Disease relevance of Roflumilast

• OBJECTIVES: This study evaluated the effects of roflumilast, a phosphodiesterase 4 (PDE4) inhibitor on acute lung inflammation and chronic lung changes in models of cigarette exposure in mice.METHODS: Roflumilast was given orally either at 1 mg/kg (R1) or at 5 mg/kg (R5) [1].
• The initially detected side effects, mainly nausea and emesis, appear at least partially overcome by the 'second generation' PDE4 inhibitors, some of which like roflumilast and cilomilast are in the later stages of clinical development for treatment of chronic obstructive pulmonary disease [2].
• Roflumilast fully prevents emphysema in mice chronically exposed to cigarette smoke [1].
• In addition, in the smoke-exposure group, 63% of the mice showed goblet cell metaplasia, and neither of the doses of roflumilast had any effect [1].
• We have tested the effects of combined treatment with a recombinant surfactant protein C based surfactant (rSP-C surfactant) containing a phosphodiesterase-4 (PDE-4) inhibitor, roflumilast, in a lung lavage model of acute lung injury [3].
• 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 [4].

High impact information on Roflumilast

• The role of PDE4 inhibitors in modulating cytokines, lipid mediators and in mucociliary clearance, along with clinical efficacy in asthma and/or COPD demonstrated with roflumilast and cilomilast, suggest a broad anti-inflammatory spectrum for these compounds [5].
• Roflumilast, 250 and 500 microg, also attenuated early asthmatic reactions by 25% (P = .0038) and 28% (P = .0046), although not to the same extent as LAR attenuation [6].
• OBJECTIVE: The main objective of this study was to investigate the efficacy of oral roflumilast (500 microg/day) in allergic rhinitis [7].
• In human isolated bronchus, EGF induced MUC5AC mRNA and protein expression was inhibited by roflumilast (1 microM) as well as the MUC5AC positive staining shown by immunohistochemistry [8].
• The strong anti-proliferative effect of the second-generation PDE4 inhibitors, cilomilast and roflumilast, suggest a benefit for the effective inhibition of immune cell and fibroblast proliferation contributing to the development of obliterative bronchiolitis [9].

Chemical compound and disease context of Roflumilast

• The new phosphodiesterase 4 inhibitor roflumilast is efficacious in exercise-induced asthma and leads to suppression of LPS-stimulated TNF-alpha ex vivo [10].

Biological context of Roflumilast

• Obtaining plasma levels at the IC(50) determined in vitro for L-826,141 and roflumilast provides significant inhibition of bronchoconstriction [11].
• Roflumilast inhibited the DNA binding activity of NF-kappaB by preventing inhibitor kappaBalpha phosphorylation and degradation [12].
• Dose-proportional intraindividual single- and repeated-dose pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor [13].
• Dose-adjusted point estimates and 90% confidence intervals of test (500 mug)/reference (250 mug) ratios for AUC and C(max) of roflumilast and its pharmacologically active N-oxide metabolite after single and repeated dosing were all within the standard equivalence acceptance range (0.80, 1.25) indicating dose proportionality [13].
• METHODS: In a double blind, double-dummy, randomized, noninferiority study, 499 patients (forced expiratory volume in 1 s [FEV1] = 50-85% predicted) received roflumilast 500 microg once daily or BDP 200 microg twice daily (400 microg/day) for 12 weeks [14].

Anatomical context of Roflumilast

• These results suggest that the inhibitory activity of roflumilast on the production of inflammatory mediators seems to be mediated via inhibition of NF-kappaB, p38 MAP kinase, and JNK activation in macrophages [12].
• In the present study, we investigated the mechanism of anti-inflammatory effects of roflumilast in murine macrophage cell line RAW264.7 cells [12].
• Compared with neutrophils and eosinophils, representing the terminal inflammatory effector cells, the relative potency of roflumilast and its N-oxide for monocytes, CD4+ T cells, and dendritic cells is substantially higher compared with cilomilast and rolipram, probably reflecting an improved immunomodulatory potential [15].
• Likewise, roflumilast was a more potent inhibitor of neutrophil influx (ID(50)=0.9mg/kg) than rolipram (ID(50)=6.9mg/kg), piclamilast (ID(50)=28.1mg/kg), or cilomilast (ID(50)=37.7mg/kg) [16].

Associations of Roflumilast with other chemical compounds

• In the absence of forskolin, the iodide secretion was insensitive to PDE4 inhibitor L-826,141 [4-[2-(3,4-bis-difluoromethoxyphenyl)-2-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-ethyl]-3-methylpyridine-1-oxide], roflumilast, or to PDE3 inhibitor trequinsin [17].
• Roflumilast co-administration did not alter the pharmacokinetics of steady state salbutamol [18].
• Roflumilast did not affect LTD4-induced bronchoconstriction [19].
• Roflumilast did not inhibit serotonin-induced bronchoconstriction 4.5h after administration, suggesting that inhibition of AHR by roflumilast results from anti-inflammatory, not bronchodilatory, effects [16].
• The inhibitory effects of roflumilast on lipopolysaccharide-induced nitric oxide production in RAW264.7 cells are mediated by heme oxygenase-1 and its product carbon monoxide [20].

Gene context of Roflumilast

• In this study, we investigated whether roflumilast, a newly developed specific phosphodiesterase 4 (PDE4) inhibitor, mediates some of its anti-inflammatory effects by blocking nitric oxide (NO) and tumor necrosis factor alpha (TNF-alpha) via the induction of HO-1 expression in macrophages [20].
• The phosphorylation of mitogen-activated protein (MAP) kinases, including stress-activated protein kinase/c-Jun NH2-terminal kinase (JNK) and p38 MAP kinase, was also markedly inhibited by roflumilast [12].
• Moreover, the inhibitory effects of roflumilast on NO production were abrogated by a HO-1 inhibitor and a CO scavenger [20].
• INTERPRETATION: Roflumilast is a promising candidate for anti-inflammatory COPD treatment because it improved lung function and reduced exacerbations compared with placebo [21].
• METHODS: Five allogenic groups were investigated and treated with the PDE4 inhibitors: rolipram, cilomilast (Ariflo, SB-207499, SmithKline Beecham, Munich, Germany), roflumilast (Altana Pharmacia, Bad Homburg, Germany) or cyclosporine A (CsA), or left without immunosuppression [9].

Analytical, diagnostic and therapeutic context of Roflumilast

• METHODS: In a randomized, placebo-controlled, double-blinded, crossover study, 25 subjects (16 male, 9 female; median age, 28 years) with histories of allergic rhinitis but asymptomatic at screening received roflumilast (500 microg once daily) and placebo for 9 days each with a washout period of at least 14 days in between treatment periods [7].
• Cilomilast and roflumilast are selective PDE4 inhibitors that are currently in pre-registration and phase III clinical trials, respectively, for the treatment of COPD (cilomilast and roflumilast) and asthma (roflumilast) [22].

References