Bertagna X
Groupe d'Etude en Physiopathologie Endocrinienne, INSERM CIF 9208, Institut Cochin de Génétique Moléculaire, Faculté Cochin, Paris, France.
Psychoneuroendocrinology. 1997;22 Suppl 1:S51-5. doi: 10.1016/s0306-4530(97)00006-1.
New therapeutic indications of the antiprogesterone RU 486 are emerging which require long-term administration and raise the question of its safety because of the associated antiglucocorticoid action of the drug. A trial was designed to assess the antiglucocorticoid effect of RU 486, possible manifestations of peripheral cortisol deprivation, and the adrenocortical and corticotrophin reserves. Ten normal males were given RU 486 per os (200 mg/day) or placebo between 0800-0900 h for eight days in a randomized, double-blind, crossover design, with a 1-month interval between the two periods. RU 486 induced the overactivation of the pituitary-adrenal axis. Baseline values (mean +/- SEM) before and at end of treatment were, respectively: 0800 h plasma cortisol, 147.3 +/- 15.5 and 257.6 +/- 8.8 ng/ml; 0800 h salivary cortisol, 5.8 +/- 1.2 and 15.2 +/- 0.8 ng/ml; nocturnal (2200-0800 h) urinary cortisol, 8.4 +/- 1.5 and 33.7 +/- 11.1 micrograms; and 0800 h plasma ACTH, 29.2 +/- 3.7 and 60.2 +/- 8.4 pg/ml. All of these variations were different from those during placebo treatment (0.0001 < p < .03) and disappeared four days after the end of treatment. A daily record of subjective clinical symptoms, body weight and temperature, blood pressure, and heart rate showed no side effects, and no significant variation during treatment. Blood electrolyte and eosinophil counts were unchanged; fasting blood glucose was slightly higher at the end of treatment (5.0 +/- 0.2 vs. 4.7 +/- 0.1 mmol/L; p < .04). The adrenocortical response to Cortrosyn (0.25 mg IM) was exaggerated during RU 486 treatment (p < .006). Peak values before and at the end of treatment were, respectively: plasma cortisol, 272.5 +/- 15.2 and 347.1 +/- 20.6 ng/ml; and salivary cortisol, 17.0 +/- 2.2 and 31.1 +/- 3.1 ng/ml. Direct pituitary stimulation (100 micrograms ovine corticotrophin release hormone (CRH), followed by 1 IU LVP) also induced exaggerated corticotroph and adrenocortical responses (p < .005). Peak values before and at the end of treatment were, respectively: plasma ACTH, 147.7 +/- 24.6 and 254.0 +/- 41.3 pg/ml: and plasma cortisol, 231.6 +/- 7.3 and 319.2 +/- 12.3 ng/ml. These data show that 8-day treatment with 200 mg RU 486 daily induces a hormonally detectable antiglucocorticoid effect without clinical symptoms. This state results in a reversible cortisol overproduction and a preservation of adrenocortical and pituitary reserves.
抗孕激素RU 486新的治疗适应症不断涌现，这些适应症需要长期用药，并且由于该药物具有抗糖皮质激素作用，因而引发了其安全性问题。为此设计了一项试验，以评估RU 486的抗糖皮质激素作用、外周皮质醇缺乏可能出现的表现以及肾上腺皮质和促肾上腺皮质激素储备情况。10名正常男性参与了该试验，采用随机、双盲、交叉设计，于08:00 - 09:00口服给予RU 486（200毫克/天）或安慰剂，为期8天，两个阶段之间间隔1个月。RU 486导致垂体 - 肾上腺轴过度激活。治疗前及治疗结束时的基线值（均值±标准误）分别为：08:00时血浆皮质醇，147.3±15.5和257.6±8.8纳克/毫升；08:00时唾液皮质醇，5.8±1.2和15.2±0.8纳克/毫升；夜间（22:00 - 08:00）尿皮质醇，8.4±1.5和33.7±11.1微克；以及08:00时血浆促肾上腺皮质激素，29.2±3.7和60.2±8.4皮克/毫升。所有这些变化均与安慰剂治疗期间不同（0.0001 < p <.03），且在治疗结束后4天消失。对主观临床症状、体重和体温、血压及心率的每日记录显示无副作用，治疗期间也无显著变化。血液电解质和嗜酸性粒细胞计数未改变；治疗结束时空腹血糖略高（5.0±0.2对4.7±0.1毫摩尔/升；p <.04）。在RU 486治疗期间，对考的松（0.25毫克，肌肉注射）的肾上腺皮质反应增强（p <.006）。治疗前及治疗结束时的峰值分别为：血浆皮质醇，272.5±15.2和347.1±20.6纳克/毫升；以及唾液皮质醇，17.0±2.2和31.1±3.1纳克/毫升。直接垂体刺激（100微克羊促肾上腺皮质激素释放激素（CRH），随后给予1国际单位促黄体激素释放激素（LHRH））也引发了促肾上腺皮质激素和肾上腺皮质反应增强（p <.005）。治疗前及治疗结束时的峰值分别为：血浆促肾上腺皮质激素，147.7±24.6和254.0±41.3皮克/毫升；以及血浆皮质醇，231.6±7.3和319.2±12.3纳克/毫升。这些数据表明，每日200毫克RU 486治疗8天可诱导出激素水平可检测到的抗糖皮质激素作用，但无临床症状。这种状态导致可逆性皮质醇过度产生，并保留了肾上腺皮质和垂体储备。
