Juniewicz P E, McCarthy M, Lemp B M, Barbolt T A, Shaw C, Hollenbaugh D M, Winneker R C, Reel J R, Batzold F H
Department of Pharmacology, Sterling Research Group, Rensselaer, New York 12144.
Endocrinology. 1990 May;126(5):2625-34. doi: 10.1210/endo-126-5-2625.
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.
在比格犬中研究了甾体类雄激素受体拮抗剂Win 49,596对前列腺和睾丸的作用，并与非甾体类雄激素受体拮抗剂ICI 176,334和甾体类5α-还原酶抑制剂MK-906的作用进行了比较。结果显示，Win 49,596与正常犬前列腺中的雄激素受体结合，其解离常数（Ki）为2.2微摩尔。治疗16周后，经直肠超声检查估计，完整对照组的前列腺大小未发生变化，去势对照组的前列腺大小为初始大小的26%。口服剂量为0.625 - 40毫克/千克·天的Win 49,596持续16周，可导致剂量依赖性的前列腺萎缩，以及前列腺腺体萎缩的发生率和严重程度与剂量相关的增加。Win 49,596治疗还抑制了前列腺的分泌功能。每天40毫克/千克的Win 49,596对前列腺重量、总DNA、组织形态学和分泌功能的影响与去势相似，而每天10毫克/千克的Win 49,596的作用与每天0.25毫克/千克的ICI 176,334和每天1.0毫克/千克的MK-906相似。未观察到对睾丸重量、每日精子生成或精子发生的影响；然而，在接受每天40毫克/千克Win 49,596治疗的两只犬中观察到轻度的睾丸间质细胞增生。此外，每天10毫克/千克和40毫克/千克的Win 49,596可导致血清睾酮水平出现中度但可变的升高。总之，Win 49,596可使肥大的犬前列腺萎缩，且对精子发生和/或性功能无影响，这支持了其可能用于治疗人类良性前列腺肥大/增生的用途。
