title: Pharmacological properties of the enhanced-affinity glucocorticoid fluticasone furoate in vitro and in an in vivo model of respiratory inflammatory disease.
abstract: Fluticasone furoate (FF) is a novel enhanced-affinity glucocorticoid that has been developed as topical therapy for allergic rhinitis. The pharmacological properties of FF have been investigated using a number of in vitro experimental systems. FF demonstrated very potent glucocorticoid activity in several key pathways downstream of the glucocorticoid receptor (GR) as follows: the transrepression nuclear factor-kappaB (NF-kappaB) pathway, the transactivation glucocorticoid response element pathway, and inhibition of the proinflammatory cytokine tumor necrosis factor-alpha. Furthermore, FF showed the greatest potency compared with other glucocorticoids for preserving epithelial integrity and reducing epithelial permeability in response to protease- and mechanical-induced cell damage. FF showed a 30- to >330,000-fold selectivity for GR-mediated inhibition of NF-kappaB vs. the other steroid hormone receptors, substantially better than a number of other clinically used glucocorticoids. In studies examining the respiratory tissue binding properties of glucocorticoids, FF had the largest cellular accumulation and slowest rate of efflux compared with other clinically used glucocorticoids, consistent with greater tissue retention. The in vivo anti-inflammatory activity of FF was assessed in the Brown Norway rat ovalbumin-induced lung eosinophilial model of allergic lung inflammation. At a dose of only 30 microg, FF achieved almost total inhibition of eosinophil influx in the lung, an inhibition that was greater than that seen with the same dose of fluticasone propionate. In conclusion, the potent and selective pharmacological profile of FF described here could deliver an effective, safe, and sustained topical treatment of respiratory inflammatory diseases such as allergic rhinitis and asthma.
authors.affiliation: Global Project Management, Bldg. 1, GlaxoSmithKline, Park Rd., Ware SG12 0DP, UK. mark.2.salter@gsk.com
authors.forename: Mark
authors.initials: M
authors.lastname: Salter
authors.forename: Keith
authors.initials: K
authors.lastname: Biggadike
authors.forename: Joyce L
authors.initials: JL
authors.lastname: Matthews
authors.forename: Michael R
authors.initials: MR
authors.lastname: West
authors.forename: Michael V
authors.initials: MV
authors.lastname: Haase
authors.forename: Stuart N
authors.initials: SN
authors.lastname: Farrow
authors.forename: Iain J
authors.initials: IJ
authors.lastname: Uings
authors.forename: David W
authors.initials: DW
authors.lastname: Gray
mesh_terms: D000730:Androstadienes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D000068298:Fluticasone; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D006967:Hypersensitivity; D007249:Inflammation; D008070:Lipopolysaccharides / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D010196:Pancreatic Elastase / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D011987:Receptors, Steroid / Q000378:metabolism; D012120:Respiration Disorders / Q000378:metabolism* / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000730:Androstadienes; D005938:Glucocorticoids; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011987:Receptors, Steroid; D014409:Tumor Necrosis Factor-alpha; D000068298:Fluticasone; D010196:Pancreatic Elastase; C523187:fluticasone furoate