Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, attenuates allergen-induced asthmatic reactions

Background: Asthma is a chronic inflammatory disease with increasing incidence worldwide. Roflumilast is an oral, once-daily inhibitor of phosphodiesterase type 4 that prevents the breakdown of cyclic adenosine monophosphate levels, leading to inhibition of proinflammatory signaling. Objective: The objective of this study was to investigate the effects of repeated doses of 250 or 500 mu g of roflumilast on asthmatic airway responses to allergen. Methods: Twenty-three patients with mild asthma with an FEV1 of 70% of predicted value or greater were enrolled in a randomized, double-blind, placebo-controlled, 3-period crossover study. Patients participated in 3 treatment periods (7-10 days) separated by washout periods (2-5 weeks). Patients received 250 jig of oral roflumilast, 500 mu g of roflumilast, or placebo once daily. Allergen challenge was performed at the end of each treatment period, followed by FEV1 measurements over the ensuing 24 hours. Results: Late asthmatic reactions (LARs) were reduced by 27% (P = .0110) and 43 % (P = .0009) in patients treated with 250 and 500 mu g of roflumilast, respectively, versus placebo. Roflumilast, 250 and 500 mu g, also attenuated early asthmatic reactions by 25 % (P = .0038) and 28 % (P = .0046), although not to the same extent as LAR attenuation. Roflumilast was well tolerated. No serious adverse events or discontinuations caused by adverse events were reported. Conclusion: Once-daily oral roflumilast modestly attenuated early asthmatic reactions and, to a greater extent, LARs to allergen in patients with mild allergic asthma. Pronounced suppression of late responses in an allergen challenge model suggests that roflumilast might have anti-inflammatory activity, which could provide clinical efficacy in chronic inflammatory pulmonary diseases, such as asthma.