Phosphodiesterase-4 Inhibitor Roflumilast Research Articles

Inhibition of late asthmatic reaction in allergic asthma by the novel, selective PDE4 inhibitor Roflumilast

Rationale Many immune effector cells that are implicated in asthma express phosphodiesterase 4 (PDE4). Inhibition of PDE4 decreases eosinophil chemotaxis and tissue infiltration. Roflumilast is a novel, potent, selective PDE4 inhibitor in clinical development for the treatment of asthma and COPD. Methods Two separate, randomized, placebo-controlled studies assessed inhibition of early asthmatic response (EAR) and late asthmatic response (LAR) by Roflumilast in patients with mild allergic asthma. In the first study, designed as a pilot study (2-period crossover, N=13), patients received a single oral dose of 1000μg Roflumilast or placebo 1 h before allergen challenge. In the second study (3-period crossover, N=23), patients were treated for 7–10 days with oral Roflumilast 250μg, 500μg, or placebo once daily. Allergen challenge was performed on the last day of each treatment period. Results A single dose of 1000μg Roflumilast significantly inhibited maximal LAR by 62% ( P<0.05) vs. placebo and tended toward EAR inhibition. In the second study, dose-dependent inhibition of both LAR and EAR was observed. Roflumilast 250μg and 500μg significantly inhibited LAR by 27% and 43% ( P<0.025) vs. placebo. Inhibition of EAR was also statistically significant ( P<0.01) but less marked (25% and 28%). Trends towards attenuation of airway hyperresponsiveness were noted. Roflumilast was well tolerated in both studies. Conclusions Roflumilast significantly inhibited LAR in patients with allergic asthma. Eosinophils are the major effector cells in LAR, and the more pronounced inhibition of LAR by roflumilast supports the hypothesis that potent anti-inflammatory properties of Roflumilast may translate into clinical efficacy.