Efficacy of the novel phosphodiesterase-4 inhibitor BAY 19-8004 on lung function and airway inflammation in asthma and chronic obstructive pulmonary disease (COPD)

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Abstract

Selective inhibitors of phosphodiesterase-4 (PDE4) inhibit the hydrolysis of intracellular cAMP, which may result in bronchodilation and suppression of inflammation. We examined the effect of 1 week treatment with BAY 19-8004 (5 mg once daily), a novel orally administered PDE4 inhibitor, on trough FEV1 and markers of inflammation in induced sputum in patients with asthma or chronic obstructive pulmonary disease (COPD). Seven patients with asthma (mean [SD] FEV1 69.5 [9.3]% predicted; reversibility in FEV1 26.2 [10.1]%; all non-smokers) and 11 patients with COPD (FEV1 58.6 [8.3]% predicted; reversibility in FEV1 6.5 [4.7]%; median [range] 44 [21–90] pack years of smoking) were included in this randomized, double-blind, placebo-controlled trial. FEV1 was measured before and after 1 week of treatment; sputum was induced by 4.5% saline inhalation on the last day of treatment. FEV1 did not improve during either treatment in both patient groups (p>0.2). Sputum cell counts were not different following placebo and BAY 19-8004 treatment in asthma and COPD patients (p>0.2). However, only in patients with COPD, small but significant reductions in sputum levels of albumin and eosinophil cationic protein were observed (p<0.05). In conclusion, 1 week of treatment with the selective PDE4 inhibitor BAY 19-8004 does not affect FEV1 and sputum cell numbers in patients with asthma or COPD. However, such treatment does seem to reduce levels of albumin and eosinophil cationic protein in sputum samples obtained from patients with COPD.

Introduction

Phosphodiesterases (PDEs) are intracellular enzymes involved in the inactivation of the second messengers cAMP and cGMP [1]. The subtype PDE4 is expressed in smooth muscle cells and inflammatory cells and as such represents a potential target in asthma and chronic obstructive pulmonary disease (COPD) [2], [3]. Inhibition of PDE4 results in increases in intracellular cAMP which in turn results in smooth muscle relaxation and suppression of activation of inflammatory cells [1], [2]. In vivo administration of ‘second generation’ PDE4 inhibitors such as cilomilast has been shown to be clinically effective. In patients with severe asthma using inhaled steroids, PDE4 inhibition by a single dose of cilomilast provides rapid bronchodilation which is sustained during prolonged treatment [4]. Furthermore, in COPD patients with poorly reversible lung function, PDE4 inhibition by cilomilast during 6 weeks of treatment results in additional bronchodilation, on top of β2-agonist use [5].

BAY 19-8004 is a novel, selective second generation PDE4 inhibitor which is under development for the treatment of patients with asthma or COPD [6]. Phase I studies in healthy volunteers have indicated that once daily dosing with 5 mg of BAY 19-8004 is optimal [6]. To date, there have been no studies reporting on the effects of BAY 19-8004 in patient populations. Therefore, the aim of this study was to investigate the acute effect of a single dose of BAY 19-8004 on lung function in patients with asthma and in patients with COPD. Furthermore, we aimed to examine whether such acute bronchodilation was sustained during 1 week of treatment with BAY 19-8004 and whether this effect was associated with changes in markers of inflammation. To that end, both patient groups were treated for 1 week with PDE4 inhibitor BAY 19-8004 (5 mg once daily) or placebo using a cross-over design. Lung function was recorded during 7 h following the first (acute effect) and last dose (medium term effect) of study medication. Markers of inflammation were studied in induced sputum samples, collected following 1 week of treatment. Finally, to evaluate systemic effects of BAY 19-8004, whole blood was stimulated ex vivo with bacterial lipopolysaccharide (LPS) and subsequent cytokine production was measured.

Section snippets

Patients

Eleven patients with COPD (3 female) and seven patients with asthma (3 female), aged between 18 and 80 years, were recruited for this study. Patients had to fulfill the following inclusion criteria. COPD: a clinical diagnosis of the disease [7], post-bronchodilator FEV1 40–70% of predicted value, reversibility in FEV1 following inhalation of 400 μg of salbutamol <12% from pre-bronchodilator value and smoking history ≥20 pack years. Asthma: a clinical diagnosis of the disease [8],

Results

All patients completed the study. Patient characteristics at baseline are shown in Table 1, Table 2.

Discussion

The results of this study show that 1 week of treatment with the novel PDE4 inhibitor BAY 19-8004, 5 mg once daily, reduces albumin and ECP levels in induced sputum of patients with COPD. These reductions in inflammatory mediators were not accompanied by acute or medium term changes in lung function, nor in cell numbers in induced sputum. Furthermore, BAY 19-8004 treatment did not change any of the endpoints in patients with asthma. These results may suggest that in patients with COPD treated

Acknowledgements

This study was supported by Bayer B.V., Mijdrecht, the Netherlands. The authors thank Hilly van der Veen for performing differential cell counts, and Renate Verhoosel and Bram van der Linden for performing ELISAs.

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