New therapies for chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a major global health problem which is increasing throughout the world and a major cause of death. However, current therapies fail to prevent disease progression or mortality. The mainstay of current drug therapy are long-acting bronchodilators; several longer-acting inhaled beta(2)-agonists and muscarinic antagonists (and combinations) are now in development. No treatments have so far been shown to suppress chronic inflammation in COPD lungs. With better understanding of the inflammatory and destructive process in the pathophysiology of COPD, several new targets have been identified. Several mediator antagonists tested in COPD have so far been disappointing, but CXCR2 antagonists that block pulmonary neutrophil and monocyte recruitment may be more promising. Broad-spectrum anti-inflammatory drugs may be more effective, and include inhibitors of the enzymes phosphodiesterase-4, p38 mitogen-activated protein kinase, NF-kappaB kinase and phosphoinositide 3 kinase-gamma and -delta, but side effects will be a major limitation so that inhaled delivery may be necessary. Perhaps the most promising approach is reversal of corticosteroid resistance through increasing histone deacetylase-2 activity. This might be achieved by theophylline-like drugs, phosphoinositide 3 kinase-delta inhibitors, more effective antioxidants and non-antibiotic macrolides.