Recent studies have suggested that
theophylline, a nonspecific phospho-diesterase inhibitor, has useful anti-inflammatory actions in
asthma.
Phosphodiesterase 4 (PDE4) represents the predominant PDE
isoenzyme present in inflammatory cells.
PDE4 inhibitors might, therefore, have beneficial effects in
asthma. Side-effects, specifically
nausea, have limited the use of existing agents.
CDP840 is an orally active, potent and selective
PDE4 inhibitor. We have examined the effect of
CDP840 on the
allergen-induced asthmatic response, its possible modes of action, and its tolerability at therapeutic doses. A total of 54 patients were recruited to three double-blind, placebo-controlled studies. The first study examined the effect of
CDP840 (15 mg b.i.d. for 9.5 days) on the
allergen-induced asthmatic response in patients with known dual response to
allergen. A second study examined the effect of
CDP840 (15 mg b.i.d. for 9.5 days) on airway responsiveness to
histamine. A third study examined whether single dose
CDP840 (15 and 30 mg) had significant bronchodilatory effects. In all studies,
CDP840 was well-tolerated, with no patients reporting
nausea.
CDP840 did not lead to changes in baseline forced expiratory volume in one second (FEV1) as compared to placebo. The late asthmatic response (LAR) to
allergen, expressed as area under the curve at 3-8 h (AUC3-8h), was inhibited by 30% (p=0.016), an effect which persisted to the end of the observation period. The early asthmatic response (EAR) was unaffected, and there was no bronchodilatory effect at the doses used. Treatment with
CDP840 did not affect bronchial hyperresponsiveness to
histamine. In conclusion,
CDP840 significantly attenuated the late asthmatic response to
allergen challenge in the absence of any bronchodilatory or
histamine antagonist effect. This suggests that
CDP840 may exert its effects via an anti-inflammatory mechanism.