid phosphatase decreased almost immediately in group 1, but increased transiently, then decreased on day 14 in group 2. Median levels of prostate-specific antigen decreased immediately in group 1 and decreased on day 8 in group 2. We conclude that nilutamide can prevent the adverse consequences of the buserelin-induced transient rise in plasma testosterone levels in men with advanced prostate cancer treated with a GnRH analogue.

SUMMARYIn order to evaluate the peripheral antiglucocorticoid activity of RU 486 in man we examined its ability to antagonize the effects of acutely administered glucocorticoids on blood leukocyte counts. The study was performed on eight normal male subjects. They were given 400 mg RU 486 (or placebo) orally at 0730 h and 1 mg dexamethasone (or placebo) orally at 0830 h, using a double‐blind, cross‐over, latin‐square design with a one week interval between each of the four different treatments. Circulating eosinophils, lymphocytes, and neutrophils were counted at 0730 h and 1330 h, and their variations (1330 h counts/0730 h counts × 100) were compared under each treatment. For each cell type, dexamethasone induced variations (eosinophil and lymphocyte drop, neutrophil rise) which were significantly (P < 0.05) different from those under the three other treatments; these latter treatments (placebo, RU 486, and RU 486 + dexamethasone) were equivalent to each other, inducing no variations of leucocyte counts. These data show that RU 486 inhibits dexamethasone induced leukocyte changes; this simple test provides a useful means to further analyse the peripheral antiglucocorticoid activity of RU 486 in man.

This paper summarizes the animal and human studies with Anandron available at the time of the meeting. The following was demonstrated in the rat and confirmed in man: interaction of Anandron with the prostatic androgen receptor, antiandrogen activity against testosterone (in particular against the early transient rise induced by LHRH analogs) and adrenal androgens. Thus, as shown in 4 different double blind studies performed in stage D2 prostrate cancer patients, the combination of Anandron with surgical or chemical castration enhanced the beneficial effects of castration alone and thus seems a step forward in the hormonal treatment of prostatic carcinoma.

RU 486 [17 beta-hydroxy-11 beta-(4-dimethylaminophenyl)17 alpha-(prop-1-ynyl)estra-4,9-dien-3-one] is a steroid analog which antagonizes glucocorticoid action at the receptor level. The pituitary-adrenal response to RU 486 was evaluated in patients with Cushing's syndrome. The acute administration of 400 mg RU 486 at 0800 h in five patients with Cushing's disease induced no significant change in plasma cortisol during the next 10 h compared with the administration of placebo. However, prolonged administration (400 mg daily for 3 days) caused activation of the pituitary-adrenal axis; urinary cortisol increased the most from 727 to 5720, 830 to 8200, 610 to 1020, 110 to 570, and 300 to 990 micrograms/day. Plasma cortisol and lipotropins increased to a lesser extent. Hormone changes appeared on the second day of drug administration and lasted up to 3-4 days after the drug was discontinued. In two patients with nonpituitary-dependent Cushing's syndrome, RU 486 induced no significant change in steroid secretion. We conclude that RU 486 induced a delayed and prolonged pituitary-adrenal response in Cushing's disease; whether the resulting cortisol overproduction will overcome the peripheral effect of RU 486 remains to be determined.

The antimineralocorticoid effect of a single dose of RU 28318, has been assessed in healthy men with exogenous or endogenous hypermineralocorticism. For exogenous hypermineralocorticism induced by ingestion of 9α-fluorohydrocortisone (9α-FHC) and aldosterone infusion, RU 28318 100 mg (9α-FHC ingestion) or 200 mg (aldosterone infusion) was administered, and its effect compared with identical doses of spironolactone or a placebo. For endogenous hypermineralocorticism induced by ingestion of furosemide, RU 28318 100 and 300 mg was tested in comparison with 100 mg spironolactone or placebo. In all 3 studies, both RU 28318 and spironolactone significantly raised the urinary Na/K ratio when compared to placebo administration. No significant difference was apparent between RU 28318 and spironolactone. Thus, a single dose of RU 28318 in man has an antimineralocorticoid effect identical to those produced by the identical molar dose of spironolactone. In addition, the results show that furosemide-induced hyperaldosteronism constitutes a simple and reproducible test for assessing the antimineralocorticoid effect of a drug.

