Effect of 1-Year Treatment with Roflumilast in Severe Chronic Obstructive Pulmonary Disease

Calverley, Peter M.A.; Sánchez-Toril, Fernando; McIvor, Andrew; Teichmann, Peter; Bredenbroeker, Dirk; Fabbri, Leonardo M.

doi:10.1164/rccm.200610-1563oc

Cited by 294 publications

(298 citation statements)

References 29 publications

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“…While showing potential as therapies in stable asthma and COPD and also exacerbations of COPD (Calverley et al. 2007b; Rennard et al. 2011), few studies have investigated the effects of PDE4 inhibitors in the control of virus‐induced inflammation (Ikemura et al.…”

Section: Discussionmentioning

confidence: 99%

Anti‐inflammatory effects of the novel inhaled phosphodiesterase type 4 inhibitor CHF6001 on virus‐inducible cytokines

Edwards

Facchinetti

Civelli

et al. 2016

Pharmacology Res & Perspec

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Respiratory virus infections precipitate asthma and chronic obstructive pulmonary disease (COPD) exacerbations, with most exacerbations due to rhinovirus infection. Both asthma and COPD exacerbations are not well controlled by steroid therapies, and there is a much research interest in finding improved therapies or combinations of therapies for controlling exacerbations. CHF6001 is a new, inhaled highly potent and selective phosphodiesterase type 4 (PDE4) inhibitor. Using in vitro human bronchial epithelial cells (BEAS‐2B), we investigated the potential anti‐inflammatory effects of CHF6001 on rhinovirus (RV1B)‐induced cytokines. Cytokine mRNA was measured by real‐time PCR, while protein release was measured by ELISA. CHF6001 was used in a 7‐point dose–response curve (1000–0.001 nmol/L) as a 1.5‐h pretreatment prior to infection in comparison with roflumilast. Both roflumilast and CHF6001 reduced RV1B‐induced IL‐8, IL‐29, IP‐10, and RANTES mRNA and protein in a concentration‐dependent manner. Generally, CHF6001 was 13‐ to 16‐fold more potent (subnanomolar EC 50 values) than roflumilast at reducing IL‐8, IL‐29, IP‐10, and RANTES mRNA and protein release, but had similar efficacies. In combination with the steroid fluticasone propionate (1 nmol/L), CHF6001 had additive effects, significantly reducing RV‐induced cytokines when compared with steroid or CHF6001 alone. Combined low‐dose steroid and low‐dose CHF6001 had a similar efficacy as high‐dose steroid or CHF6001 alone, indicating the combination had steroid and PDE4 inhibitor sparing effects. Overall results indicate that PDE4 inhibitors have anti‐inflammatory activity against virus‐induced inflammatory mediators and that CHF6001 is more potent than roflumilast.

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Section: Discussionmentioning

confidence: 99%

Anti‐inflammatory effects of the novel inhaled phosphodiesterase type 4 inhibitor CHF6001 on virus‐inducible cytokines

Edwards

Facchinetti

Civelli

et al. 2016

Pharmacology Res & Perspec

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show abstract

“…Adverse events mostly became evident during the first 4-12 weeks and although usually subsiding with continued treatment, these events caused an increased patient withdrawal in the roflumilast-arms. In addition, no clinically relevant cardiac toxicity was reported in none of the patients [39][40][41][42].…”

Section: Adverse Events During Long-term Pde4-inhibitionmentioning

confidence: 89%

“…As compared to placebo, patients in both roflumilast-arms showed improvements in terms of postbronchodilator FEV1 (p <0.014), health-related quality of life (NS) and the number of COPD-exacerbations (p=0.0114) [39]. In another study, subjects with moderate to (very) severe COPD (GOLD stages II to IV) received roflumilast for one year, resulting in a small but significant improvement in baseline FEV1, a modest reduction in exacerbation rates in GOLD-stage IV patients, but quality of life scores did not reach statistical significance [40].…”

Section: Roflumilast: Pharmacokinetics Clinical Efficacy From Phase mentioning

confidence: 99%

“…The inclusion criteria were based on a post-hoc analysis of a previous study, suggesting a decrease in exacerbations by roflumilast in this COPD-phenotype [40]. Initially, 44% of the patients were using ICS or LAMA or both: these drugs have been discontinued for the duration of the study (1 year).…”

Section: Roflumilast: Pharmacokinetics Clinical Efficacy From Phase mentioning

confidence: 99%

“…In all 6-12 months randomized controlled trials, the most commonly roflumilast-related adverse events, reported by COPD-patients, included central adverse events (nausea, headache, insomnia), gastro-intestinal side effects (diarrhea) and (modest) weight loss [39][40][41][42]. Adverse events mostly became evident during the first 4-12 weeks and although usually subsiding with continued treatment, these events caused an increased patient withdrawal in the roflumilast-arms.…”

Section: Adverse Events During Long-term Pde4-inhibitionmentioning

confidence: 99%

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PDE4-inhibitors: A novel, targeted therapy for obstructive airways disease

Diamant

Spina

2011

Pulmonary Pharmacology & Therapeutics

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SummaryRoflumilast is a selective once daily, oral phosphodiesterase-4 inhibitor that has recently been registered in all European Union countries as novel targeted therapy for COPD, while FDA approval for the USA market is expected in 2011. In several phase III trials in patients with moderate to (very) severe COPD and in patients with symptoms of chronic bronchitis and recurrent exacerbations, roflumilast showed sustained clinical efficacy by improving lung function and by reducing exacerbation rates. These beneficial effects have also been demonstrated when added to long-acting bronchodilators (both LABA and LAMA), underscoring the anti-inflammatory activity of roflumilast in COPD. Pooled data analysis showed overall mild to moderate, mostly self-limiting adverse events, mainly consisting of nausea, diarrhea and weight loss. In this review we discuss the results of the 4 registration studies showing promising effects of roflumilast in COPD and provide an overview of the topics that still need to be addressed. keywords: PDE4-inhibitor, roflumilast, clinical trials, chronic obstructive airways disease 3

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Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease

Chong¹,

Poole²,

Leung³

et al. 2011

Cochrane Database of Systematic Reviews

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Effect of 1-Year Treatment with Roflumilast in Severe Chronic Obstructive Pulmonary Disease

Abstract: In severe, stable COPD, PDE4 inhibition with roflumilast produced a modest but significant improvement in lung function without changing the exacerbation rate or health status. However, patients with very severe disease experienced fewer exacerbations with roflumilast.

Cited by 294 publications

References 29 publications

Anti‐inflammatory effects of the novel inhaled phosphodiesterase type 4 inhibitor CHF6001 on virus‐inducible cytokines

Anti‐inflammatory effects of the novel inhaled phosphodiesterase type 4 inhibitor CHF6001 on virus‐inducible cytokines

PDE4-inhibitors: A novel, targeted therapy for obstructive airways disease

Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease

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