Authors: Donnelly L.E.; Rogers D.F.

Source: Drugs, Volume 63, Number 19, 2003 , pp. 1973-1998(26)

Publisher: Adis International

Abstract:

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--phenylnitrone). New anti-inflammatory interventions include phosphodiesterase-4 inhibitors (e.g. cilomilast), inhibitors of tumour necrosis factor- (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-B (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 B₄ (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 P2Y₂ 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.

Keywords: Chronic obstructive pulmonary disease, treatment; Smoking withdrawal, treatment; Smoking cessation therapies, therapeutic use; Bronchodilators, therapeutic use; Beta 2 adrenoceptor agonists, therapeutic use; Sibenadet, therapeutic use; Research and development; Acetylcholine receptor antagonists, therapeutic us; Neurokinin antagonists, therapeutic use; Protease inhibitors, therapeutic use; Leucocyte elastase inhibitors, therapeutic use; Metalloproteinase inhibitors, therapeutic use; Cysteine protease inhibitors, therapeutic use; Anti inflammatories, therapeutic use; Corticosteroids, therapeutic use; Theophylline, therapeutic use; Phosphodiesterase inhibitors, therapeutic use; Adenosine A2 receptor agonists, therapeutic use; Tumour necrosis factor antagonists, therapeutic us; Chemokine antagonists, therapeutic use; Interleukin 10, therapeutic use; Leukotriene B4 antagonists, therapeutic use; Cyclo oxygenase 2 inhibitors, therapeutic use; Adhesion molecule antagonists, therapeutic use; NF kappa B Decoy, therapeutic use; Nitric oxide synthase inhibitors, therapeutic use; Mitogen activated protein kinase inhibitors, thera; Retinoids, therapeutic use; Antioxidants, therapeutic use; Mucolytics, therapeutic use; P2Y2 receptor agonists, therapeutic use

Document Type: Leading article

Affiliations: 1: Thoracic Medicine, National Heart & Lung Institute, Imperial College, London, UK

Publication date: 2003-01-01

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