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

doi:10.1016/S1094-5539(03)00090-7

Pulmonary Pharmacology & Therapeutics

Volume 16, Issue 6, December 2003, Pages 341-347

https://doi.org/10.1016/S1094-5539(03)00090-7 Get rights and content

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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Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death among non-contagious diseases in the world. PDE inhibitors are among current medicines prescribed for COPD treatment of which, PDE-4 family is the predominant PDE isoform involved in hydrolyzing cyclic adenosine monophosphate (cAMP) that regulates the inflammatory responses in neutrophils, lymphocytes, macrophages and epithelial cells The aim of this study is to investigate the cellular and molecular mechanisms of cAMP-PDE signaling, as an important pathway in the treatment management of patients with COPD. In this review, a comprehensive literature review was performed about the effect of PDEs in COPD. Generally, PDEs are overexpressed in COPD patients, resulting in cAMP inactivation and decreased cAMP hydrolysis from AMP. At normal amounts, cAMP is one of the essential agents in regulating metabolism and suppressing inflammatory responses. Low amount of cAMP lead to activation of downstream inflammatory signaling pathways. PDE4 and PDE7 mRNA transcript levels were not altered in polymorphonuclear leukocytes and CD8 lymphocytes originating from the peripheral venous blood of stable COPD subjects compared to healthy controls. Therefore, cAMP-PDE signaling pathway is one of the most important signaling pathways involved in COPD. By examining the effects of different drugs in this signaling pathway critical steps can be taken in the treatment of this disease.
Identification of long non-coding RNA and circular RNA in mice after intra-tracheal instillation with fine particulate matter
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To explore the underlying mechanism and therapeutic method of the adverse effects caused by PM2.5 exposure is very important as it cannot be eliminated completely in a short time. Chronic inflammation plays a crucial role in the pathogenesis and development of many respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma (Grootendorst et al., 2003). Once inhaled, particles deposit in lung from airway to alveoli and diffuse in blood which induces respiratory and systematic inflammation (Bernstein et al., 2004; Brunekreef and Holgate, 2002).
Fine particulate matter (PM_2.5) exposure has been proved to be associated with respiratory diseases in epidemiological studies, but the underlying mechanisms are not clear. One of the most important mechanisms involved is inflammation. Non-coding RNAs are proposed to play crucial roles in epigenetic modulation and post-transcriptional regulation. Identification of non-coding RNAs can show us the new insight into the molecular toxicity of PM_2.5.
Intra-tracheal instillation of saline or PM_2.5 was performed in BALB/c Mice once a week for consecutive eight weeks. Genomewide transcriptome profiling of coding genes, long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) in mice lung were done by ribosomal RNA-depleted RNA sequencing. Lung histological alternations were observed in haematoxylin and eosin (HE) staining sections. The expressions of pro-inflammatory cytokines and Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome were quantified by qRT-PCR、ELISA and Western blot.
1873 coding genes, 885 lncRNAs and 142 circRNAs were differentially expressed in lung tissues of the saline and PM_2.5 exposed mice. The upregulated expressions of lncRNA NONMMUT065867, lncRNA NONMMUT064312, lncRNA NONMMUT018123 and the downregulated expressions of circRNA CBT15_circR_1011, circRNA mm9_circ_005915 were identified by qRT-PCR in PM_2.5 group. The pulmonary inflammation score was higher in PM_2.5 group. What’s more, the expressions of pro-inflammatory cytokines and NLRP3 inflammasome were upregulated in PM_2.5 exposed mice.
PM_2.5 causes lung inflammation and increases the expression of NLRP3 inflammasome. The identified novel lncRNAs and circRNAs may paly important role in the development of lung inflammation caused by PM_2.5.
Efficacy and safety of RPL554, a dual PDE3 and PDE4 inhibitor, in healthy volunteers and in patients with asthma or chronic obstructive pulmonary disease: Findings from four clinical trials
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Further supporting this notion, PDE3 was recently reported to be upregulated in the airways of patients with asthma.24 Although we cannot formally exclude a contributory role of PDE4 inhibition in the acute bronchodilator response after one dose of RPL554, such an effect of PDE4 inhibition seems highly unlikely because neither inhaled25 nor oral26,27 PDE4 inhibitors produce an acute increase in FEV1 in human beings. Taken together, these data suggest that PDE3 plays an important part in maintenance of airway tone in healthy and diseased airways.
