Inhibitors of
phosphodiesterase type 4 (PDE4) act by increasing intracellular concentrations of
cyclic AMP, which has a broad range of anti-inflammatory effects on various key effector cells involved in
asthma and
chronic obstructive pulmonary disease (
COPD). The therapeutic ratio for
PDE4 inhibitors is thought to be determined by selectivity on receptor subtypes for relative effects on PDE4B (anti-inflammatory) and PDE4D (
emesis). The two main orally active
PDE4 inhibitors in the late phase III of clinical development are
cilomilast and
roflumilast; the latter (and its active metabolite N-
oxide) is more selective and potent with a superior therapeutic ratio. Studies on
cilomilast in
COPD based on bronchial biopsy material have shown a broad range of anti-inflammatory activity, and the available evidence on clinical outcomes for up to 6 months with
cilomilast 15 mg twice daily and
roflumilast 500 mug once daily have shown variable but significant effects on exacerbations and quality of life, with small improvements in measures of pulmonary function.
Roflumilast has a better safety and tolerability profile than
cilomilast, with the main adverse effects being
nausea, diarrhoea, and
abdominal pain.
Roflumilast also has activity in
asthma as assessed by its attenuation of
allergen and exercise challenges, and it shows clinical efficacy equivalent to that of
beclomethasone dipropionate 400 mug daily. The emerging results of clinical trials on
PDE4 inhibitors in
asthma and
COPD should be interpreted with cautious optimism since much of the evidence has been published only in abstract form to date. The next few years should resolve important issues about the potential role of these drugs as oral non-steroidal anti-inflammatory
therapy for
asthma and
COPD and their place in management guidelines. Ultimately, clinicians will want to know whether
PDE4 inhibitors are anything more than expensive "designer"
theophylline, the archetypal non-selective
phosphodiesterase inhibitor.