Combination Therapy of Long-Acting ??2-Adrenoceptor Agonists and Corticosteroids for Asthma

Abstract

Twice-daily combination therapy of inhaled corticosteroids and long-acting beta2-adrenoceptor agonists (LABA) is now established as a most effective treatment for moderate to severe asthma and is available in a combined single inhaler. The benefits of combination therapy include better day-to-day control and a reduction in exacerbations compared with monotherapy with inhaled corticosteroids at a lower dose. Total control of asthma, defined as no daytime or night-time symptoms, no use of rescue beta2-adrenoceptor agonists (beta2-agonists), no exacerbations and a peak flow rate of >80% predicted, may be achieved with the use of combined salmeterol/fluticasone in up to 41% of patients with moderate to severe asthma, compared with only 28% of patients treated with fluticasone alone. Adjustable maintenance dosing with budesonide/formoterol may provide better control when compared with fixed-dosing combination regimens. Other therapies combining effectively with inhaled corticosteroids include slow-release theophylline and leukotriene inhibitors, montelukast and zafirlukast, but LABA are the most efficacious. Molecular interactions between corticosteroids and beta2-adrenoceptors may underlie the clinical added benefits of combination therapy. Corticosteroids may increase the number of beta2-adrenoceptors and their coupling with Gs proteins, while beta2-agonists may induce glucocorticoid receptor nuclear translocation, activate transcription factor/enhancer binding protein C/EBPalpha together with corticosteroids, or phosphorylate corticosteroid receptors. The combination of corticosteroids and LABA potentiates inhibition of interleukin-8 and eotaxin release from human airway smooth muscle cells and granulocyte-macrophage colony-stimulating factor release from epithelial cells, and also the inhibition of airway smooth muscle cell proliferation. It is important to determine whether there is a potentiating effect of combination therapy compared with corticosteroid treatment alone on airway inflammation and airway wall remodelling. Improvements in combination therapy include a once-daily preparation and possible combination of inhaled corticosteroids with newer drugs such as phosphodiesterase IV inhibitors.