The potential role of phosphodiesterase inhibitors in the management of asthma.

Abstract

Asthma is a chronic inflammatory condition characterised by reversible airflow obstruction and airway hyperreactivity. The course of the illness may be punctuated by exacerbations resulting in deterioration in quality of life and, in some cases, days lost from school or work. That asthma is common and increasingly prevalent magnifies the importance of any potential economic costs, and promoting asthma control represents an important public health agenda. While lifestyle changes represent a valuable contribution in some patients, the majority of asthmatic patients require therapeutic intervention. The recognition of the role of inflammation in the pathogenesis of asthma has led to an emphasis on regular anti-inflammatory therapy, of which inhaled corticosteroid treatment remains the most superior. In selected patients, further improvements in asthma control may be gained by the addition of regular inhaled long-acting beta(2)-adrenoceptor agonists or oral leukotriene receptor antagonists to inhaled corticosteroid therapy. However, a significant minority of patients with asthma remain poorly controlled despite appropriate treatment, suggesting that additional corticosteroid nonresponsive inflammatory pathways may be operative. Furthermore, some patients with asthma display an accelerated decline in lung function, suggesting that active airway re-modeling is occurring. Such observations have focused attention on the potential to develop new therapies which complement existing treatments by targeting additional inflammatory pathways. The central role of phosphodiesterase (PDE), and in particular the PDE4 enzyme, in the regulation of key inflammatory cells believed to be important in asthma - including eosinophils, lymphocytes, neutrophils and airway smooth muscle - suggests that drugs designed to target this enzyme will have the potential to deliver both bronchodilation and modulate the asthmatic inflammatory response. In vivo studies on individual inflammatory cells suggest that the effects are likely to be favorable in asthma, and animal study models have provided proof of concept; however, first-generation PDE inhibitors have been poorly tolerated due to adverse effects. The development of second-generation agents such as cilomilast and roflumilast heralds a further opportunity to test the potential of these agents, although to date only a limited amount of data from human studies has been published, making it difficult to draw firm conclusions.