Phosphodiesterase inhibitors for chronic obstructive pulmonary disease: what does the future hold?

Phosphodiesterase-4 (PDE4) inhibitors have broad anti-inflammatory activity, inhibiting the airway inflammation associated with chronic obstructive pulmonary disease (COPD), especially by reducing airway neutrophils that are key cells in COPD. A careful evaluation of the results of several meta-analyses allows us to consider the use of PDE4 inhibitors as very important in those patients with COPD who are particularly susceptible to exacerbations, the so-called 'frequent exacerbators'. Consequently, PDE4 inhibitors should be used earlier and more frequently than is the case today, but they are prescribed sporadically because of side effects. Several strategies are conceivable to avoid side effects, but, unfortunately, many of these approaches are yet to be successfully translated into clinical effectiveness after several decades of research. A novel alternative approach is to administer multiple drugs simultaneously or drugs capable of two distinct primary pharmacological actions based on distinct pharmacophores (bifunctional drugs) in order to produce additive or synergistic effects and, consequently, to dispense these drugs at lower doses, inducing fewer side effects. The fact that we have realized that there is a need to target simultaneously more PDEs unquestionably represents an advance in the possible use of PDE inhibitors. Actually, the possibility that multivalent (multifunctional) ligands, which feature two or more pharmacophores, may deliver superior efficacy is an approach that is being explored. Recognizing the role of specific targeted therapy aimed at subcellular domains has changed our understanding of the use of PDE inhibitors, and offers an opportunity to improve both the therapeutic tolerability and efficacy of these drugs.