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.
SourceAvailable from: Mark M Perry[Show abstract] [Hide abstract]
ABSTRACT: Glucocorticoids are the mainstay for the treatment of chronic inflammatory diseases including asthma and chronic obstructive pulmonary disease (COPD). However, it has been recognized that glucocorticoids do not work well in certain patient populations suggesting reduced sensitivity. The ultimate biologic responses to glucocorticoids are determined by not only the concentration of glucocorticoids but also the differences between individuals in glucocorticoid sensitivity, which is influenced by multiple factors. Studies are emerging to understand these mechanisms in detail, which would help in increasing glucocorticoid sensitivity in patients with chronic airways disease. This review aims to highlight both classical and emerging concepts of the anti-inflammatory mechanisms of glucocorticoids and also review some novel strategies to overcome steroid insensitivity in airways disease.Pulmonary Pharmacology & Therapeutics 09/2014; DOI:10.1016/j.pupt.2014.08.008 · 2.54 Impact Factor
Dataset: YIM Review PPT 2014
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ABSTRACT: Fluticasone furoate nasal spray (FFNS) is a glucocorticoid developed for the treatment of allergic rhinitis (AR). This study aimed to assess the safety, efficacy, and systemic exposure of FFNS in Japanese children with perennial AR (PAR). In this multicentre, open-label, phase 3 study, 61 children aged 2 to <15 years were treated with FFNS 55 μg, once daily for 12 weeks. Nasal and ocular symptoms were scored by parents/guardians/patients and recorded in a patient's daily diary. In addition, rhinoscopy findings, including mucosal swelling, were scored by the investigators as an efficacy measure. As a safety measure, adverse events and clinical laboratory data were evaluated. An adverse event was reported by 67% of patients during the treatment and follow-up period, all of which were mild in intensity. The most commonly reported adverse events were nasopharyngitis and acute sinusitis (acute rhinosinusitis). There were no serious adverse events. FFNS 55 μg improved nasal symptom scores and rhinoscopy findings compared with the baseline. Ocular symptom scores were also improved compared with the baseline in FFNS 55 μg in a sub-group of patients with any ocular symptoms at baseline. FFNS 55 μg was shown to be well tolerated over the 12-week treatment period. Majority of patients receiving FFNS 55 μg had unquantifiable plasma levels of fluticasone furoate (FF). Twelve-week treatment with FFNS 55 μg, once daily, is well tolerated and effective with low systemic exposure in Japanese children aged 2 to <15 years with PAR. Copyright © 2014 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.Allergology International 01/2015; 64(1):60-5. DOI:10.1016/j.alit.2014.07.002