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| roflumilast |
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| CHEBI:47657 |
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| A benzamide obtained by formal condensation of the carboxy group of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid with the amino group of 3,5-dichloropyridin-4-amine. Used for treatment of bronchial asthma and chronic obstructive pulmonary disease. |
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This entity has been manually annotated by the ChEBI Team.
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| ChemicalBook:CB7875719 |
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more structures >>
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0 24 25 4 0 0 0 0 24 40 1 0 0 0 0 25 26 1 0 0 0 0 M END): 21 ms reading 40 atoms ModelSet: haveSymmetry:false haveUnitcells:false haveFractionalCoord:false 1 model in this collection. 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| Roflumilast, sold under the brand name Daxas among others, is a medication used for the treatment of chronic obstructive pulmonary disease, plaque psoriasis, seborrheic dermatitis, and atopic dermatitis. It acts as a selective, long-acting inhibitor of the enzyme phosphodiesterase-4 (PDE-4). It has anti-inflammatory effects.
It was approved for medical use in the European Union in 2010, in the United States in 2011, and in Canada in 2017. It is available as a generic medication. |
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Read full article at Wikipedia
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InChI=1S/C17H14Cl2F2N2O3/c18- 11-6-22-7-12(19)15(11)23-16(24)10-3-4-13(26-17(20)21)14(5-10)25-8-9-1-2-9/h3-7,9,17H,1-2,8H2,(H,22,23,24) |
| MNDBXUUTURYVHR-UHFFFAOYSA-N |
| FC(F)Oc1ccc(cc1OCC1CC1)C(=O)Nc1c(Cl)cncc1Cl |
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phosphodiesterase IV inhibitor
An EC 3.1.4.53 (3',5'-cyclic-AMP phosphodiesterase) inhibitor that specifically blocks the action of phosphodiesterase IV.
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anti-asthmatic drug
A drug used to treat asthma.
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View more via ChEBI Ontology
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3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide
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roflumilast
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WHO MedNet
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roflumilast
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WHO MedNet
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roflumilast
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KEGG DRUG
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roflumilastum
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WHO MedNet
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162401-32-3
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CAS Registry Number
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ChemIDplus
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162401-32-3
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CAS Registry Number
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KEGG DRUG
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9802592
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Reaxys Registry Number
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Reaxys
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Blasco LM (2013)
If roflumilast inhibits the innate immunity in the stable patient, what about infection?
The clinical respiratory journal 7, e11-2 [PubMed:22364166] | Buenestado A, Grassin-Delyle S, Guitard F, Naline E, Faisy C, Israël-Biet D, Sage E, Bellamy JF, Tenor H, Devillier P (2012)
Roflumilast inhibits the release of chemokines and TNF-α from human lung macrophages stimulated with lipopolysaccharide.
British journal of pharmacology 165, 1877-1890 [PubMed:21913898]
[show Abstract]
Background and purposeLung macrophages are critically involved in respiratory diseases. This study assessed the effects of the PDE4 inhibitor roflumilast and its active metabolite, roflumilast N-oxide on the release of a range of chemokines (CCL2, 3, 4, CXCL1, 8, 10) and of TNF-α, from human lung macrophages, stimulated with bacterial lipopolysaccharide LPS.Experimental approachLung macrophages isolated from resected human lungs were incubated with roflumilast, roflumilast N-oxide, PGE(2), the COX inhibitor indomethacin, the COX-2 inhibitor NS-398 or vehicle and stimulated with LPS (24 h). Chemokines, TNF-α, PGE(2) and 6-keto PGF(1α) were measured in culture supernatants by immunoassay. COX-2 mRNA expression was assessed with RT-qPCR. PDE activities were determined in macrophage homogenates.Key resultsExpression of PDE4 in lung macrophages was increased after incubation with LPS. Roflumilast and roflumilast N-oxide concentration-dependently reduced the LPS-stimulated release of CCL2, CCL3, CCL4, CXCL10 and TNF-α from human lung macrophages, whereas that of CXCL1 or CXCL8 was not altered. This reduction by the PDE4 inhibitors was further accentuated by exogenous PGE(2) (10 nM) but abolished in the presence of indomethacin or NS-398. Conversely, addition of PGE(2) (10 nM), in the presence of indomethacin restored inhibition by roflumilast. LPS also increased PGE(2) and 6-keto PGF(1α) release from lung macrophages which was associated with an up-regulation of COX-2 mRNA.Conclusions and implicationsRoflumilast and roflumilast N-oxide reduced LPS-induced release of CCL2, 3, 4, CXCL10 and TNF-α in human lung macrophages. | Milara J, Armengot M, Bañuls P, Tenor H, Beume R, Artigues E, Cortijo J (2012)
Roflumilast N-oxide, a PDE4 inhibitor, improves cilia motility and ciliated human bronchial epithelial cells compromised by cigarette smoke in vitro.
