Title:Development of New Drugs for COPD
VOLUME: 20 ISSUE: 12
Author(s):Peter J. Barnes
Affiliation:National Heart and Lung Institute, Imperial College School of Medicine, Dovehouse St, London SW3 6LY, UK.
Keywords:Anti-inflammatory, bronchodilator, chemokine, cytokine, histone deacetylase, Janus kinase, nuclear factor-κB, p38
mitogen-activated protein kinase, phosphodiesterase-4, phosphoinositide-3-kinase
Abstract:Chronic obstructive pulmonary disease (COPD) is an increasing global health problem and cause of death. COPD is a chronic
inflammatory disease predominantly affecting small airways and lung parenchyma that leads to progressive airway obstruction. However,
current therapies fail to prevent either disease progression or mortality. The mainstay of current drug therapy is long-acting bronchodilators.
Several once daily inhaled β2-agonists and muscarinic antagonists (and combinations) are now in development. No treatments effectively
suppress chronic inflammation in COPD lungs. With better understanding of the inflammatory and destructive process in the
pathophysiology of COPD, several new therapeutic targets have been identified. Several mediator antagonists or inhibitors tested in
COPD have so far been disappointing, but CXCR2 antagonists that block pulmonary neutrophil and monocyte recruitment are more
promising. Broad spectrum anti-inflammatory drugs may be more effective, and include inhibitors of the proinflammatory enzymes
phosphodiesterase-4, p38 mitogen-activated protein kinase, Janus kinases, NF-κB kinase and PI3 kinase-γ and -δ, but side effects after
oral administration are a major limitation so that in future inhaled delivery may be necessary. A new promising approach is reversal of
corticosteroid resistance through increasing histone deacetylase-2 (HDAC2) activity. This might be achieved by existing treatments such
as theophylline, nortriptyline and macrolides, or more selectively by PI3 kinase-δ inhibitors. Thus although there have been major advances
in the development of long-acting bronchodilators for COPD, it has proved difficult to find anti-inflammatory treatments that are
safe and effective.
