title: Phosphodiesterase 4 inhibitors for the treatment of chronic obstructive pulmonary disease: a review of current and developing drugs.
abstract: BACKGROUND
  Phosphodiesterase (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.
  
  
  METHODS
  This 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.
  
  
  CONCLUSIONS
  After 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).
authors.affiliation: a 1 University of Cincinnati Medical Center, Division of Pulmonary and Critical Care Medicine , Cincinnati, USA zafarmd@ucmail.uc.edu.|b 2 Division of Pulmonary and Critical Care Medicine, Veterans Affairs Medical Center , Cincinnati, USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Mulhall
authors.affiliation: c 3 University of Cincinnati Medical Center, Department of Pharmacy Services , Cincinnati, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Droege
authors.affiliation: c 3 University of Cincinnati Medical Center, Department of Pharmacy Services , Cincinnati, USA.
authors.forename: Neil E
authors.initials: NE
authors.lastname: Ernst
authors.affiliation: a 1 University of Cincinnati Medical Center, Division of Pulmonary and Critical Care Medicine , Cincinnati, USA zafarmd@ucmail.uc.edu.|b 2 Division of Pulmonary and Critical Care Medicine, Veterans Affairs Medical Center , Cincinnati, USA.
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: Panos
authors.affiliation: a 1 University of Cincinnati Medical Center, Division of Pulmonary and Critical Care Medicine , Cincinnati, USA zafarmd@ucmail.uc.edu.|b 2 Division of Pulmonary and Critical Care Medicine, Veterans Affairs Medical Center , Cincinnati, USA.
authors.forename: Muhammad A
authors.initials: MA
authors.lastname: Zafar
mesh_terms: D000631:Aminopyridines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001549:Benzamides / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001993:Bronchodilator Agents / Q000627:therapeutic use; D003521:Cyclopropanes / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D016503:Drug Delivery Systems; D015195:Drug Design; D006801:Humans; D058988:Phosphodiesterase 4 Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000503:physiopathology; D012129:Respiratory Function Tests
chemical_list: D000631:Aminopyridines; D001549:Benzamides; D001993:Bronchodilator Agents; D003521:Cyclopropanes; D058988:Phosphodiesterase 4 Inhibitors; C424423:Roflumilast
keywords: chf6001; chronic obstructive pulmonary disease; gsk256066; phosphodiesterase IV; phosphodiesterase inhibitor; roflumilast; rpl554; tetomilast