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