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. Sideeffects, 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.

Preferential Inhibition of T Helper 1, but Not T Helper 2, Cytokines in Vitro by L-826,141 [4-{2-(3,4-Bisdifluromethoxyphenyl)-2-{4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-phenyl]-ethyl}-3-methylpyridine-1-oxide], a Potent and Selective Phosphodiesterase 4 Inhibitor

“…In this study, we focus on the mechanistic profile of inhibition at the enzyme and inflammatory cytokine level. The compound that has been profiled is L-826,141, which is a structural analog to CDP840, which has previously demonstrated attenuation of the late asthmatic response in humans in an allergen challenge paradigm (Harbinson et al, 1997).…”

The Effect Of The Novel Phosphodiesterase-4 Inhibitor MEM 1414 On The Allergen-induced Responses In mild Asthma

“…Clinical studies have also shown efficacy for other orally administered PDE4 selective inhibitors on relevant asthma endpoints such as inhibition of allergen challenge [9,10] and exercise induced bronchoconstriction [11], as well as improvements in lung function [12]. However, the tolerability of these orally administered drugs is limited by side effects such as gastro-intestinal symptoms [13][14][15].…”

Bifunctional drugs for the treatment of asthma and chronic obstructive pulmonary disease

“…As a consequence, a number of PDE4 inhibitors have been shown to have an anti-inflammatory activity clinically [38,48,49], which is thought to contribute to a long-term improvement in lung function and fewer exacerbations in patients with severe COPD, as has been observed with the recently approved PDE4 inhibitor, roflumilast N-oxide [50,51], although the side-effect profile of this drug still limits the wider use of this agent. However, while PDE4 is found in human airway smooth muscle, it is now clear from a number of clinical studies with a variety of PDE4 inhibitors administered either orally [52,53] or by inhalation [54], that this drug class is not able to induce acute bronchodilation [38]. In contrast, a number of selective PDE3 inhibitors have been shown to be bronchodilators in man [55,56] and, indeed, recently, PDE3 has been documented to be upregulated in airway smooth muscle obtained from patients with asthma [57].…”