• Aaron M Mulhall, Christopher A Droege, Neil E Ernst, Ralph J Panos, and Muhammad A Zafar.
• a 1 University of Cincinnati Medical Center, Division of Pulmonary and Critical Care Medicine , Cincinnati, USA zafarmd@ucmail.uc.edu.
• Expert Opin Investig Drugs. 2015 Jan 1; 24 (12): 1597-611.

IntroductionPhosphodiesterase (PDE) inhibitors modulate lung inflammation and cause bronchodilation by increasing intracellular cyclic adenosine 3', 5'-monophosphate in airway smooth muscle and inflammatory cells. Roflumilast is the only approved PDE-4 inhibitor (PDE4I) for use in chronic obstructive pulmonary disease (COPD). Its beneficial clinical effects occur preferentially in patients with chronic bronchitis and frequent COPD exacerbations. Use of roflumilast as adjunctive or alternate therapy to other COPD medications reduces exacerbations and modestly improves lung function.Areas CoveredThis article reviews the current role of PDE4I in COPD treatment emphasizing roflumilast's clinical efficacy and adverse effects. This article also reviews developing PDE4Is in early clinical trials and in preclinical studies.Expert OpinionAfter decades of research in drug development, PDE4Is are a welcomed addition to the COPD therapeutic armamentarium. In its current clinical role, the salubrious clinical effects of PDE4I in reducing exacerbations and stabilizing the frequent exacerbator phenotype have to be cautiously balanced with numerous adverse effects. Developing drugs may provide similar or better clinical benefits while minimizing adverse effects by changing the mode of drug delivery to inhaled formulations, combining dual PDE isoenzyme inhibitors (PDE1/4I and PDE3/4I) and by forming hybrid molecules with other bronchodilators (muscarinic receptor antagonist/PDE4I and β2-agonist/PDE4I).

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