Inhibition of airway hyperresponsiveness and pulmonary inflammation by roflumilast and other PDE4 inhibitors

Wollin, Lutz; Bundschuh, Daniela S.; Wohlsen, Andrea; Marx, Degenhard; Beume, Rolf

doi:10.1016/j.pupt.2005.09.002

Cited by 48 publications

(41 citation statements)

References 21 publications

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“…The differential effects of rolipram versus roflumilast on different PDE4 isozymes [32] , differential potency/activity of rolipram vs. roflumilast in vivo [33,34] , pharmacokinetics and brain penetration [35][36][37] and/or the pharmacological/CNS effects of rolipram [38][39][40][41] may explain the difference in increased fecal percent water content for rolipram 1 roflumilast. Clearly, rolipram and roflumilast have different affinities for the rolipram highaffinity and low-affinity binding sites and different affinities for each of the PDE4A/B family isozymes [4,42] .…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies [13] also have demonstrated that several antidepressants do not affect increased fecal output in this model (i.e., suggesting that PDE4 antidepressant actions might not be responsible for the present efficacy). The anti-inflammatory effect of PDE4 inhibition using rolipram produced efficacy in experimental colitis and was superior to methylprednisolone in preventing late collagen deposition and PDE4 inhibitors are being developed as anti-inflammatory agents for use in treating several diseases [2,6,7,34,35,42] . The recent hypothesis that IBS also involves aspects of immune activation and inflammation [49,50] suggests that PDE4 inhibitors be explored further to target the irritable bowel at several levels, including altered motility, transit, secretion, and perhaps inflammation.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of Phosphodiesterase Type 4 Decreases Stress-Induced Defecation in Rats and Mice

et al. 2007

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Background/Aims: Phosphodiesterase type 4 (PDE4) has been previously shown to regulate colonic contractile activity in vitro. In this study, the effects of PDE4 inhibition were assessed in a model of stress-induced defecation previously demonstrated to be due to increased colonic transit/evacuation. Methods: Rats were individually placed in a mild restraint cage and placed into a 12°C environment (cold-restraint stress) for 60 min. Mice received restraint (only) stress at room temperature for 30 min. Loperamide (positive control compound) or two different PDE4 inhibitors (rolipram and roflumilast) were administered orally at several doses to the rodents 1 h before stress began. Vehicle alone was administered for comparison. The number of fecal pellets expelled during stress (fecal pellet output), total fecal pellet wet weight and total fecal water content were measured. Results: Loperamide produced a dose-related decrease (ID₅₀s in mg/kg) in fecal pellet output (rat = 7.4, mouse = 0.7) and significantly decreased fecal wet weight (72.9%) and decreased fecal percent water content (9.4%). The two PDE4 inhibitors produced a similar dose-related inhibition of fecal pellet output. Rolipram exhibited ID₅₀s in rat and mouse of 14.1 and 27.1, respectively. Rolipram significantly decreased fecal wet weight (58.8%) but increased fecal percent water content (15.0%). For roflumilast, ID₅₀s were 24.2 mg/kg and 12.4 in the rat and mouse, respectively. Although roflumilast also significantly (p < 0.05) decreased fecal wet weight (47.2%), it did not significantly increase fecal percent water content. Conclusions: These data indicate that PDE4 inhibition is effective in reducing rodent stress-induced defecation, provides the first functional data on a potential role for PDE4 activity in the colonic evacuation response to stress, and indicates the potential utility of PDE4 inhibitors in functional bowel disease such as irritable bowel syndrome requires further evaluation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibition of Phosphodiesterase Type 4 Decreases Stress-Induced Defecation in Rats and Mice

et al. 2007

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“…In animals, roflumilast does not protect against leukotriene D 4 -or 5-hydroxytryptamine-induced bronchoconstriction (47,48). Similarly, there is no evidence that PDE4 inhibitors evoke bronchodilation in patients with COPD (49).…”

Section: Pharmacodynamics Of Pde4 Inhibitorsmentioning

confidence: 98%

Treatment of Chronic Obstructive Pulmonary Disease with Roflumilast, a New Phosphodiesterase 4 Inhibitor

