Selective PDE inhibitors as novel treatments for respiratory diseases

Phosphodiesterases (PDEs) are a family of enzymes which catalyse the metabolism of the intracellular cyclic nucleotides, c-AMP and c-GMP that are expressed in a variety of cell types and in the context of respiratory diseases, It is now recognised that the use of PDE3, PDE4 and mixed PDE3/4 inhibitors can provide clinical benefit to patients with asthma or chronic obstructive pulmonary disease (COPD). The orally active PDE4 inhibitor Roflumilast-n-oxide has been approved for treatment of severe exacerbations of COPD as add-on therapy to standard drugs. This review discusses the involvement of PDEs in airway diseases and various strategies that are currently being pursued to improve efficacy and reduce side-effects of PDE4 inhibitors, including delivery via the inhaled route, mixed PDE inhibitors and/or antisense biologicals targeted towards PDE4.

► Roflumilast has been approved for the treatment of severe exacerbations of COPD. ► Roflumilast provides benefit in patients prescribed LABAs and LAMAs. ► Clinical studies also provide proof of concept that targeting PDE4 might be beneficial for the treatment of asthma. ► Dose limiting side effects of nausea, vomiting and weight gain might limit the utility of oral formulations of PDE4 inhibitors. ► Strategies to improve risk/benefit ratio include local delivery to the lung with allosteric and mixed PDE inhibitors.