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Toremifene is a triphenylethylene antioestrogenic derivative, chemically and pharmacologically related to tamoxifen. In animals, toremifene blocks the uterotrophic effect of oestradiol and, in intact animals, uterine weights are reduced, demonstrating the antioestrogenic activity of the compound. Such antioestrogenic effects are believed to underlie the antitumour actions of toremifene in breast cancer, i.e., it competes with oestrogen for binding sites in the cancer, thus preventing the growth-stimulating effects of oestrogen. The drug is well absorbed following oral administration and the mean elimination half-life is 5 days. Toremifene is extensively metabolised and the main metabolite in human serum is N-demethyltoremifene. This metabolite has a longer half-life (10 days) than toremifene and its steady state serum concentration is about 2 times higher than that of the parent compound.Unlike tamoxifen, toremifene is not a genotoxic carcinogen in rodent studies and, similarly, is not associated with end...

Objectives To describe biological and clinical properties of antiandrogens. To demonstrate their usefulness in prostatic diseases, specifically in prostatic carcinoma. Methods Intact and orchiectomized rats were used to characterize antiandrogenic efficacy of the test agent, administered orally, for reducing ventral prostate weight. For clinical studies, the antiandrogens were orally administered, as monotherapy, in patients with advanced prostatic carcinoma. Results Flutamide (Schering-Plough), nilutamide (Roussel), and casodex (Zeneca) were all effective in advanced prostate cancer. Complete and partial remissions were observed following the daily administration of each of these antiandrogens. The flutamide results represent the first clinical study of a “pureantiandrogen. When compared with 1 mg diethystilbestrol (DES), response rates and survival with flutamide were similar, but higher toxicity rates were observed with DES. In 26 patients with advanced prostate cancer, nilutamide had a response rate of 38.5%with a median progression-free survival and overall survival of 9 and 23 months, respectively. The overall objective response rate of casodex (50 mg) in a study of 127 patients was50%, representing 33% with stable disease and the remaining 17% showing progression. Conclusions The nonsteroidal antiandrogens such as flutamide, nilutamide, and casodex have shown efficacy in animal trials. In previously untreated patients with advanced prostatic cancer these antiandrogens were also effective in ameliorating the disease.

Great interest has been generated in the past few years to uncover agents which inhibit the actions of androgens. This interest is based on the inference that such agents would be therapeutically useful in human benign prostatic hyperplasia and adenocarcinoma, hirsutism, and acne.

Flutamide (α,α,α-trifluoro-2-methyl-4'-nitro-m-propionotoluidide) at daily doses from 1–50 mg/kg reduced seminal vesicle and ventral prostate weights of intact male rats. A comparative study in castrated rats revealed that flutamide was equipotent to cyproterone acetate (CPA) as an antiandrogen. These potencies were substantiated by a newly developed assay measuring DNA synthesis rate (Sufrin and Coffey). No androgenic, estrogenic, anti-estrogenic, corticoid, progestational, anti-progestational, or antigonadotrophic activities were observed. Flutamide, given per os daily for either 6 weeks or 1 year to aged dogs with benign prostatic hyperplasia, reduced prostatic size in 6 weeks and the prostate remained reduced at 3, 6 and 12 months after the initiation of drug therapy. Flutamide, given im three times weekly for 4 weeks reduced the size of the baboon prostate (Muntzing et al.). In testosterone propionate-treated castrated rats CPA and flutamide inhibited 3H-testosterone uptake and retention by prostate and prostate nuclei. In a study in 18 patients with far-advanced carcinoma of the prostate, there were seven positive responders, 10 failures and one inconclusive report, following the daily administration of flutamide (Stoliar and Albert). In a similar study, 9 of 12 patients in stage D prostatic carcinoma responded favorably (Prout and Irwin).

The biological properties of the anti-androgen, SH 714 (Cyproterone acetate) were determined. This compound is strongly anti-androgenic in testosterone-stimulated, orchiectomized rats and in intact male rats when administered either subcutaneously or orally. The steroid is also androgenic, progestational, anti-estrogenic, and at high doses, possesses anti-gonadotropin activity. It is devoid of anti-inflammatory activity. SH 714 also exhibited an anti-fertility effect, probably due to its potent progestational activity. When administered to orchiectomized, testosterone-stimulated orchiectomized or intact male rats, adrenal atrophy occured, and in intact animals, this atrophy was accompanied by a decrease in plasma corticosterone levels. The adrenal effects are probably due to pituitary ACTH suppression. Hypercholesterolemia also occured in treated male rats.

