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JACI Highlights - March 2006
Adcock et al - Update on glucocorticoid action and resistance
All patients with asthma have a specific pattern of inflammation in the airways. It is believed that this specific pattern of inflammation underlies the clinical features of asthma. There is increasing evidence that structural cells of the airways are a major source of inflammatory mediators in asthma. Enormous progress has been made in improving glucocorticoid treatment since the introduction of hydrocortisone as the first clinically used glucocorticoid in 1948. The development of inhaled and oral glucocorticoids has resulted in highly potent molecules which have been optimized to target activity to the lung and minimize systemic exposure. These have proved highly effective for most asthmatic subjects but despite these developments there are a number of subjects with asthma who fail to respond to high doses of inhaled or even oral glucocorticoids. In the March 2006 issue of the Journal of Allergy and Clinical Immunology, Adcock et al discuss the function and limitations of glucocorticoids, treatment-insensitive asthma, and current treatment strategies for this group of subjects. The highest risk factor for side-effects with glucocorticoid treatment appears to be prolonged use of high doses of drugs. At high doses there is an increased risk of infection, adrenal suppression, and osteoporosis with topical use, and cataracts, gastrointestinal bleeding, and diabetes with oral glucocorticoids. The introduction of hydrofluoroalkanes (HFAs) has allowed for the production of drugs with smaller particle size leading to increased delivery to the small airways and reduced side-effects. An alternative approach is the use of soft drugs, such as ciclesonide, which are only activated at the site of inflammation. These drugs might have less systemic effects than earlier glucocorticoids. Severe steroid insensitive asthma results from abnormal activation of several intracellular pathways. Understanding of the multiple mechanisms by which glucocorticoids work will lead to the rational design of drugs that target and potentially restore glucocorticoid sensitivity in corticosteroid resistant asthma.
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