Phillipps G H
Glaxo Group Research Ltd, Greenford, Middlesex, U.K.
Respir Med. 1990 Nov;84 Suppl A:19-23. doi: 10.1016/s0954-6111(08)80003-0.
Although corticosteroids have long been known to be effective in the treatment of respiratory diseases, the wide range of unwanted side-effects with the systemic compounds prompted the development of safe, topically active analogues. Of these analogues, betamethasone 17-valerate, beclomethasone 17,21-dipropionate, budesonide, flunisolide and triamcinolone acetonide have been developed as aerosols for use in asthma and rhinitis with a great deal of success and very little detectable systemic activity. In attempts to avoid these minimal side-effects, further analogues were prepared. The steroid 17-carboxylates were extremely active topically when esterified, while the parent acids were inactive. Thus, it was possible that enzymic hydrolysis of the ester function would lead to systemic deactivation. The 17-carboxylate series was superseded by the corresponding carbothioates, particularly fluticasone propionate which showed unusually high topical anti-inflammatory activity in rodents but was almost inactive after oral administration. This lack of oral activity is attributed to hepatic first-pass metabolism to the corresponding 17-carboxylic acid, which is virtually inactive.
尽管长期以来人们都知道皮质类固醇在治疗呼吸系统疾病方面有效，但全身用化合物存在广泛的不良副作用，这促使人们研发安全的、具有局部活性的类似物。在这些类似物中，倍他米松17 - 戊酸酯、倍氯米松17,21 - 二丙酸酯、布地奈德、氟尼缩松和曲安奈德已被开发成气雾剂用于治疗哮喘和鼻炎，并取得了很大成功，且几乎检测不到全身活性。为了避免这些极小的副作用，人们又制备了更多类似物。类固醇17 - 羧酸盐经酯化后局部活性极高，而其母体酸则无活性。因此，酯功能的酶促水解有可能导致全身失活。17 - 羧酸盐系列被相应的硫代羧酸盐取代，尤其是丙酸氟替卡松，它在啮齿动物中表现出异常高的局部抗炎活性，但口服后几乎无活性。这种口服无活性归因于肝脏首过代谢为相应的17 - 羧酸，而该羧酸实际上无活性。
