Roles of roflumilast, a selective phosphodiesterase 4 inhibitor, in airway diseases

Kawamatawong, Theerasuk

doi:10.21037/jtd.2017.03.116

Cited by 53 publications

(55 citation statements)

References 90 publications

(93 reference statements)

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“…Oral administration of roflumilast (trade name Daxas, Figure 3A ) was licensed for the treatment of severe COPD and asthma symptoms in the EU and USA in 2010 and 2011, respectively, which marked the first approved PDE4 inhibitor. Roflumilast has been investigated to be a potent anti-inflammatory drug in the regulation of airway inflammation (Cazzola et al, 2016 ; Kawamatawong, 2017 ). In vitro , roflumilast inhibited PDE4 activity (IC 50 = 0.8 nM) in human neutrophils with high selectivity and, therefore, showed excellent anti-inflammatory potential in fMLP-induced leukotriene B 4 (LTB 4 ) and reactive oxygen species (ROS) formation in human neutrophils, lipopolysaccharides (LPS)-induced tumor necrosis factor α (TNF-α) synthesis in monocytes, dentritic cells as well as cytokines production in anti-CD3/CD28-stimulated CD4 + T cells (Hatzelmann and Schudt, 2001 ; Bros et al, 2016 ).…”

Section: Approved Pde4 Inhibitors For the Treatment Of Inflammatory Dmentioning

confidence: 99%

Phosphodiesterase-4 Inhibitors for the Treatment of Inflammatory Diseases

2018

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Phosphodiesterase-4 (PDE4), mainly present in immune cells, epithelial cells, and brain cells, manifests as an intracellular non-receptor enzyme that modulates inflammation and epithelial integrity. Inhibition of PDE4 is predicted to have diverse effects via the elevation of the level of cyclic adenosine monophosphate (cAMP) and the subsequent regulation of a wide array of genes and proteins. It has been identified that PDE4 is a promising therapeutic target for the treatment of diverse pulmonary, dermatological, and severe neurological diseases. Over the past decades, numerous PDE4 inhibitors have been designed and synthesized, among which roflumilast, apremilast, and crisaborole were approved for the treatment of inflammatory airway diseases, psoriatic arthritis, and atopic dermatitis, respectively. It is regrettable that the dramatic efficacies of a drug are often accompanied by adverse effects, such as nausea, emesis, and gastrointestinal reactions. However, substantial advances have been made to mitigate the adverse effects and obtain better benefit-to-risk ratio. This review highlights the dialectical role of PDE4 in drug discovery and the disquisitive details of certain PDE4 inhibitors to provide an overview of the topics that still need to be addressed in the future.

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Section: Approved Pde4 Inhibitors For the Treatment Of Inflammatory Dmentioning

confidence: 99%

Phosphodiesterase-4 Inhibitors for the Treatment of Inflammatory Diseases

2018

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“…PDE4, which is implicated in the pathogenesis of inflammatory lung conditions, can be further divided into four subtypes (A–D), and blockade of PDE4B is associated with reduced neutrophil chemotaxis, decreased release of pro‐inflammatory mediators and induction of neutrophil apoptosis . In addition, it reduces IgE‐mediated mast cell degranulation and enhances β2 agonist‐induced bronchodilation . Roflumilast, (tradename Daxas, AstraZeneca (Cambridge, UK)), a potent and selective PDE4 inhibitor, is the most extensively investigated of a number of therapeutic PDE4 antagonists, and is approved for use in severe COPD with recurrent exacerbations despite maximal inhaled therapy .…”

Section: Targeting Neutrophilic Inflammationmentioning

confidence: 99%

“…Phosphodiesterase (PDE) enzymes, of which 11 subtypes are expressed in mammalian tissues, are responsible for the rapid intracellular degradation of the second messenger cyclic adenosine monophosphate (cAMP). 70 PDE4, which is implicated in the pathogenesis of inflammatory lung conditions, can be further divided into four subtypes (A-D), and blockade of PDE4B is associated with reduced neutrophil chemotaxis, decreased release of pro-inflammatory mediators and induction of neutrophil apoptosis. 71 In addition, it reduces IgE-mediated mast cell degranulation and enhances β2 agonist-induced bronchodilation.…”

Section: Pde4 Inhibitorsmentioning

confidence: 99%

“…71 In addition, it reduces IgE-mediated mast cell degranulation and enhances β2 agonist-induced bronchodilation. 70 Roflumilast, (tradename Daxas, AstraZeneca (Cambridge, UK)), a potent and selective PDE4 inhibitor, is the most extensively investigated of a number of therapeutic PDE4 antagonists, and is approved for use in severe COPD with recurrent exacerbations despite maximal inhaled therapy. 72 Roflumilast has been shown to significantly improve lung function and reduce the severity of exacerbations in patients with severe COPD.…”

Section: Pde4 Inhibitorsmentioning

confidence: 99%

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Emerging therapies in adult and paediatric bronchiectasis

Regan

Hill

2018

Respirology

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Bronchiectasis is a chronic respiratory disorder characterized by persistent productive cough and recurrent chest infections secondary to permanent structural airway damage. The current treatment strategies for this debilitating disorder are limited to prompt antibiotic treatment of infective exacerbations and regular airway clearance techniques. Despite its high morbidity and associated mortality across all age groups, it has been a neglected area of research in respiratory medicine and there remain no licensed disease‐modifying therapies. In this review, we have explored the numerous potential therapeutic targets to break the vicious cycle of infection and inflammation seen in these patients and the novel therapeutic agents that have been developed to target them. We have reviewed the role of novel anti‐inflammatory agents designed to target the persistent neutrophilic inflammatory infiltrate seen in bronchiectatic airways, including neutrophil elastase inhibitors, CXCR2 (CXC chemokine receptor 2) antagonists, DPP‐1 (dipeptidyl peptidase 1) inhibitors, PDE4 (phosphodiesterase 4) inhibitors and statins. Furthermore, we have explored novel targets to improve mucociliary clearance, namely ENaC (epithelial sodium channel) inhibitors, and discussed the potential of alternative antimicrobial strategies such as inhaled phages. Our review highlights the importance of a multi‐faceted approach to bronchiectasis management, which aims not only to eradicate or suppress bronchial infection but also to break the cycle of persistent airway inflammation that results in progressive lung damage in these patients.

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“…Selective PDE4 inhibitors can play a therapeutic role in various inflammatory diseases as asthma, psoriasis, inflammatory bowel disease etc. 23,24 Cyclic AMP promotes the release of the anti-inflammatory mediators (eg IL-10) by immune cells. A decrease in PDE 4 increases a cAMP level which leads to increased transcription of genes that have CRE sites, including the gene for IL-10.…”

Section: The Cyclic Amp-dependent Protein Kinase (Pka)mentioning

confidence: 99%