Gross

Giembycz

Rennard

2010

COPD: Journal of Chronic Obstructive Pulmonary Disease

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Recent advances in chronic obstructive pulmonary disease (COPD) treatment offer symptom relief, but disease modification remains an unmet goal of pharmacotherapy. Reducing the frequency and severity of COPD exacerbations may help slow disease progression and reduce the morbidity, mortality, and costs associated with these major events. Other desirable characteristics for a COPD treatment include a once-daily dosing schedule, an oral formulation, and a low frequency of systemic side effects. Phosphodiesterase 4 inhibitors have been in clinical development for some years and roflumilast is currently the most advanced of these agents. In this review, the preclinical evidence, clinical safety, and efficacy of roflumilast available in published reports are considered. The data reviewed here suggest that the clinical efficacy of roflumilast occurs through a mechanism unrelated to bronchodilation and may be due to the suppression of lung inflammation. Lung function improved with roflumilast treatment and in some studies, the reduction in exacerbations was substantial and statistically significant. Notably, this effect appeared to be greatest in the subgroup of patients with more severe disease and more severe exacerbations. The evaluation of roflumilast safety largely centers on gastrointestinal adverse events, with diarrhea, nausea, and weight loss occurring more frequently with the drug than placebo. If approved for general use, we expect roflumilast to find its role initially as a substitute for inhaled corticosteroids in the maintenance treatment of severe and very severe disease, particularly in patients who have frequent acute exacerbations, and perhaps as a supplementary drug when symptoms are not adequately controlled by current conventional COPD therapy.

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“…Subsequent phosphorylation and inactivation of target transcription factors ultimately results in attenuation of cellular inflammatory activity [11,12]. Accordingly, roflumilast inhibits the release of inflammatory cytokines and chemokines in human cells in vitro and in animal models of COPD and asthma in vivo [13][14][15][16]. In these animal models, roflumilast also reduces the pulmonary accumulation of neutrophils, eosinophils, monocytes, and macrophages after endotoxin or allergen challenge.…”

mentioning

confidence: 99%

Roflumilast attenuates pulmonary inflammation upon segmental endotoxin challenge in healthy subjects: A randomized placebo-controlled trial

Hohlfeld

Schoenfeld²,

Lavae-Mokhtari

et al. 2008

Pulmonary Pharmacology & Therapeutics

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Objectives: The aim of this study was to explore the anti-inflammatory properties of roflumilast in a human model of segmental bronchial endotoxin challenge. A c c e p t e d m a n u s c r i p tMethods: In a randomized, placebo-controlled, double-blind, single-center parallelgroup study, 37 healthy subjects of either sex were treated for 28 days with either oral roflumilast 500 µg once daily or placebo. At Day 29, a baseline bronchoalveolar lavage was performed, followed by segmental endotoxin challenge (4 ng/kg) and saline control challenge.After 24 h, bronchoalveolar lavage fluid was sampled from the challenged segments and cells were counted and differentiated.Results: After endotoxin challenge, influx of total cells (difference from baseline) in bronchoalveolar lavage of roflumilast treated subjects was 36% lower than with placebo (p=0.02). Correspondingly, the influx of neutrophils and eosinophils of roflumilast treated subjects was 39% (p=0.02) and 74% (p=0.01) lower than with placebo, respectively. In contrast, endotoxin-induced influx of monocytes was not different between roflumilast and placebo treated subjects. No significant differences existed between the groups pertaining to endotoxin-induced influx of macrophages and lymphocytes. Roflumilast was well tolerated.No unexpected or serious treatment-emergent signs and symptoms were observed.Conclusions: Roflumilast attenuated the endotoxin-induced influx of neutrophils and eosinophils into the airways. This study demonstrates the anti-inflammatory properties of roflumilast on bronchoalveolar granulocytes in endotoxin-induced airway inflammation in healthy subjects. (Word count: 240 words)

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Inhibition of airway hyperresponsiveness and pulmonary inflammation by roflumilast and other PDE4 inhibitors

Cited by 48 publications

References 21 publications

Inhibition of Phosphodiesterase Type 4 Decreases Stress-Induced Defecation in Rats and Mice

Inhibition of Phosphodiesterase Type 4 Decreases Stress-Induced Defecation in Rats and Mice

Treatment of Chronic Obstructive Pulmonary Disease with Roflumilast, a New Phosphodiesterase 4 Inhibitor

Roflumilast attenuates pulmonary inflammation upon segmental endotoxin challenge in healthy subjects: A randomized placebo-controlled trial

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