STEROID ANTAGONISTS

存在临床上有用的雌激素、雄激素和 矿物皮质激素。糖皮质激素的拮抗剂或 具有潜在临床用途的孕激素已被发现 最近。本项目的目标是开发和研究 细胞因子的分子作用机制及其在人类中的应用 这两类类固醇的拮抗剂。我们已经测试了一个 糖皮质激素-孕激素拮抗剂(RU 486)原型研制 最近由Roussel-UCLAF撰写。这种化合物具有很强的亲和力 人糖皮质激素和孕激素受体，缺乏激动剂 对小型实验动物的影响。给非人灵长类动物或人类的 RU 486引起血浆ACTH、皮质醇和精氨酸的长期升高 后叶加压素，所有变化均可通过先前给药预防 糖皮质激素(地塞米松)。这表明抗糖皮质激素 可以用来挑战下丘脑-垂体-肾上腺轴， 当需要对患有这种疾病的患者进行临床测试时 轴心。重症库欣患者的抗糖皮质激素治疗 异位ACTH分泌或肾上腺皮质肿瘤引起的综合征 皮质醇增多症的临床表现缓解。RU 486 增强对标准刺激的炎症/免疫反应 完整的动物，这表明糖皮质激素对 生理水平的炎症/免疫抑制效应。我们 最近发现促肾上腺皮质激素释放激素(CRH)是 在发炎部位局部产生，具有深刻的促炎作用 自分泌/旁分泌水平的炎症效应。我们已经打电话给 这种“免疫的”CRH。糖皮质激素抑制，RU 486明显 在炎症部位增加局部免疫CRH的分泌。免疫 CRH在卵巢和子宫内膜中发现，它可能参与了 排卵、黄体溶解和月经的炎症现象。 RU 486允许识别一种中枢神经系统缺陷 容易患关节炎的老鼠。在这些动物中，糖皮质激素对 应激介质不足以抑制以下免疫系统 这是一种侮辱。实际的缺陷是全局的，并且位于 下丘脑CRH神经元，对所有已知的信息反应很差 兴奋剂，包括几种细胞因子，以及5-羟色胺， 乙酰胆碱和去甲肾上腺素。这种病理生理机制是 新发现及其与人类关节炎和自身免疫性疾病的相关性 接受检查。

Clinically useful antagonists exist for estrogens, androgens, and mineralocorticoids. Antagonists for the glucocorticoids or the progestins with potential clinical usefulness have been discovered recently. The objective of this project is to develop and study the molecular mechanisms of action and the human applications of the antagonists for both of these classes of steroids. We have tested a prototype glucocorticoid-progestin antagonist (RU 486) developed recently by Roussel-UCLAF. This compound has strong affinities for the human glucocorticoid and progestin receptor and is devoid of agonist effects in small experimental animals. Given to nonhuman primates or man RU 486 causes prolonged elevations of plasma ACTH, cortisol and arginine vasopressin, all changes preventable by previous administration of a glucocorticoid (dexamethasone). This suggests that antiglucocorticoids could be used for challenging the hypothalamic-pituitary-adrenal axis, when clinical testing is required in patients with disorders of this axis. Antiglucocorticoid therapy of patients with severe Cushing's syndrome due to ectopic ACTH secretion or adrenocortical tumors causes remission of the clinical manifestations of hypercortisolism. RU 486 potentiated the inflammatory/immune response to a standard stimulus in intact animals, suggesting that glucocorticoids exert anti- inflammatory/immunosuppressive effects at physiological levels. We recently demonstrated that corticotropin releasing hormone (CRH) is produced locally at the site of inflammation and has profound pro- inflammatory effects at an autocrine/paracrine level. We have called this "immune" CRH. Glucocorticoids suppress, and RU 486 markedly augments local secretions of immune CRH at an inflammatory site. Immune CRH was found in the ovary and endometrium where it may participate in the inflammatory phenomena of ovulation, luteolysis, and menstruation. RU 486 allowed the identification of a central nervous system defects in rats prone to arthritis. In these animals glucocorticoid response to stress-mediators is inadequate to restrain the immune system following an insult. The actual defect is global and located at the level of the hypothalamic CRH neuron, which responds poorly to all its known stimulants, including several cytokines, as well as serotonin, acetylcholine and norepinephrine. This pathophysiologic mechanism is novel and its relevance to human arthritis and autoimmune disease will be examined.