The preparation of several 3s-hydroxy-Δ1,5 -androstanes and pregnanes is described. The rotational and NMR effects of the 3β-hydroxy-Δ1,5-system are presented. The anabolic and androgenic results in the rat of one of these (3, RR'H) are also presented.

Sch 13521 (4'–nitro–3'–trifluoromethylisobutyranilide) at daily doses from 1–50 mg/kg reduced seminal vesicles and ventral prostate wt of intact male rats treated orally for 1–3 weeks. No alterations in sex structures of female rats were observed with doses as high as 50 mg/kg. Sch 13521 antagonized the effects of testosterone, testosterone propionate, androstenedione, and dihydrotestosterone on seminal vesicles and ventral prostate wt in castrated rats as well as the effects of hCG in hypophysectomized rats. A comparative study in castrated rats revealed that Sch 13521 was equipotent to cyproterone acetate (CPA) as an antiandrogen. However, when Sch 13521 was given to gravid rats, days 16–19, it reduced the anogenital distance in male fetuses and altered the normal development of the scrotum and penis, but unlike CPA, Sch 13521 did not effect parturition time. In the majority of these male rats, hypospadias and vaginal tracts were present and ventral prostates and seminal vesicles were absent or markedly...

Canine benign prostatic hyperplasia was reported to be due to excessive or prolonged androgenic stimulation. To test this hypothesis, aged dogs with prostatic hyperplasia were either injected im with the anti-androgen, SH 714 (cyproterone acetate), or were orchiectomized. In addition, aged dogs with “normal” prostates were injected im with testosterone propionate. Six weeks following orchiectomy or treatment with SH 714, a reduction in prostatic size occurred. Microscopic examination revealed a marked diminution in the diameters of the glands, epithelial cell heights and a loss in the acid phosphatase content. The ratio of fibromuscular stroma was altered (i.e., fibrous tissue elements increased relative to smooth muscle). Conversely, increases in both epithelial cell height and diameters of glands were observed following injection of testosterone propionate. The acid phosphatase content increased to comparable levels seen in the hyperplastic prostate. Plasma 11-hydroxycorticoid levels were reduced after ...

Flutamide (alpha,alpha,alpha-trifluoro-2-methyl-4'-nitro-m-propionotoluidide), at daily oral doses of 20 mg/day for 24 days, reduced the number and size of skin sebaceous gland cells, and reduced sebum production in ovariectomized, testosterone-stimulated rats. The weight of the preputial glands was also reduced. Unilateral topical application of flutamide (0.1-3.0 mg/day) to flank organs (androgen-sensitive cutaneous sebaceous structures) of testosterone propionate-treated female hamsters for 14 days resulted in bilateral reductions in flank organ weight and in inhibition of in vitro incorporation of 14-C from sodium [1--14C]acetate into lipids. Flutamide inhibition of flank organ weight paralleled the drug effect on lipogenesis. Unilateral topical application of flutamide to flank organs of intact male hamsters for 14 days resulted in significant bilateral reductions of flank organ weight at doses as low as 0.375 mg/day (the lowest dose tested). These weight changes were marked by reduction in sebaceous gland size, accompanied by focal cytoplasmic degeneration, and reductions in cytoplasmic organelles and in the size of the lipid bodies. Flutamide did not, however, seemingly alter the pattern of endogenous total lipids in sebaceous glands, nor did it alter the pattern of 14-C-incorporation into the lipids of male flank organ epidermis and isolated sebaceous glands, when compared to control, untreated preparations.

Flutamide is rapidly metabolized by hydroxylation of the side chain to SCH 16423 (alpha, alpha, alpha-trifluoro-2-methyl-4'-nitro-m-lactotoluidide), the major metabolic product in all species studied, which is biologically active in vivo and in vitro studies. Flutamide exhibits its antiandrogenic activity by inhibiting androgen uptake and/or inhibition of nuclear binding of the androgens in the target tissues. At daily doses from 1 to 50 mg/kg body weight, flutamide reduced seminal vesicle and ventral prostate weights of intact male rats without affecting sexual potency. In addition, flutamide reduced the rate of DNA synthesis in the prostate of rats to a greater degree than other steroidal antiandrogens. The antiandrogenic activity was corroborated by the inhibition of androgen-induced prostate hypertrophy in orchiectomized rats through the use of testosterone, testosterone propionate, dihydrotestosterone, androstenedione, and dehydroepiandrosterone. Flutamide, given orally, reduced prostatic size in aged dogs with benign prostate hyperplasia after six weeks and one year. The baboon prostate was also reduced in size when flutamide was administered three times a week for four weeks.