British journal of pharmacology 166, 2243-2262 [PubMed:22385203]
[show Abstract]
Background and purposeMucociliary malfunction occurs in chronic obstructive pulmonary disease (COPD) and compromised functions of ciliated bronchial epithelial cells may contribute to this. Cigarette smoke, a major risk factor for COPD, impairs ciliary beat frequency (CBF). cAMP augments CBF. This in vitro study addressed, in differentiated, primary human bronchial epithelial cells, whether roflumilast N-oxide, a PDE4 inhibitor, (i) augments CBF; (ii) prevents the reduction in CBF induced by cigarette smoke extract (CSE); and (iii) protects against the loss of the ciliated phenotype following long-term CSE exposure.Experimental approachAir-liquid interface cultured human bronchial epithelial cells were incubated with roflumilast N-oxide and exposed to CSE. CBF was assessed by digital high speed video microscopy (DHSV). Ciliated cells were characterized by β-tubulin IV staining and analyses of Foxj1 and Dnai2 mRNA and protein (real-time quantitative PCR, Western blotting).Key resultsRoflumilast N-oxide concentration-dependently triggered a rapid and persistent increase in CBF and reversed the decrease in CBF following CSE. Long-term incubation of bronchial epithelial cells with CSE resulted in a loss in ciliated cells associated with reduced expression of the ciliated cell markers Foxj1 and Dnai2. The PDE4 inhibitor prevented this loss in the ciliated cell phenotype and the compromised Foxj1 and Dnai2 expression. The enhanced release of IL-13 following CSE, a cytokine that diminishes the proportion of ciliated cells and in parallel, reduces Foxj1 and Dnai2, was reversed by roflumilast N-oxide.Conclusion and implicationsRoflumilast N-oxide protected differentiated human bronchial epithelial cells from reduced CBF and loss of ciliated cells following CSE. | Pinner NA, Hamilton LA, Hughes A (2012)
Roflumilast: a phosphodiesterase-4 inhibitor for the treatment of severe chronic obstructive pulmonary disease.
Clinical therapeutics 34, 56-66 [PubMed:22284994]
[show Abstract]
BackgroundRoflumilast 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.ObjectiveThe objective of this article is to review the pharmacology, clinical efficacy, and tolerability of roflumilast in the treatment of COPD.MethodsArticles 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 (FEV(1)) 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.ResultsA 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 FEV(1) 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.ConclusionRoflumilast significantly improved FEV(1) 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. | Greulich T, Koczulla AR, Vogelmeier C (2012)
[Chronic obstructive pulmonary disease : new pharmacotherapeutic options].
Der Internist 53, 1364-70, 1373-5 [PubMed:22955248]
[show Abstract]
Data about the clinical presentation of chronic obstructive pulmonary disease (COPD) have resulted in a new classification of the disease. The degree of airflow limitation has been amended by symptoms and exacerbation rate. The standard pharmacotherapy of stable COPD is in transition, as fixed combinations of long acting beta agonists and long acting anticholinergics are in the late stages of clinical development. On this background inhaled corticosteroids will need to be re-evaluated. Roflumilast is a recently approved therapeutic option that primarily diminishes exacerbation frequency in patients with chronic bronchitis and severe airflow obstruction (FEV(1) < 50%). In COPD patients with acute exacerbations procalcitonin levels can be used to guide antibiotic therapy. Comparable clinical outcomes can be achieved while using significantly less amounts of antibiotics. | Vollert S, Kaessner N, Heuser A, Hanauer G, Dieckmann A, Knaack D, Kley HP, Beume R, Weiss-Haljiti C (2012)
The glucose-lowering effects of the PDE4 inhibitors roflumilast and roflumilast-N-oxide in db/db mice.
