title: Selective Inhibition of Phosphodiesterases 4A, B, C and D Isoforms in Chronic Respiratory Diseases: Current and Future Evidences.
abstract: Chronic respiratory diseases affect millions of people every day. According to the World Health Organization estimates, ~235 million people suffer from asthma, ~64 million suffer from chronic obstructive pulmonary disease (COPD), and millions more suffer from allergic rhinitis around the world. In recent last years, the first phosphodiesterase 4 (PDE4) inhibitor, roflumilast, was approved as a treatment to reduce the risk of exacerbations in stable and severe COPD associated with chronic bronchitis and a history of exacerbations. PDE4 exists as four subtypes (A, B, C, and D) each with a capacity to degrade cAMP, a second messenger involved in inflammatory responses. PDE4 inhibitors inhibit PDE4 activity, consequently increasing cAMP levels. This results in an anti-inflammatory effect, improving lung function. Roflumilast is a selective and non-specific PDE4 inhibitor, with the potential to inhibit all PDE4 isoforms to some degree. Despite the pharmacological effects of roflumilast, its lack of specificity can induce side effects, such as diarrhea, nausea, and dizziness. Thus, there is a continuing need to develop more specific inhibitors of the individual PDE4 subtypes. PDE4B and D inhibitors have been investigated the most, because the levels of these two subtypes are upregulated in moderate and severe COPD. Current and new evidences show that PDE4B and D inhibitors are the most studied, because their expressions are up-regulated in moderate and severe COPD. This review highlights the major advantages of the selective specific inhibition of PDE4A, B, C, and D versus selective, non-specific inhibitors as treatments for chronic respiratory diseases.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Avenida Blasco Ibañez 15, E-46010 Valencia, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Contreras
authors.affiliation: Pharmacy Department, University General Hospital of Valencia. C/ Casa Misericordia 12, E-46014 Valencia, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Milara
authors.affiliation: Pharmacology Department, Faculty of Medicine, University of Valencia, Spain.
authors.forename: Esteban
authors.initials: E
authors.lastname: Morcillo
authors.affiliation: Teaching and research Unit of University General Hospital of Valencia, Spain.
authors.forename: Julio
authors.initials: J
authors.lastname: Cortijo
mesh_terms: D000818:Animals; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases
keywords: Phospodiesterase 4; cAMP; chronic respiratory diseases; non-selective inhibitors; roflumilast.; selective inhibitors