Patients with moderate to severe asthma

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ICSs, the cornerstone of therapy for patients with persistent asthma, bind to cytoplasmic glucocorticoid receptors in target cells, promoting their activation and translocation to the cell nucleus, where the receptor functions as a transcriptional modulator to repress the expression of inflammatory genes. In asthma patients, ICSs reduce the levels of markers of airway inflammation; these effects are lost once treatment is discontinued. Bronchial biopsy specimens have revealed that ICSs reduce inflammatory cell influx vs placebo or a short-acting P2-agonist.Subepithelial collagen deposition and basement membrane thickness also decrease, suggesting that ICSs may control the intensity of airway remodeling. The antiinflammatory effects of ICSs are expressed clinically by improved lung function, asthma symptoms, and rescue medication requirements.

Clinical guidelines recommend adding a LABA to ICS therapy in patients with moderate to severe asthma. LABAs act primarily as bronchodilators, but also inhibit mast cell mediator release and plasma exudation. LABAs potentiate nuclear translocation of glucocorticoid receptors and synergisti-cally suppress inflammatory mediator release; ICSs increase adrenergic receptor expression to counteract the potential receptor down-regulation associated with long-term LABA therapy. Adding a LABA to therapy is generally more effective than increasing the ICS dose; however, controversy exists regarding LABA safety. A metaanalysis has suggested that the use of LABAs may be associated with an increased risk of exacerbations requiring hospitalization and life-threatening exacerbations vs placebo. However, in the largest study evaluating LABA safety , life-threatening exacerbations and asthma-related deaths occurred mostly in patients receiving LABA monotherapy. Interestingly, there appeared to be an imbalance in the safety profile of subjects receiving monotherapy, in that African-American subjects appeared to be at greater risk of exacerbations than white subjects. It remains unclear whether this difference in risk was due to physiologic treatment effect, genetic factors, or patient behaviors. Significant differences in risk were not seen for patients receiving ICSs plus salmeterol . Similarly, systematic Cochrane reviews sildenafil citrate have shown that patients treated with ICSs plus LABA add-on therapy and ICS alone had comparable adverse event rates.