Diabetologia 55, 2779-2788 [PubMed:22790061]
[show Abstract]
Aims/hypothesisThe cAMP-degrading phosphodiesterase 4 (PDE4) enzyme has recently been implicated in the regulation of glucagon-like peptide-1 (GLP-1), an incretin hormone with glucose-lowering properties. We investigated whether the PDE4 inhibitor roflumilast elevates GLP-1 levels in diabetic db/db mice and whether this elevation is accompanied by glucose-lowering effects.MethodsPlasma GLP-1 was determined in db/db mice after single oral administration of roflumilast or its active metabolite roflumilast-N-oxide. Diabetes-relevant variables including HbA(1c), blood glucose, serum insulin, body weight, food and water intake, and pancreas morphology were determined in db/db mice treated daily for 28 days with roflumilast or roflumilast-N-oxide. Pharmacokinetic/pharmacodynamic analysis clarified the contribution of roflumilast vs its metabolite. In addition, the effect of roflumilast-N-oxide on insulin release was investigated in primary mouse islets.ResultsSingle treatment of db/db mice with 10 mg/kg roflumilast or roflumilast-N-oxide enhanced plasma GLP-1 2.5- and fourfold, respectively. Chronic treatment of db/db mice with roflumilast or roflumilast-N-oxide at 3 mg/kg showed prevention of disease progression. Roflumilast-N-oxide abolished the increase in blood glucose, reduced the increment in HbA(1c) by 50% and doubled fasted serum insulin compared with vehicle, concomitant with preservation of pancreatic islet morphology. Furthermore, roflumilast-N-oxide amplified forskolin-induced insulin release in primary islets. Roflumilast-N-oxide showed stronger glucose-lowering effects than its parent compound, consistent with its greater effect on GLP-1 secretion and explainable by pharmacokinetic/pharmacodynamic modelling.Conclusions/interpretationOur results suggest that roflumilast and roflumilast-N-oxide delay the progression of diabetes in db/db mice through protection of pancreatic islet physiology potentially involving GLP-1 and insulin activities. | Kubo S, Kobayashi M, Iwata M, Miyata K, Takahashi K, Shimizu Y (2012)
Anti-neutrophilic inflammatory activity of ASP3258, a novel phosphodiesterase type 4 inhibitor.
International immunopharmacology 12, 59-63 [PubMed:22041526]
[show Abstract]
Neutrophil-dominant pulmonary inflammation is an important feature of chronic obstructive pulmonary disease (COPD). Here, we evaluated the in vitro and in vivo anti-neutrophilic inflammatory activities of ASP3258, a novel, orally active, and selective phosphodiesterase (PDE) 4 inhibitor with anti-inflammatory potency comparable to that of second-generation compound roflumilast but with lower emetic activity in vivo. In in vitro experiments using human peripheral blood neutrophils, PDE4 inhibitors ASP3258, cilomilast, and roflumilast inhibited fMLP-induced superoxide production in a concentration-dependent manner with IC50 values of 5.0, 96, and 4.7 nM, respectively. ASP3258, cilomilast, and roflumilast also attenuated fMLP-induced neutrophil chemotaxis in a concentration-dependent manner with IC30 values of 18, 270, and 9.7 nM, respectively. In contrast, the glucocorticoid prednisolone inhibited neither superoxide production nor chemotaxis up to 1 μM. In a rat model of lipopolysaccharide (LPS)-induced lung inflammation, orally administered ASP3258, cilomilast, roflumilast, and prednisolone (at 10 or 30 mg/kg) dose-dependently attenuated pulmonary accumulation of neutrophils. The inhibitory effect of ASP3258 was more potent than cilomilast and almost the same as roflumilast and prednisolone. Treatment with ASP3258 inhibited the elevation of TNF-α in the bronchoalveolar lavage fluid following LPS instillation. Histological examination revealed significant inhibition of neutrophil and macrophage infiltration into alveoli by ASP3258. Overall, these findings suggest that ASP3258 has therapeutic potential for treating neutrophilic inflammation such as COPD, partly through direct inhibition of neutrophil activation as well as possibly through inhibition of the TNF-α-mediated pathway. | Hertel N, Kotchie RW, Samyshkin Y, Radford M, Humphreys S, Jameson K (2012)
Cost-effectiveness of available treatment options for patients suffering from severe COPD in the UK: a fully incremental analysis.
