下丘脑-垂体-肾上腺轴抑制与吸入性糖皮质激素治疗。2. 文献综述。
Hypothalamic-pituitary-adrenal axis suppression and inhaled corticosteroid therapy. 2. Review of the literature.
作者信息
Chrousos G P, Harris A G
机构信息
Developmental Endocrinology Branch, NICHD, National Institutes of Health, Bethesda, Md., USA.
出版信息
Neuroimmunomodulation. 1998 Nov-Dec;5(6):288-308. doi: 10.1159/000026349.
In the first part of this two-part review it was noted that inhaled corticosteroids had become the mainstay of treatment for chronic asthma and yet the effects of long-term use of these compounds on the hypothalamic-adrenal-pituitary (HPA) axis were largely being determined by testing methods of limited reliability, especially by morning plasma cortisol measurements. It was established in our examination of the published literature and in our presentation of current knowledge of the structure and function of the HPA axis that safe, accurate and discriminating techniques to assess the functional status of the HPA axis were available. It was concluded that two state-of-the-art tests that have been insufficiently used were the ACTH stimulation test and measurement of the 24-hour integrated serial plasma cortisol concentrations. These two tests can detect adrenal suppression before the appearance of clinical effects. For part 2 of this review we conducted an exhaustive search of the English language clinical and pharmacological literature on the use of inhaled corticosteroids from 1988 until the present time to identify studies in which one or both of these testing methods have been used. We present our analysis of this limited number of studies to determine what accurately can be known of the HPA axis safety profile of three of the most commonly used and investigated inhaled corticosteroids - beclomethasone dipropionate, budesonide and fluticasone propionate. The first finding of significance was that only 50 reports were identified in which information on the HPA axis safety effects of orally inhaled steroids in asthma patients or in clinical pharmacological studies met our inclusion requirements. By analysis of the data presented in these reports we were able to reach the following conclusions: (1) inhaled corticosteroids administered chronically, and prudently, within recommended dose ranges do not endanger the functioning of the HPA axis, (2) the increasing tendency to use higher doses of inhaled corticosteroids on the assumption that there are clear dose-response benefits and no adverse HPA axis effects from long-term high-dose regimens is misguided and not supported by reliable published information, (3) the corollary - that higher corticosteroid potencies (as measured, for example, by skin-blanching activity) can have greater therapeutic effect in lung tissue without greater concomitant systemic activity - is a flawed concept, and (4) the limited clinical and pharmacological data support our part 1 conclusions that discriminating techniques to assess the functional HPA axis status should be an integral part of the drug development process and that further HPA axis function studies are required on existing inhaled corticosteroids - if they lack a rigorous testing history or long-term record of clinical safety.
在这篇分两部分的综述的第一部分中提到,吸入性糖皮质激素已成为慢性哮喘治疗的主要手段,然而长期使用这些化合物对下丘脑 - 垂体 - 肾上腺(HPA)轴的影响,很大程度上是由可靠性有限的检测方法决定的,尤其是早晨血浆皮质醇测量。在我们对已发表文献的审查以及对HPA轴结构和功能的现有知识的阐述中发现,有安全、准确且具鉴别力的技术可用于评估HPA轴的功能状态。得出的结论是,两项尚未充分应用的先进检测方法是促肾上腺皮质激素(ACTH)刺激试验和24小时连续血浆皮质醇浓度的测定。这两项检测能够在临床效应出现之前检测到肾上腺抑制。在本综述的第二部分中,我们详尽检索了1988年至今关于吸入性糖皮质激素使用的英文临床和药理学文献,以确定使用了这两种检测方法中的一种或两种的研究。我们对这数量有限的研究进行了分析,以确定对于三种最常用且研究较多的吸入性糖皮质激素——二丙酸倍氯米松、布地奈德和丙酸氟替卡松,关于其HPA轴安全性特征究竟能确切了解到什么。第一个有意义的发现是,仅识别出50篇报告,其中关于哮喘患者口服吸入类固醇或临床药理学研究中HPA轴安全效应的信息符合我们的纳入标准。通过对这些报告中呈现的数据进行分析,我们能够得出以下结论:(1)在推荐剂量范围内长期且谨慎地使用吸入性糖皮质激素不会危及HPA轴的功能;(2)认为高剂量吸入性糖皮质激素有明确的剂量 - 反应益处且长期高剂量方案不会产生HPA轴不良影响而增加使用高剂量的趋势是错误的,且未得到可靠的已发表信息的支持;(3)相应地——即更高的糖皮质激素效力(例如通过皮肤变白活性来衡量)在肺组织中可产生更大的治疗效果而不会伴随更大的全身活性——是一个有缺陷的概念;(4)有限的临床和药理学数据支持我们在第一部分中的结论,即评估功能性HPA轴状态的鉴别技术应成为药物研发过程的一个组成部分,并且对于现有的吸入性糖皮质激素,如果它们缺乏严格的检测历史或长期临床安全记录,则需要进一步进行HPA轴功能研究。