Document Detail

Corticosteroid resistance and novel anti-inflammatory therapies in chronic obstructive pulmonary disease: current evidence and future direction.
MedLine Citation:
PMID:  22731962     Owner:  NLM     Status:  MEDLINE    
Corticosteroids are widely used in the treatment of chronic obstructive pulmonary disease (COPD). However, in contrast to their use in mild-to-moderate asthma, they are much less effective in enhancing lung function and have little or no effect on controlling the underlying chronic inflammation. In most clinical trials in COPD patients, corticosteroids have shown little benefit as monotherapy, but have shown a greater clinical effect in combination with long-acting bronchodilators. Several mechanisms of corticosteroid resistance have been postulated, including a reduction in histone deacetylase (HDAC)-2 activity and expression, impaired corticosteroid activation of the glucocorticoid receptor (GR) and increased pro-inflammatory signalling pathways. Reversal of corticosteroid resistance in COPD patients by restoring HDAC2 levels has proved effective in a small study, and long-term studies are needed to determine whether novel HDAC2 activators or theophylline improve disease progression, exacerbations or mortality. Advances in the understanding of the cellular and molecular mechanisms of corticosteroid resistance in COPD pathophysiology have supported the development of new emerging classes of anti-inflammatory drugs in COPD treatment. These include treatments such as inhibitors of phosphoinositide-3-kinase-delta (PI3Kδ), phosphodiesterase-4 (PDE4), p38 mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB), and therapeutic agents such as chemokine receptor antagonists. Of these, PI3Kδ, PDE4, p38 MAPK inhibitors and chemokine receptor antagonists are in clinical patient trials. Of importance, patient adverse effects associated with oral administration of these novel agents needs to be addressed in order to optimize therapy and patient compliance. Combinations of these drugs with corticosteroids may have additional benefits.
Amir Hakim; Ian M Adcock; Omar S Usmani
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Review    
Journal Detail:
Title:  Drugs     Volume:  72     ISSN:  0012-6667     ISO Abbreviation:  Drugs     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-07-03     Completed Date:  2012-12-03     Revised Date:  2014-03-14    
Medline Journal Info:
Nlm Unique ID:  7600076     Medline TA:  Drugs     Country:  New Zealand    
Other Details:
Languages:  eng     Pagination:  1299-312     Citation Subset:  IM    
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MeSH Terms
Adrenal Cortex Hormones / administration & dosage,  therapeutic use*
Anti-Inflammatory Agents / administration & dosage,  therapeutic use*
Drug Resistance*
Drug Therapy, Combination
Enzyme Inhibitors / administration & dosage,  therapeutic use*
Pulmonary Disease, Chronic Obstructive / drug therapy*,  enzymology,  immunology
Treatment Outcome
Grant Support
CDF-2011-04-053//Department of Health
Reg. No./Substance:
0/Adrenal Cortex Hormones; 0/Anti-Inflammatory Agents; 0/Enzyme Inhibitors

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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