International journal of chronic obstructive pulmonary disease 7, 183-199 [PubMed:22500119]
[show Abstract]
PurposeFrequent exacerbations which are both costly and potentially life-threatening are a major concern to patients with chronic obstructive pulmonary disease (COPD), despite the availability of several treatment options. This study aimed to assess the lifetime costs and outcomes associated with alternative treatment regimens for patients with severe COPD in the UK setting.Patients and methodsA Markov cohort model was developed to predict lifetime costs, outcomes, and cost-effectiveness of various combinations of a long-acting muscarinic antagonist (LAMA), a long-acting beta agonist (LABA), an inhaled corticosteroid (ICS), and roflumilast in a fully incremental analysis. Patients willing and able to take ICS, and those refusing or intolerant to ICS were analyzed separately. Efficacy was expressed as relative rate ratios of COPD exacerbation associated with alternative treatment regimens, taken from a mixed treatment comparison. The analysis was conducted from the UK National Health Service (NHS) perspective. Parameter uncertainty was explored using one-way and probabilistic sensitivity analysis.ResultsBased on the results of the fully incremental analysis a cost-effectiveness frontier was determined, indicating those treatment regimens which represent the most cost-effective use of NHS resources. For ICS-tolerant patients the cost-effectiveness frontier suggested LAMA as initial treatment. Where patients continue to exacerbate and additional therapy is required, LAMA + LABA/ICS can be a cost-effective option, followed by LAMA + LABA/ICS + roflumilast (incremental cost-effectiveness ratio [ICER] versus LAMA + LABA/ICS: £16,566 per quality-adjusted life-year [QALY] gained). The ICER in ICS-intolerant patients, comparing LAMA + LABA + roflumilast versus LAMA + LABA, was £13,764/QALY gained. The relative rate ratio of exacerbations was identified as the primary driver of cost-effectiveness.ConclusionThe treatment algorithm recommended in UK clinical practice represents a cost-effective approach for the management of COPD. The addition of roflumilast to the standard of care regimens is a clinical and cost-effective treatment option for patients with severe COPD, who continue to exacerbate despite existing bronchodilator therapy. | Calverley PM, Martinez FJ, Fabbri LM, Goehring UM, Rabe KF (2012)
Does roflumilast decrease exacerbations in severe COPD patients not controlled by inhaled combination therapy? The REACT study protocol.
International journal of chronic obstructive pulmonary disease 7, 375-382 [PubMed:22791991]
[show Abstract]
BackgroundMany patients with chronic obstructive pulmonary disease (COPD) continue to suffer exacerbations, even when treated with maximum recommended therapy (eg, inhaled combinations of long-acting β2-agonist and high dose inhaled corticosteroids, with or without a long-acting anticholinergic [long-acting muscarinic antagonist]). Roflumilast is approved to treat severe COPD in patients with chronic bronchitis--and a history of frequent exacerbations--as an add-on to bronchodilators.PurposeThe REACT (Roflumilast in the Prevention of COPD Exacerbations While Taking Appropriate Combination Treatment) study (identification number RO-2455-404-RD, clinicaltrials. gov identifier NCT01329029) will investigate whether roflumilast further reduces exacerbations when added to inhaled combination therapy in patients still suffering from frequent exacerbations.Patients and methodsREACT is a 1-year randomized, double-blind, multicenter, phase III/IV study of roflumilast 500 μg once daily or placebo on top of a fixed long-acting β2-agonist/inhaled corticosteroid combination. A concomitant long-acting muscarinic antagonist will be allowed at stable doses. The primary outcome is the rate of moderate or severe COPD exacerbations. Using a Poisson regression model with a two-sided significance level of 5%, a sample size of 967 patients per treatment group is needed for 90% power. COPD patients with severe to very severe airflow limitation, symptoms of chronic bronchitis, and at least two exacerbations in the previous year will be recruited.ConclusionIt is hypothesized that because roflumilast (a phosphodiesterase-4 inhibitor) has a different mode of action to bronchodilators and inhaled corticosteroids, it may provide additional benefits when added to these treatments in frequent exacerbators. REACT will be important to determine the role of roflumilast in COPD management. Here, the design and rationale for this important study is described. | Knebel NG, Herzog R, Reutter F, Zech K (2012)
Sensitive quantification of roflumilast and roflumilast N-oxide in human plasma by LC-MS/MS employing parallel chromatography and electrospray ionisation.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 893-894, 82-91 [PubMed:22425388]
[show Abstract]
A high throughput bioanalytical method based on semi-automated liquid extraction and liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been developed for the sensitive quantification of roflumilast and its metabolite roflumilast N-oxide, a phosphodiesterase (PDE) inhibitor in human plasma and serum. The sample work-up procedure comprised liquid extraction using penta-deuterated analogues of both analytes as internal standards. Chromatography was performed on C18 revered phase analytical columns at a flow rate of 0.5 mL/min in the dual column mode employing a column switching technique and a linear gradient from 18% to 54% acetonitrile in 0.005 M aqueous ammonium acetate containing 0.006% formic acid. Mass spectrometry was performed on an API 4000 instrument in the positive ion SRM-mode (selected reaction monitoring) with the Turbo-V ionspray interface. The method showed linear detector responses over the entire calibration range between 0.1 ng/mL (lower limit of quantification (LLOQ)) and 50 ng/mL (upper limit of quantification (ULOQ)) for both analytes. Linear regression analysis with concentration-squared weighting (1/x(2) for roflumilast and 1/x for roflumilast N-oxide) yielded inaccuracy and precision values <15% and coefficients of correlation (r) for the calibration curves >0.99 for both analytes. | Zhong Y, Wu Y, Liu R, Deng Y, Mallipattu SK, Klotman PE, Chuang PY, He JC (2012)
Roflumilast enhances the renal protective effects of retinoids in an HIV-1 transgenic mouse model of rapidly progressive renal failure.
