DIFFERENTIAL ANTI-INFLAMMATORY ACTIVITY OF GLUCOCORTICOID AND PDE 4 INHIBITORS ON NEUTROPHILS FROM COPD AND NON-COPD SUBJECTS
Executive Director, Pharmacology and Discovery, Forest Research Institute, Harborside Financial Center, Plaza V, Jersey City, NJ 07311, USA
Glucocorticoids have been used for many years as broad spectrum anti-inflammatory, immunosuppressive agents, but their clinical use is limited by their side effects. PDE4 inhibitor emerged in the 1980s as one of the potential alternatives to glucocorticoids particularly in asthma and COPD, supported by the predominant tissue distribution of PDE4 enzymes in leukocytes and its potential to target both airway inflammation and bronchoconstriction. The initial enthusiasm was followed by disappointments due to their emetic side effect and limited bronchodilatory activity in the clinic. However the approval of roflumilast in the US and Europe for the treatment of COPD and the positive results of apremilast in psoriasis has revived the interest in these class of compounds as potential anti-inflammatory agents particularly in conditions refractory to glucocorticoid treatment. According to Thomson Pharma there are currently 20 PDE4 inhibitors in various stages of clinical development for multiple indications.
Contrary to asthma, COPD is considered an inflammatory condition refractory to glucocorticoid treatment. There have been significant efforts to identify the mechanism of corticosteroid resistance in COPD and alternative therapeutic approaches for COPD treatment . In the last several years our group has been working on the characterization of roflumilast pharmacological activity, particularly as related to COPD, its effect on inflammation, mucus production and clearance. Lately we have focused on a series of studies to characterize and contrast the effects of roflumilast and dexamethasone on neutrophils from COPD patients and healthy volunteers. This talk will discuss the results from those studies, the differential response to dexamethasone and roflumilast of neutrophils from COPD and non-COPD subjects and the potential utility of roflumilast in conditions refractory to glucocorticoid treatment.