Flutamide (α,α,α-trifluoro-2-methyl-4′-nitro-m-propionotoluidide) at daily doses from 1–50 mg/kg reduced seminal vesicle and ventral prostate weights of intact male rats. A comparative study in castrated rats revealed that flutamide was equipotent to cyproterone acetate (CPA) as an antiandrogen. These potencies were substantiated by a newly developed assay measuring DNA synthesis rate (Sufrin and Coffey). No androgenic, estrogenic, anti-estrogenic, corticoid, progestational, anti-progestational, or antigonadotrophic activities were observed. Flutamide, given per os daily for either 6 weeks or 1 year to aged dogs with benign prostatic hyperplasia, reduced prostatic size in 6 weeks and the prostate remained reduced at 3, 6 and 12 months after the initiation of drug therapy. Flutamide, given im three times weekly for 4 weeks reduced the size of the baboon prostate (Muntzing et al.). In testosterone propionate-treated castrated rats CPA and flutamide inhibited 3H-testosterone uptake and retention by prostate and prostate nuclei. In a study in 18 patients with far-advanced carcinoma of the prostate, there were seven positive responders, 10 failures and one inconclusive report, following the daily administration of flutamide (Stoliar and Albert). In a similar study, 9 of 12 patients in stage D prostatic carcinoma responded favorably (Prout and Irwin).

The preparation and antisebaceous gland activities of a series of 17 alpha-chloro-17 beta-sulfinyl steroids are described. They were obtained from the corresponding 17 alpha-sulfides by chlorination and oxidation with iodobenzene dichloride in aqueous pyridine at -40 degrees C. A single-crystal X-ray structure determination of 17 alpha-chloro-17 beta-(benzylsulfinyl)-1,4-androstadiene-3,11-dione (4) established the absolute configuration at sulfur to be R. From an analysis of their CD spectra, some of the other alpha-chloro sulfoxides were also assigned the same absolute stereochemistry at sulfur. Inhibition of sebaceous gland activity, after topical application of the test compounds, was determined in hamsters and found to reach a maximum with 4. The 17 beta-sulfone and 17 alpha-sulfide corresponding to 4 were less potent. Subcutaneous administration of 4 produced no antiandrogenic effects in either hamsters or rats.

Synthesis and biological activity of 17-esters of 6-dehydro-16-methylene-17 alpha-hydroxyprogesterone are presented. A systematic study of the influence of the alteration of halogen at 6 and the acyl group at 17 on the progestational and antiandrogenic activities of the resulting structures is described. A convenient general method for synthesis of all of the members of the generic family from the precursors in common is described. It is believed that 6-chloro-16-methylene-17 alpha-hydroxy-4,6-pregnadiene 17-acetate, because of its structural similarity to chlormadinone acetate and its high progestational potency, will perform as a contraceptive at perhaps a lower dose than that of chlormadinone acetate.

The effect of [α-α-α-trifluoro-2- methyl-4'-nitro-m-propionotoluidide], flutamide, on 3H-testosterone and 3H-dihydrotestosterone uptake and metabolism in rat ventral prostate and semial vesicle has been studied and compared to cyproterone acetate. Testosterone-treated castrated rats were given an oral dose of 15 mg/kg of either drug for 3–7 days; neither agent suppressed 3H-testosterone uptake by the tissue at 60 min following an intraperitoneal injection of the labeled steroid given 24 hr after the last dose of drug. Both, however, fully antagonized the effect of testosterone on maintaining prostate and seminal vesicle weights in these rats. In contrast to these results both flutamide and cyproterone acetate, administered p. o. at IS mg/kg/4 days, markedly inhibited 3H-testosterone uptake and retention by prostate and prostate nuclei when labeled androgen was given 3 hr following the last dose of the drug. Similarly, a single dose of these drugs co-administered via ip injection with either 3H-testosteron...