Kidney international 81, 856-864 [PubMed:22258322]
[show Abstract]
Retinoic acid decreases proteinuria and glomerulosclerosis in several animal models of kidney disease by protecting podocytes from injury. Our recent in vitro studies suggest that all-trans retinoic acid induces podocyte differentiation by activating the retinoic acid receptor-α (RARα)/cAMP/PKA/CREB pathway. When used in combination with all-trans retinoic acid, an inhibitor of phosphodiesterase 4 further enhanced podocyte differentiation by increasing intracellular cAMP. Additionally, we found that Am580, a specific RARα agonist, has similar renal protective effects as all-trans retinoic acid in a rederived colony of HIV-1 transgenic mice with rapidly progressive renal failure (HIV-Tg) that mimics human HIV-associated nephropathy. Treatment with either the inhibitor of phosphodiesterase 4, roflumilast, or Am580 significantly reduced proteinuria, attenuated kidney injury, and improved podocyte differentiation in these HIV-Tg mice. Additional renal protective effects were found when roflumilast was combined with Am580. Consistent with the in vitro data, glomeruli from HIV-Tg mice treated with both Am580 and roflumilast had more active phosphorylated CREB than with either agent alone. Thus, phosphodiesterase 4 inhibitors could be used in combination with RARα agonists to provide additional renal protection. | Baye J (2012)
Roflumilast (daliresp): a novel phosphodiesterase-4 inhibitor for the treatment of severe chronic obstructive pulmonary disease.
P & T : a peer-reviewed journal for formulary management 37, 149-161 [PubMed:22605906] | Seehase S, Lauenstein HD, Schlumbohm C, Switalla S, Neuhaus V, Förster C, Fieguth HG, Pfennig O, Fuchs E, Kaup FJ, Bleyer M, Hohlfeld JM, Braun A, Sewald K, Knauf S (2012)
LPS-induced lung inflammation in marmoset monkeys - an acute model for anti-inflammatory drug testing.
PloS one 7, e43709 [PubMed:22952743]
[show Abstract]
Increasing incidence and substantial morbidity and mortality of respiratory diseases requires the development of new human-specific anti-inflammatory and disease-modifying therapeutics. Therefore, new predictive animal models that closely reflect human lung pathology are needed. In the current study, a tiered acute lipopolysaccharide (LPS)-induced inflammation model was established in marmoset monkeys (Callithrix jacchus) to reflect crucial features of inflammatory lung diseases. Firstly, in an ex vivo approach marmoset and, for the purposes of comparison, human precision-cut lung slices (PCLS) were stimulated with LPS in the presence or absence of the phosphodiesterase-4 (PDE4) inhibitor roflumilast. Pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF-α) and macrophage inflammatory protein-1 beta (MIP-1β) were measured. The corticosteroid dexamethasone was used as treatment control. Secondly, in an in vivo approach marmosets were pre-treated with roflumilast or dexamethasone and unilaterally challenged with LPS. Ipsilateral bronchoalveolar lavage (BAL) was conducted 18 hours after LPS challenge. BAL fluid was processed and analyzed for neutrophils, TNF-α, and MIP-1β. TNF-α release in marmoset PCLS correlated significantly with human PCLS. Roflumilast treatment significantly reduced TNF-α secretion ex vivo in both species, with comparable half maximal inhibitory concentration (IC(50)). LPS instillation into marmoset lungs caused a profound inflammation as shown by neutrophilic influx and increased TNF-α and MIP-1β levels in BAL fluid. This inflammatory response was significantly suppressed by roflumilast and dexamethasone. The close similarity of marmoset and human lungs regarding LPS-induced inflammation and the significant anti-inflammatory effect of approved pharmaceuticals assess the suitability of marmoset monkeys to serve as a promising model for studying anti-inflammatory drugs. | Tannheimer SL, Sorensen EA, Haran AC, Mansfield CN, Wright CD, Salmon M (2012)
Additive anti-inflammatory effects of beta 2 adrenoceptor agonists or glucocorticosteroid with roflumilast in human peripheral blood mononuclear cells.
