title: Long-acting fluticasone furoate has a superior pharmacological profile to fluticasone propionate in human respiratory cells.
abstract: Currently available glucocorticoids are relatively short acting and may be less effective in patients with chronic obstructive pulmonary disease (COPD) where high levels of oxidative stress are seen. Here we show that a novel glucocorticoid, fluticasone furoate (FF), has a longer duration of action in several cell systems compared with fluticasone propionate (FP) and budesonide, and unlike FP, FF is resistant to oxidative stress. FF had similar or slightly higher potency to FP and was 2-9 fold more potent than budesonide, when assessed at 4h, in inhibiting inflammatory cytokine production in epithelial cell lines (BEAS2B, A549), primary bronchial epithelial cells and a monocytic cell line (U937). The potency of FF was sustained beyond 16 h with or without washout compared with FP or budesonide, such that it showed a greater duration of action in this range of cellular assays. The activated YFP-conjugated glucocorticoid receptor was detectable in nuclei of FF treated BEAS2B cells for at least for 30 h, and FF had a longer duration of action than FP in inhibiting activation of transcription factors such as NF-κB and AP-1. In addition, FF showed superior effects to FP in peripheral blood mononuclear cells from patients with COPD and also in U937 cells or primary bronchial epithelial cells under conditions of oxidative stress. The longer duration of action and oxidative stress insensitivity of FF compared with FP has potential clinical implications for the control of inflammation in respiratory diseases, such as COPD.
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London, London SW3 6LY, United Kingdom.
authors.forename: Christos
authors.initials: C
authors.lastname: Rossios
authors.forename: Yasuo
authors.initials: Y
authors.lastname: To
authors.forename: Masako
authors.initials: M
authors.lastname: To
authors.forename: Misako
authors.initials: M
authors.lastname: Ito
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Barnes
authors.forename: Ian M
authors.initials: IM
authors.lastname: Adcock
authors.forename: Malcolm
authors.initials: M
authors.lastname: Johnson
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ito
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000730:Androstadienes / Q000494:pharmacology*; D001249:Asthma / Q000473:pathology; D019819:Budesonide / Q000494:pharmacology; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D000068298:Fluticasone; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D029424:Pulmonary Disease, Chronic Obstructive / Q000473:pathology; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D012137:Respiratory System / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000730:Androstadienes; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D051996:Transcription Factor RelA; D019819:Budesonide; D000068298:Fluticasone; D048051:p38 Mitogen-Activated Protein Kinases; C523187:fluticasone furoate