Chronic obstructive pulmonary disease (
COPD) is a common, smoking-related, severe respiratory condition characterised by progressive, irreversible airflow limitation. Current treatment of
COPD is symptomatic, with no drugs capable of halting the relentless progression of airflow obstruction. Better understanding of the airway
inflammation, oxidative stress and alveolar destruction that characterise
COPD has delineated new disease targets, with consequent identification of novel compounds with therapeutic potential. These new drugs include
aids to smoking cessation (e.g.
bupropion) and improvements to existing
therapies, for example long-acting rather than short-acting
bronchodilators, as well as combination
therapy. New
antiproteases include acyl-
enzyme and transition state inhibitors of
neutrophil elastase (e.g.
sivelestat and
ONO-6818), matrix
metalloprotease inhibitors (e.g.
batimastat),
cathepsin inhibitors and
peptide protease inhibitors (e.g.
DX-890 [EPI-HNE-4] and trappin-2). New
antioxidants include
superoxide dismutase mimetics (e.g. AEOL-10113) and spin trap compounds (e.g.
N-tert-butyl-alpha-phenylnitrone). New anti-inflammatory interventions include
phosphodiesterase-4 inhibitors (e.g.
cilomilast), inhibitors of tumour
necrosis factor-alpha (e.g. humanised
monoclonal antibodies),
adenosine A(2a) receptor agonists (e.g. CGS-21680), adhesion molecule inhibitors (e.g.
bimosiamose [TBC1269]), inhibitors of
nuclear factor-kappaB (e.g. the naturally occurring compounds
hypoestoxide and (-)-
epigallocatechin-3-gallate) and activators of
histone deacetylase (e.g.
theophylline). There are also selective inhibitors of specific extracellular mediators such as
chemokines (e.g. CXCR2 and CCR2 antagonists) and
leukotriene B(4) (e.g.
SB201146), and of intracellular signal transduction molecules such as
p38 mitogen activated protein kinase (e.g. RWJ67657) and
phosphoinositide 3-kinase.
Retinoids may be one of the few potential treatments capable of reversing alveolar destruction in
COPD, and a number of compounds are in clinical trial (e.g.
all-trans-retinoic acid).
Talniflumate (MSI-1995), an inhibitor of human
calcium-activated chloride channels, has been developed to treat mucous hypersecretion. In addition, the
purinoceptor P2Y(2) receptor agonist
diquafosol (
INS365) is undergoing clinical trials to increase mucus clearance. The challenge to transferral of these new compounds from preclinical research to disease management is the design of effective clinical trials. The current scarcity of well characterised
surrogate markers predicts that long-term studies in large numbers of patients will be needed to monitor changes in
disease progression.