Pulmonary pharmacology & therapeutics 25, 178-184 [PubMed:22306235]
[show Abstract]
The phosphodiesterase 4 inhibitor (PDE4i) roflumilast has been approved in the US and EU for treatment of GOLD stage 3 and 4 chronic obstructive pulmonary disease (COPD). Inhaled β2 adrenoceptor agonist bronchodilators and anti-inflammatory glucocorticosteroids are also used as standard of care in COPD. We investigated the anti-inflammatory interaction of roflumilast in combination with long-acting β2 agonists (LABA), salmeterol or formoterol, or a glucocorticosteroid, dexamethasone, on cytokine production from LPS-stimulated human primary peripheral blood mononuclear cells (PBMC). Salmeterol or formoterol caused a concentration-dependent inhibition of tumor necrosis factor-α (TNFα) secretion with an IC50 of 0.33 pM (C.I. 0.006-19) and 34 pM (C.I. 13-87), respectively. When roflumilast was evaluated, the addition of salmeterol (1 nM) to roflumilast caused the IC50 for roflumilast to shift from 1.8 nM (C.I. 0.8-4) to 4.1 pM (C.I.0.3-69) (p < 0.01), and maximal inhibition increased from 72.5 ± 3.2% to 90.9 ± 3.1%. Addition of formoterol to roflumilast also produced an increased TNFα inhibition more than either drug alone (p < 0.05). The inhibition of TNFα production with salmeterol was both β2 adrenoceptor- and protein kinase A-dependent. Addition of roflumilast (10 nM) in the presence of dexamethasone increased the inhibition of LPS-induced TNFα and CCL3. Roflumilast in combination with salmeterol, formoterol, or dexamethasone increased the inhibition of LPS-induced TNFα from human PBMC, in an additive manner. Addition of roflumilast to either a β2 adrenoceptor agonist or a glucocorticosteroid may provide superior anti-inflammatory activity and greater efficacy in COPD patients and be dose sparing. | Tannheimer SL, Wright CD, Salmon M (2012)
Combination of roflumilast with a beta-2 adrenergic receptor agonist inhibits proinflammatory and profibrotic mediator release from human lung fibroblasts.
Respiratory research 13, 28 [PubMed:22452977]
[show Abstract]
BackgroundSmall airway narrowing is an important pathology which impacts lung function in chronic obstructive pulmonary disease (COPD). The accumulation of fibroblasts and myofibroblasts contribute to inflammation, remodeling and fibrosis by production and release of mediators such as cytokines, profibrotic factors and extracellular matrix proteins. This study investigated the effects of the phosphodiesterase 4 inhibitor roflumilast, combined with the long acting β2 adrenergic agonist indacaterol, both approved therapeutics for COPD, on fibroblast functions that contribute to inflammation and airway fibrosis.MethodsThe effects of roflumilast and indacaterol treatment were characterized on transforming growth factor β1 (TGFβ1)-treated normal human lung fibroblasts (NHLF). NHLF were evaluated for expression of the profibrotic mediators endothelin-1 (ET-1) and connective tissue growth factor (CTGF), expression of the myofibroblast marker alpha smooth muscle actin, and fibronectin (FN) secretion. Tumor necrosis factor-α (TNF-α) was used to induce secretion of chemokine C-X-C motif ligand 10 (CXCL10), chemokine C-C motif ligand 5 (CCL5) and granulocyte macrophage colony-stimulating factor (GM-CSF) from NHLF and drug inhibition was assessed.ResultsEvaluation of roflumilast (1-10 μM) showed no significant inhibition alone on TGFβ1-induced ET-1 and CTGF mRNA transcripts, ET-1 and FN protein production, alpha smooth muscle expression, or TNF-α-induced secretion of CXCL10, CCL5 and GM-CSF. A concentration-dependent inhibition of ET-1 and CTGF was shown with indacaterol treatment, and a submaximal concentration was chosen for combination studies. When indacaterol (0.1 nM) was added to roflumilast, significant inhibition was seen on all inflammatory and fibrotic mediators evaluated, which was superior to the inhibition seen with either drug alone. Roflumilast plus indacaterol combination treatment resulted in significantly elevated phosphorylation of the transcription factor cAMP response element-binding protein (CREB), an effect that was protein kinase A-dependent. Inhibition of protein kinase A was also found to reverse the inhibition of indacaterol and roflumilast on CTGF.ConclusionsThese results demonstrate that addition of roflumilast to a LABA inhibits primary fibroblast/myofibroblast function and therapeutically this may impact lung fibroblast proinflammatory and profibrotic mediator release which contributes to small airway remodeling and airway obstruction in COPD. | Taegtmeyer AB, Leuppi JD, Kullak-Ublick GA (2012)
Roflumilast--a phosphodiesterase-4 inhibitor licensed for add-on therapy in severe COPD.