Many patients with asthma or chronic obstructive pulmonary disease (COPD) routinely receive a combination of an inhaled bronchodilator and anti-inflammatory glucocorticosteroid, but those with severe disease often respond poorly to these classes of drug. We assessed the efficacy and safety of a novel inhaled dual phosphodiesterase 3 (PDE3) and PDE4 inhibitor, RPL554 for its ability to act as a bronchodilator and anti-inflammatory drug.
Between February, 2009, and January, 2013, we undertook four proof-of-concept clinical trials in the Netherlands, Italy, and the UK. Nebulised RPL554 was examined in study 1 for safety in 18 healthy men who were randomly assigned (1:1:1) to receive an inhaled dose of RPL554 (0·003 mg/kg or 0·009 mg/kg) or placebo by a computer-generated randomisation table. Subsequently, six non-smoking men with mild allergic asthma received single doses of RPL554 (three received 0·009 mg/kg and three received 0·018 mg/kg) in an open-label, adaptive study, and then ten men with mild allergic asthma were randomly assigned to receive placebo or RPL554 (0·018 mg/kg) by a computer-generated randomisation table for an assessment of safety, bronchodilation, and bronchoprotection. Study 2 examined the reproducibility of the bronchodilator response to a daily dose of nebulised RPL554 (0·018 mg/kg) for 6 consecutive days in a single-blind (patients masked), placebo-controlled study in 12 men with clinically stable asthma. The safety and bronchodilator effect of RPL554 (0·018 mg/kg) was assessed in study 3, an open-label, placebo-controlled crossover trial, in 12 men with mild-to-moderate COPD. In study 4, a placebo-controlled crossover trial, the effect of RPL554 (0·018 mg/kg) on lipopolysaccharide-induced inflammatory cell infiltration in induced sputum was investigated in 21 healthy men. In studies 3 and 4, randomisation was done by computer-generated permutation with a block size of two for study 3 and four for study 4. Unless otherwise stated, participants and clinicians were masked to treatment assignment. Analyses were by intention to treat. All trials were registered with EudraCT, numbers 2008-005048-17, 2011-001698-22, 2010-023573-18, and 2012-000742-34.
Safety was a primary endpoint of studies 1 and 3 and a secondary endpoint of studies 2 and 4. Overall, RPL554 was well tolerated, and adverse events were generally mild and of equal frequency between placebo and active treatment groups. Efficacy was a primary endpoint of study 2 and a secondary endpoint of studies 1 and 3. Study 1 measured change in forced expiratory volume in 1 s (FEV₁) and provocative concentration of methacholine causing a 20% fall in FEV₁ (PC₂₀MCh) in participants with asthma. RPL554 produced rapid bronchodilation in patients with asthma with an FEV₁ increase at 1 h of 520 mL (95% CI 320–720; p<0·0001), which was a 14% increase from placebo, and increased the PC₂₀MCh by 1·5 doubling doses (95% CI 0·63–2·28; p=0·004) compared with placebo. The primary endpoint of study 2 was maximum FEV₁ reached during 6 h after dosing with RPL554 in patients with asthma. RPL554 produced a similar maximum mean increase in FEV₁ from placebo on day 1 (555 mL, 95% CI 442–668), day 3 (505 mL, 392–618), and day 6 (485 mL, 371–598; overall p<0·0001). A secondary endpoint of study 3 (patients with COPD) was the increase from baseline in FEV₁. RPL554 produced bronchodilation with a mean maximum FEV₁ increase of 17·2% (SE 5·2). In healthy individuals (study 4), the primary endpoint was percentage change in neutrophil counts in induced sputum 6 h after lipopolysaccharide challenge. RPL554 (0·018 mg/kg) did not significantly reduce the percentage of neutrophils in sputum (80·3% in the RPL554 group vs 84·2% in the placebo group; difference −3·9%, 95% CI −9·4 to 1·6, p=0·15), since RPL554 significantly reduced neutrophils (p=0·002) and total cells (p=0·002) to a similar degree.
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Verona Pharma.
Roflumilast: A Phosphodiesterase-4 Inhibitor for the Treatment of Severe Chronic Obstructive Pulmonary Disease
2012, Clinical Therapeutics
Citation Excerpt :
In this population, roflumilast reduced inflammatory cells and markers of inflammation in the sputum and provided modest improvements in FEV1. Improvement in lung function is likely due to the effects on inflammation, as PDE4 inhibitors have not exhibited direct bronchodilating effects in previous studies.13,19,20 Since roflumilast is metabolized by CYP 3A4, 2C19, and 1A2, multiple possibilities for drug-drug interactions exist.
