Search results for "Roflumilast"
showing 10 items of 22 documents
Selective Inhibition of Phosphodiesterases 4A, B, C and D Isoforms in Chronic Respiratory Diseases: Current and Future Evidences
2016
Chronic respiratory diseases affect millions of people every day. According to the World Health Organization estimates, ~235 million people suffer from asthma, ~64 million suffer from chronic obstructive pulmonary disease (COPD), and millions more suffer from allergic rhinitis around the world. In recent last years, the first phosphodiesterase 4 (PDE4) inhibitor, roflumilast, was approved as a treatment to reduce the risk of exacerbations in stable and severe COPD associated with chronic bronchitis and a history of exacerbations. PDE4 exists as four subtypes (A, B, C, and D) each with a capacity to degrade cAMP, a second messenger involved in inflammatory responses. PDE4 inhibitors inhibit …
The combination of PDE4 and PDE5 inhibitors reduces YAP expression in IPF
2017
Background: Pathological fibrosis is associated with repeated episodes of injury to alveolar epithelial cells of largely. Yes-associated protein (YAP) is prominently expressed in fibrotic lung. Roflumilast has demonstrated to exhibit anti-fibrosis effects, while PDE5 inhibitors (sildenafil) combinated with PDE4 inhibitors reduce fibrotic-effects secondary to TGFs1. Apparently, no studies of PDE4 and PDE5 inhibitors on YAP expression there are. Objectives: To study the effects from adding a sildenafil to Roflumilast N- oxide (RNO) on TGF-β/SMAD3/YAP pathway in IPF in vitro models. Methods: A549 cells were pre-incubated with therapeutical concentrations of RNO (2nM) and/or sildenafil (10nM) a…
Roflumilast N-oxide combined with PI3Kδ inhibitor improves the phenotype of early-onset COPD
2016
Background: Severe, early-onset COPD (Chronic Obstructive Pulmonary Disease) is characterized by a rapid decline in lung function at an early age with neutrophil over-activation. Roflumilast is approved as treatment for moderate and severe COPD at risk of exacerbation as add on therapy. Recent evidence indicates that the combination of PDE4 and PI3Kδ inhibitors show synergic anti-inflammatory properties. Objectives: To explore the effects from adding a selective PI3Kδ inhibitor to roflumilast N-oxide (RNO) in neutrophils isolated from peripheral blood of severe, early-onset COPD patients in in vitro models. Methods: Neutrophils were isolated from peripheral blood of 20 severe, early-onset C…
The phosphodiesterase 4 inhibitor roflumilast augments the Th17-promoting capability of dendritic cells by enhancing IL-23 production, and impairs th…
2016
Phosphodiesterase 4 (PDE4) inhibitors serve to prevent degradation of the intracellular second messenger cAMP, resulting in broad anti-inflammatory effects on different cell types including immune cells. Agents that elevate cAMP levels via activation of adenylate cyclase have been shown to imprint a Th17-promoting capacity in dendritic cells (DCs). Therefore, we studied the potential of therapeutically relevant PDE inhibitors to induce a pronounced Th17-skewing capacity in DCs. Here we show that mouse bone marrow-derived (BM-) DCs when treated with the PDE4 inhibitor roflumilast (ROF, trade name: Daxas) in the course of stimulation with LPS (ROF-DCs) evoked elevated IL-17 levels in cocultur…
PDE4 inhibitors as new anti-inflammatory drugs: effects on cell trafficking and cell adhesion molecules expression.