Swiss medical weekly 142, w13628 [PubMed:22833385]
[show Abstract]
Roflumilast is a selective phosphodiesterase 4 inhibitor which has been licensed in the European Union since 2010 and in Switzerland since November 2011 as an add-on treatment for patients with chronic obstructive pulmonary disease (COPD) in GOLD (Global Initiative for Chronic Obstructive Lung Disease) stages 3 and 4 (FEV(1) <50% predicted after bronchodilatation) and frequent exacerbations despite correctly-dosed therapy with a long-acting bronchodilator. Roflumilast is designed to target both the systemic and pulmonary inflammation associated with COPD. In this review roflumilast's chemistry, pharmacodynamics, pharmacokinetics, clinical efficacy, safety and tolerability and the current ongoing clinical trials involving roflumilast are outlined. Information has been sourced from the Swiss and US product information monographs, peer-reviewed published literature (identified from a PubMed MEDLINE search 1966 - March 2012 using the term "roflumilast"), the COPD GOLD international guidelines for the management of COPD (Revised 2011) and an independent analysis of phase 3 clinical trial data by FDA staff physicians. Clinical efficacy in terms of a modest gain in FEV(1)% and a reduction in exacerbation rate has been demonstrated in phase 3 clinical trials and roflumilast has been recently incorporated into international treatment guidelines. However data examining roflumilast as add-on therapy to long-acting bronchodilators and ICS (standard therapy) is currently awaited and phase 4 post-marketing studies are required to determine the incidence and severity of adverse events and the long-term beneficial effects of roflumilast as a maintenance therapy for COPD in every-day clinical practice. | Shmelev EI, Shmeleva NM (2012)
[Current anti-inflammatory therapy in patients with chronic obstructive pulmonary disease].
Terapevticheskii arkhiv 84, 73-76 [PubMed:22997924]
[show Abstract]
The lecture analyses current tools of anti-inflammatory treatment of patients with chronic obstructive pulmonary disease (COPD). Anti-inflammatory treatment is aimed at a key element of COPD pathogenesis. The results of treatment with main anti-inflammatory drugs and methods in COPD management are reviewed as well as efficacy of a new anti-inflammatory drug roflumilast in COPD patients. | Reid DJ, Pham NT (2012)
Roflumilast: a novel treatment for chronic obstructive pulmonary disease.
The Annals of pharmacotherapy 46, 521-529 [PubMed:22433610]
[show Abstract]
ObjectiveTo evaluate the efficacy and safety of roflumilast, approved by the Food and Drug Administration in February 2011 as a treatment to reduce the risk of chronic obstructive pulmonary disease (COPD) exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations.Data sourcesLiterature was retrieved through MEDLINE (1977-December 2011), using the terms roflumilast and COPD. In addition, US government Web sites, including clinicaltrials.gov and fda.gov, were reviewed for pertinent information. Lastly, reference citations from publications identified were reviewed.Study selection and data extractionAll articles published in English identified from the data sources were evaluated. For the evaluation of clinical efficacy and safety, only Phase 3 studies were included.Data synthesisLimited treatment options are available for patients with moderate-to-severe COPD and repeated exacerbations. In 6 published Phase 3 trials to date, roflumilast 500 μg daily exhibited modest improvements in lung function, measured by pre- and postbronchodilator forced expiratory volume in 1 second, and reduced rates of moderate and severe exacerbations. Roflumilast was generally well tolerated, with diarrhea, nausea, and headache the most common adverse events seen in clinical trials, although it has also been associated with an increased risk of neuropsychiatric abnormalities and dose-limiting weight loss. The greatest benefit seen with roflumilast was among patients with moderate-to-severe COPD associated with chronic bronchitis along with a recent history of exacerbations. The benefits were demonstrated with monotherapy and in combination with long-acting β(2)-agonists or anticholinergic agents.ConclusionsDespite its only modest benefits in improving lung function and reducing exacerbation rates, roflumilast serves as a safe and effective option in the treatment of COPD. | Kelly Freeman ML (2012)
Clinical Considerations for Roflumilast: A New Treatment for COPD.
The Consultant pharmacist : the journal of the American Society of Consultant Pharmacists 27, 189-193 [PubMed:22421519]
[show Abstract]
Chronic obstructive pulmonary disease (COPD) causes significant morbidity and mortality and represents the fourth leading cause of death in the world. Roflumilast is the first oral phosphodiesterase inhibitor indicated to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and history of exacerbations. Roflumilast and its active metabolite have been associated with increased cyclic adenosine monophosphate (cyclic AMP) in the lungs and positive responses with inflammatory markers. Significant improvements in forced expiratory volume (1 sec) have been observed in clinical trials comparing roflumilast with placebo. Combination therapy of roflumilast (500 μg) with long-acting beta agonists resulted in reduced COPD exacerbations in patients with severe COPD. Adverse effects include weight loss, diarrhea, nausea, and psychiatric disturbances. Roflumilast may be associated with significant drug-drug interactions with CYP3A4 inducers (strong) and immunosuppressants. Roflumilast is a promising new agent in the treatment of COPD; however, additional studies comparing roflumilast with inhaled corticosteroids plus long-acting bronchodilators are needed. | O'Donnell DE, Bredenbröker D, Brose M, Webb KA (2012)
Physiological effects of roflumilast at rest and during exercise in COPD.