RU 486 [17 beta-hydroxy-11 beta-(4- dimethylaminophenyl )-17 alpha-(prop-1- ynyl )-estra-4,9-dien-3-one] is a new steroid analog which antagonizes glucocorticoid action at the receptor level in animals. To assess its potential antiglucocorticoid activity in man we studied the pituitary-adrenal response to RU 486 in normal men. The compound was administered at 0200 h and plasma cortisol and lipotropins (LPH) were measured hourly for 10 h. After 400 mg RU 486 significant and sustained elevation of both hormones occurred during the 0700-1200 h period: mean (+/- SE) plasma levels after placebo or RU 486 during this interval were, respectively, for cortisol (ng/ml), 63.4 +/- 8.2 and 112.7 +/- 2.9 (P less than 0.02); and for LPH (pg/ml), 34.8 +/- 11.3 and 71.6 +/- 15.4 (P less than 0.01). The 200- and 100-mg doses induced only transient cortisol and LPH increases. Administration of RU 486 (400 mg) at 1400 h induced no increase in plasma cortisol compared to placebo in the corresponding 2000 to 2400 h period. When RU 486 was administered concomitantly with dexamethasone (1 mg) at 2400 h, dose-dependent blockade of the dexamethasone-induced cortisol suppression at 0900 h was found (r = 0.62, P less than 0.01); this blockade was partial after the 100-mg dose, but complete after the 400-mg dose. Plasma LPH and ACTH showed parallel variations. We conclude that RU 486 antagonizes the negative pituitary feedback of both the nocturnal endogenous cortisol rise and exogenously administered dexamethasone. These actions are consistent with an antiglucocorticoid activity of this compound in man.

AbstractIn the search for a relationship between subjective and electrophysiologic sleep parameters and blood levels of loprazolam during night sleep after single and repeated administration, eight normal volunteers took loprazolam, a novel imidazo‐benzodiazepine, on eight consecutive evenings. The assessment of the pharmacokinetics of the drug was done by two different methods: a high‐pressure liquid chromatography‐gas chromatography (HPLC‐GC) measuring the parent drug specifically and a radioreceptor assay (RRA) measuring both the parent drug and the metabolites binding to the benzodiazepine‐receptor; the latter gave slightly higher values indicating the existence of metabolites binding to the benzodiazepine‐receptor. The elimination half‐life of the parent drug was about eight hr and did not significantly increase after repeated administration; the half‐life when using the RRA was some‐what longer since steady state was not reached until the fourth day. A relationship was looked for between pharmacokinetic data and either self‐evaluated or polygraphic sleep parameters obtained from all‐night recordings on the first and eighth treatment nights. No correspondence could be demonstrated, suggesting that the drug does not act directly on sleep systems and that its hypnotic effects may be indirect, secondary to anxiolytic effects or to deactivation of wake systems.

We reviewed 150 findings in 58 patients (14 males and 44 females) with adrenocortical tumors (26 with adenoma and 32 with carcinoma) admitted to Vanderbilt Hospital during 28 years. In general, our findings agree with those reported by others in multi-institutional series or literature reviews. Adenomas took longer to diagnose than carcinomas. Adenomas usually caused Cushing's syndrome, but two caused virilization and three caused no endocrine syndrome. There was no difference in time required for diagnosis of carcinoma in men or women or in those with Cushing's syndrome, virilization or no endocrine syndrome. Urinary 17-hydroxycorticoid (17-OHCS) levels were similar in those with adenoma and those with carcinoma, but 17-ketosteroid (17-KS) levels were usually less than 20 mg per day in patients with adenoma and greater than 20 mg per day in patients with carcinoma. Adenomas were uniformly independent of endogenous ACTH stimulation, but frequently responded to exogenous ACTH. As with adenomas, no carcinoma demonstrated normal suppression with dexamethasone or normal response to metyrapone, but only one responded to exogenous ACTH. Some patients had no clinical Cushing's syndrome despite high levels of plasma cortisol and urine 17-OHCS. “Nonfunctional” tumors probably merely secreted insufficient steroids to cause signs and symptoms. Patients with adenoma were uniformly cured by surgical tumor resection. Occasional patients with carcinoma enjoyed long survival despite incomplete resection of their tumors, but most patients died of recurrent or metastatic carcinoma within seven years, often within a year or two. Small tumor size and benign histologic features were insufficient to predict benign clinical behavior. The adrenocorticolytic drug, o,p′ DDD, offered objective remission for only an occasional patient.