O2.2 Phosphodiesterase type-4 inhibitors

Cilomilast and roflumilast are inhibitors of phosphodiesterase type-4 (PDE-4).  They act by increasing intracellular concentrations of cyclic adenosine monophosphate and causing a range of anti-inflammatory effects.

Placebo controlled studies of up to six months duration (Rennard et al., 2006),(Rabe et al., 2005) have found that PDE-4 inhibitors attenuate decline in lung function and quality of life, and decrease acute exacerbations when compared to placebo [evidence level II].

PDE-4 inhibitors significantly increase the FEV₁, by an order of 40 - 100ml, compared to placebo.  Placebo controlled RCTs have now been extended to 52 weeks.(Calverley et al., 2009) They confirm a consistent improvement in pre-bronchodilator FEV₁ and a 17% reduction in the annual rate of exacerbations with roflumilast. The effects on lung function, exacerbations and breathlessness are additive to those of long acting bronchodilators such as salmeterol and tiotropium(Fabbri et al., 2009)[evidence level II]. A recent Cochrane meta-analysis (Chong et al., 2011) concluded that although PDE4 inhibitors improve short term lung function and reduce exacerbations (OR 0.78 95% CI 0.72-0.85), they lead, overall, to marginal improvements in health related quality of life and symptoms.

Drug related adverse effects mainly affect the gastrointestinal system; diarrhoea, abdominal pain, nausea and vomiting and weight loss are approximately twice as common in subjects taking PDE-4 inhibitors as in those taking placebo.

PDE-4 inhibitors are promising candidates for the treatment of chronic obstructive pulmonary disease. Further research is required to determine their long-term impact and role when used with other treatments including glucocorticoids and long-acting bronchodilators.