The European respiratory journal 39, 1104-1112 [PubMed:21965226]
[show Abstract]
The purpose of this study was to investigate the effects of 500 μg roflumilast, taken once daily for 12 weeks, on airway physiology during rest and exercise in patients with moderate-to-severe chronic obstructive pulmonary disease. This randomised, double-blind, placebo-controlled, parallel-group study was conducted in 250 patients with a post-bronchodilator forced expiratory volume in 1 s (FEV(1)) of 30-80% predicted and a functional residual capacity of ≥ 120% pred. Pre- and post-bronchodilator spirometry and body plethysmography, and pre-bronchodilator constant work rate cycle exercise at 75% of peak work rate were evaluated. Exercise measurements included ventilation, breathing pattern, inspiratory capacity (IC) and arterial oxygen saturation measured by pulse oximetry (S(p,O(2))). Compared with placebo, 12 weeks of treatment with roflumilast was associated with: small but progressive increases in pre- and post-bronchodilator FEV(1) and FEV(1)/forced vital capacity; small decreases in specific airway resistance; and no significant changes in resting vital capacity, IC or measurements of lung hyperinflation. There was no treatment effect on exercise endurance time. At a standardised exercise time after roflumilast, compared with placebo, IC increased by 0.12 L (p = 0.008) and S(p,O(2)) increased by 0.7% (p = 0.020); peak ventilation increased by 1.9 L · min(-1) (p = 0.014). Roflumilast treatment was associated with progressive improvement of airway function but not lung hyperinflation. Newly described non-bronchodilator effects of roflumilast included small but consistent improvements in air trapping and S(p,O(2)) during exercise. | Wouters EF, Bredenbröker D, Teichmann P, Brose M, Rabe KF, Fabbri LM, Göke B (2012)
Effect of the phosphodiesterase 4 inhibitor roflumilast on glucose metabolism in patients with treatment-naive, newly diagnosed type 2 diabetes mellitus.
The Journal of clinical endocrinology and metabolism 97, E1720-5 [PubMed:22723325]
[show Abstract]
ContextThe phosphodiesterase 4 inhibitor roflumilast is a first-in-class antiinflammatory treatment for severe chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis and a history of frequent exacerbations. In previous clinical studies, a transient and reversible weight decrease was reported with roflumilast, suggesting the systemic actions of this drug may impact metabolism.ObjectiveOur objective was to investigate the effects of roflumilast on glucose homeostasis and body weight.Design and settingWe conducted a 12-wk, randomized, double-blind, placebo-controlled multicenter study with outpatients.PatientsPatients (n = 205) with newly diagnosed type 2 diabetes mellitus (DM2) but without COPD were included in the study.InterventionsRoflumilast 500 μg or placebo was administered once daily.Primary outcomeWe evaluated mean change in blood glycated hemoglobin levels.Secondary outcomesWe also evaluated mean change from baseline in the postmeal area under the curve (AUC) for a range of metabolic parameters.ResultsRoflumilast was associated with a significantly greater reduction in glycated hemoglobin levels than placebo (least square mean = -0.45%; P < 0.0001) in patients with DM2. In the roflumilast group, postmeal AUC decreased significantly from baseline to last visit for free fatty acids, glycerol, glucose, and glucagon, whereas they slightly increased for C-peptide and insulin. In contrast to roflumilast, the glucagon AUC increased with placebo, and the insulin AUC decreased. Between-treatment analysis revealed statistically significant differences in favor of roflumilast for glucose (P = 0.0082), glycerol (P = 0.0104), and C-peptide levels (P = 0.0033). Patients in both treatment groups lost weight, although the between-treatment difference of the changes from baseline to last visit [-0.7 (0.4) kg] was not statistically significant (P = 0.0584).ConclusionRoflumilast lowered glucose levels in patients with newly diagnosed DM2 without COPD, suggesting positive effects on glucose homoeostasis. | (2011)
Roflumilast (Daliresp) for COPD.
The Medical letter on drugs and therapeutics 53, 59-60 [PubMed:21778965] |
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