Roflumilast is a newly approved phosphodiesterase-4 inhibitor for the treatment of severe chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis and a history of exacerbations.
The objective of this article is to review the pharmacology, clinical efficacy, and tolerability of roflumilast in the treatment of COPD.
Articles were identified using MEDLINE (1966–August 1, 2011) and EMBASE (1947–August 1, 2011). Searches were conducted using the terms roflumilast and COPD. Included in the search were all English-language clinical trials that were randomized, had durations of >6 weeks, and studied the effects of roflumilast on the forced expiratory volume in 1 second (FEV₁) or rates of exacerbations in patients with COPD. Abstracts from the annual meetings of the American Thoracic Society, American College of Chest Physicians, and European Respiratory Society were also searched to identify relevant publications. In addition, all pertinent studies evaluating the pharmacokinetics and pharmacodynamics of roflumilast were included.
A total of 6 clinical trials (4 publications) evaluating the efficacy of roflumilast were identified and included. For the treatment of COPD, roflumilast was associated with a significant improvement in lung function (increase in FEV₁ of 36–88 mL) when compared with placebo. Roflumilast also reduced the rate of exacerbations in subsets of patients with chronic cough and a history of exacerbations. Overall, health-related quality of life was not significantly affected. Adverse effects were common in clinical trials, with 9% to 16% of patients discontinuing therapy as a result. The most frequently reported adverse effects were gastrointestinal issues, headache, and weight loss. Suicide-related adverse effects have occurred in 5 patients receiving roflumilast and 1 patient receiving placebo.
Roflumilast significantly improved FEV₁ in clinical trials but had inconsistent reductions in the rates of exacerbations. Comparative studies with recommended therapies for COPD, particularly inhaled corticosteroids, are needed to better assess the role of roflumilast in the management of COPD.
Differential effects of PDE4 inhibitors on cortical neurons and T-lymphocytes
2008, Journal of Pharmacological Sciences
Inhibitors of PDE4 (cAMP-specific phosphodiesterase) induce side effects, including nausea and emesis, that limit their therapeutic potential. We investigated the function of two catalytically active conformations of PDE4 (a low-affinity conformer detected by conventional cAMP hydrolytic activity and a high-affinity conformer detected by [³H]rolipram binding) in neuronal cells. We assessed enhancement of β-adrenoceptor-mediated cAMP accumulation in cortical neurons in vitro by eleven PDE4 inhibitors with diverse biochemical profiles. The compounds tested have a wide inhibition range of PDE4 catalytic activity and [³H]rolipram binding. Inhibition potency for PDE4 catalytic activity and [³H]rolipram binding for each compound was different. Potency in augmentation of cAMP correlated significantly with the inhibitory effect on [³H]rolipram binding, but not with that against PDE4 catalytic activity. On the other hand, the inhibitory effect on proliferation of T-lymphocytes of the same PDE4 inhibitors correlated both with inhibition of PDE4 catalytic activity and with inhibition of [³H]rolipram binding. These findings indicate that the high affinity PDE4 conformer exists at a high level in cortical neurons and is important in the regulation of cAMP. Furthermore, the relative contributions of the two PDE4 conformers in cell function may cause different PDE4 inhibitor effects on cortical neurons and T-lymphocytes.
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Efficacy of the novel phosphodiesterase-4 inhibitor BAY 19-8004 on lung function and airway inflammation in asthma and chronic obstructive pulmonary disease (COPD)

Abstract

Introduction

Section snippets

Patients

Results

Discussion

Acknowledgements

J Allergy Clin Immunol

Lancet

Chest

Pulm Pharmacol Ther

Lancet

Phosphodiesterase isozymes: molecular targets for novel antiasthma agents

Am J Respir Crit Care Med

Selective phosphodiesterase inhibitors for the treatment of asthma and chronic obstructive pulmonary disease

Curr Opin Allergy Clin Immunol

SB207499 improves pulmonary function in patients with asthma receiving concomitant inhaled corticosteroids

Eur Respir J

Optimal assessment and management of chronic obstructive pulmonary disease (COPD). The European Respiratory Society Task Force

Eur Respir J

Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO global initiative for chronic obstructive lung disease (GOLD) workshop summery

Am J Respir Crit Care Med

Reference spirometric values using techniques and equipment that meet ATS recommendations

Am Rev Respir Dis

Repeatability of cellular and soluble markers in induced sputum from patients with asthma

Eur Respir J