title: The effect of a novel orally active selective PDE4 isoenzyme inhibitor (CDP840) on allergen-induced responses in asthmatic subjects.
abstract: 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.
authors.affiliation: Sackler Institute of Pulmonary Pharmacology, Dept of Respiratory Medicine, King's College Hospital Medical School, London, UK.
authors.forename: P L
authors.initials: PL
authors.lastname: Harbinson
authors.forename: D
authors.initials: D
authors.lastname: MacLeod
authors.forename: R
authors.initials: R
authors.lastname: Hawksworth
authors.forename: S
authors.initials: S
authors.lastname: O'Toole
authors.forename: P J
authors.initials: PJ
authors.lastname: Sullivan
authors.forename: P
authors.initials: P
authors.lastname: Heath
authors.forename: S
authors.initials: S
authors.lastname: Kilfeather
authors.forename: C P
authors.initials: CP
authors.lastname: Page
authors.forename: J
authors.initials: J
authors.lastname: Costello
authors.forename: S T
authors.initials: ST
authors.lastname: Holgate
authors.forename: T H
authors.initials: TH
authors.lastname: Lee
mesh_terms: D000293:Adolescent; D000328:Adult; D000485:Allergens / Q000276:immunology; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology; D001980:Bronchi / Q000187:drug effects / Q000502:physiology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy; D001985:Bronchial Provocation Tests; D004311:Double-Blind Method; D005541:Forced Expiratory Volume; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D012882:Skin Tests
chemical_list: D000485:Allergens; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; C102660:CDP 840; D006632:Histamine