2004
Phosphodiesterase 4 (PDE4) is a major cyclic AMP-hydrolyzing enzyme in inflammatory and immunomodulatory cells. The wide range of inflammatory mechanisms under control by PDE4 points to this isoenzyme as an attractive target for new anti-inflammatory drugs. Selective inhibitors of PDE4 have demonstrated a broad spectrum of anti-inflammatory activities including the inhibition of cellular trafficking and microvascular leakage, cytokine and chemokine release from inflammatory cells, reactive oxygen species production, and cell adhesion molecule expression in a variety of in vitro and in vivo experimental models. The initially detected side effects, mainly nausea and emesis, appear at least pa…
Roflumilast N-oxide reverses corticosteroid resistance in neutrophils from patients with chronic obstructive pulmonary disease
2013
Background Glucocorticoid functions are markedly impaired in patients with chronic obstructive pulmonary disease (COPD). The phosphodiesterase 4 inhibitor roflumilast N-oxide (RNO) is the active metabolite of roflumilast approved as a treatment to reduce the risk of exacerbations in patients with severe COPD. Objective We sought to characterize the differential effects of RNO versus corticosteroids and their potential additive/synergistic effect in neutrophils from patients with COPD, thus providing scientific rationale for the combination of roflumilast with corticosteroids in the clinic. Methods Peripheral blood neutrophils were isolated from patients with COPD (n = 32), smokers (n = 7), …
Roflumilast improves corticosteroid resistance COPD bronchial epithelial cells stimulated with toll like receptor 3 agonist
2015
Chronic obstructive pulmonary disease (COPD) is characterised by chronic pulmonary inflammation punctuated by periods of viral exacerbations. Recent evidence suggests that the combination of roflumilast with corticosteroids may improve the compromised anti-inflammatory properties of corticosteroids in COPD. We analyzed differential and combination anti-inflammatory effects of dexamethasone and roflumilast N-oxide in human bronchial epithelial cells (HBECs) stimulated with viral toll like receptor (TLR) agonists. Lung tissue and HBECs were isolated from healthy (n = 15), smokers (n = 12) and smokers with COPD (15). TLR3 expression was measured in lung tissue and in HBECs. IL-8 secretion was …
Roflumilast Prevents the Metabolic Effects of Bleomycin-Induced Fibrosis in a Murine Model
2015
Fibrotic remodeling is a process common to chronic lung diseases such as chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, acute respiratory distress syndrome and asthma. Based on preclinical studies phosphodiesterase 4 (PDE4) inhibitors may exhibit beneficial anti-inflammatory and anti-remodeling properties for the treatment of these respiratory disorders. Effects of PDE4 inhibitors on changes in the lung metabolome in models of pulmonary fibrotic remodeling have not yet been explored. This work studies the effects of the PDE4 inhibitor roflumilast on changes in the lung metabolome in the common murine model of bleomycin-induced lung fibrosis by nuclear magnetic resonance (…
Roflumilast, a phosphodiesterase 4 inhibitor, alleviates bleomycin-induced lung injury
2009
Mandarin translation of abstract Background and purpose: The effects of a phosphodiesterase 4 (PDE4) inhibitor, roflumilast, on bleomycin-induced lung injury were explored in ‘preventive’ and ‘therapeutic’ protocols and compared with glucocorticoids. Experimental approach: Roflumilast (1 and 5 mg·kg−1·d−1, p.o.) or dexamethasone (2.5 mg·kg−1·d−1, p.o.) was given to C57Bl/6J mice from day 1 to 14 (preventive) or day 7 to 21 (therapeutic) after intratracheal bleomycin (3.75 U·kg−1). In Wistar rats, roflumilast (1 mg·kg−1·d−1, p.o.) was compared with methylprednisolone (10 mg·kg−1·d−1, p.o.) from day 1 to 21 (preventive) or from day 10 to 21 (therapeutic), following intratracheal instillatio…
The preclinical pharmacology of roflumilast--a selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease
2009
After more than two decades of research into phosphodiesterase 4 (PDE4) inhibitors, roflumilast (3-cyclopropylmethoxy-4-difluoromethoxy-N-[3,5-di-chloropyrid-4-yl]-benzamide) may become the first agent in this class to be approved for patient treatment worldwide. Within the PDE family of 11 known isoenzymes, roflumilast is selective for PDE4, showing balanced selectivity for subtypes A-D, and is of high subnanomolar potency. The active principle of roflumilast in man is its dichloropyridyl N-oxide metabolite, which has similar potency as a PDE4 inhibitor as the parent compound. The long half-life and high potency of this metabolite allows for once-daily, oral administration of a single, 500…