THE EFFECT OF A NOVEL ORALLY-ACTIVE SELECTIVE PDE4 ISOENZYME INHIBITOR (CDP840) ON ALLERGEN-INDUCED RESPONSES IN ASTHMATIC SUBJECTS

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 pr esent in inflammatory cells. PDE4 inhibitors might, therefore, have be neficial effects in asthma. Side-effects, specifically nausea, have li mited the use of existing agents. CDP840 is an orally active, potent a nd 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 wer e recruited to three double-blind, placebo-controlled studies, The fir st 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 re sponse to allergen. A second study examined the effect of CDP840 (15 m g 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 significa nt bronchodilatory effects. In all studies, CDP840 was well-tolerated, with no patients reporting nausea CDP840 did not lead to changes in b aseline forced expiratory volume in one sec second (FEV1) as compared to placebo, The late asthmatic response (LAR) to allergen, expressed a s area under the curve at 3-8 h (AUC3-8h), was inhibited by 30% (p=0.0 16), an effect which persisted to the end of the observation period. T he early asthmatic response (EAR) was unaffected, and there was no bro nchodilatory effect at the doses used. Treatment with CDP840 did not a ffect bronchial hyperresponsiveness to histamine. In conclusion, CDP84 0 significantly attenuated the late asthmatic response to allergen cha llenge in the absence of any bronchodilatory or histamine antagonist e ffect, This suggests that CDP840 may exert its effects via an anti-inf lammatory mechanism.