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: Loretta Jacques
[Show abstract] [Hide abstract]
- "Structurally, FF is distinct from the twice-daily (BD) ICS, fluticasone propionate (FP) . Preclinically, FF exhibits a greater antiinflammatory activity than FP  . Clinically, FF, administered once-daily in the evening is non-inferior to the same daily dose administered twice daily with respect to lung function ; exhibits significant effects versus placebo with respect to lung function over a range of doses and asthma severities [8e10]; has shown a significant effect on the allergen-induced early asthmatic response 23e24 h after dosing ; and is indicated as a once-daily therapy for allergic rhinitis  . "
ABSTRACT: Inhaled corticosteroids (ICSs) improve asthma disease control; once-daily ICS administration may have advantages for patients. Our objective was to assess the efficacy and safety of the novel ICS fluticasone furoate (FF) over 24 weeks versus placebo. This was a 24-week double-blind, double-dummy, placebo- and active-controlled study (NCT01159912) of 343 asthma patients (≥12 years) not controlled by their current ICS. Patients were randomised (1:1:1) to FF100 μg, placebo (both administered once-daily [OD] via ELLIPTA™ dry powder inhaler in the evening) or fluticasone propionate (FP) 250 μg (administered twice-daily (BD) via DISKUS™/ACCUHALER™). Primary endpoint was change from baseline in pre-dose evening forced expiratory volume in 1s (FEV1) at Week 24; change from baseline in % rescue-free 24-h periods was a powered secondary endpoint. Adverse events (AEs) were assessed. FF100 μg OD and FP250 μg BD significantly improved pre-dose evening FEV1 compared with placebo at Week 24 (+146 ml [p = 0.009] and +145 ml [p = 0.011], respectively). Percentage of rescue-free 24-h periods was increased with FF100 μg OD (+14.8%) and FP250 μg BD (+17.9%) compared to placebo (both p < 0.001). On-treatment AEs were reported by 53% (FF100 μg OD), 42% (FP250 μg BD) and 40% (placebo) of patients. On-treatment severe asthma exacerbations were lower with FF100 μg OD (3%) and FP250 μg BD (2%) than placebo (7%). There was significant suppression of urinary cortisol at week 24 with FF100 μg OD (p = 0.030) and FP250 μg BD (p = 0.036) relative to placebo. FF100 μg OD, administered in the evening, achieves significant improvements in lung function and rescue inhaler use over 24 weeks, comparable to FP250 μg BD with similar safety profile.Respiratory medicine 11/2013; 108(1). DOI:10.1016/j.rmed.2013.11.009 · 2.92 Impact Factor
[Show abstract] [Hide abstract]
- "Several immunoregulatory genes including VCAM-1, TNF-a (tumor necrosis factor a), RANTES (regulated upon activation, normal T-cell expressed and secreted), and GM-CSF (granulocyte-macrophage colony stimulating factor), contain NF-jB and/or AP-1 sites in their promoters or regulatory regions (De Bosscher et al. 2003). Several studies have investigated the potency of various GCs to inhibit the expression of the aforementioned immunoregulatory genes (Adcock et al. 1999; Atsuta et al. 1999; Stellato et al. 1999; Jaffuel et al. 2000; Salter et al. 2007). While the EC 50 values observed in these studies differ from those for transrepression of AP-1 and NF-jB activity in the current study, in general, the rank potencies for transrepression coincided with those for inhibition of VCAM-1, TNF-a, RANTES, and GM-CSF expression. "
ABSTRACT: The anti-inflammatory activity of inhaled glucocorticoids is primarily mediated through transrepression of pro-inflammatory transcription factors such as AP-1 and NF-kappaB, while systemic side effects are largely attributed to transactivation via glucocorticoid response elements (GRE) in the promoter region of responsive genes. The objective of this study is to investigate whether inhaled corticosteroids exhibit differences in their transactivation and transrepression potencies. A549 human alveolar epithelial type II like cells, stably transfected with a reporter plasmid containing an AP-1, NF-kappaB or GRE induced secreted alkaline phosphatase reporter gene (SEAP), were exposed to a panel of concentrations of the six inhaled and three systemic glucocorticoids. Glucocorticoid-induced changes in SEAP expression were quantified by chemiluminescence. For eight glucocorticoids (budesonide, desisobutyryl-cicle-sonide, dexamethasone, flunisolide, fluocortolone, fluticasone propionate, mometasone furoate, prednisolone) the EC50 for NF-kappaB mediated transrepression was significantly larger than that for both transactivation and transrepression via AP-1. For the remaining glucocorticoid (triamcinolone acetonide), it was greater than that for transactivation. It is concluded that, within the studied cell system, inhaled corticosteroids did not exhibit preferential transrepression, but had higher potencies for transactivation than for transrepression via NF-kappaB and had differential potencies for the two transrepression pathways.Pharmazie 01/2009; 63(12):893-8. DOI:10.1691/ph.2008.8638 · 1.00 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Fluticasone furoate is a new enhanced-affinity glucocorticoid with a unique combination of pharmacodynamic and physicochemical properties suitable for topical activity. In this multicentre, randomized, double-blind, placebo-controlled, parallel-group study, patients [adults and adolescents >or=12 years of age with seasonal allergic rhinitis (SAR)] received once-daily (od) treatment for 2 weeks with either fluticasone furoate nasal spray 110 microg (n = 141) or placebo nasal spray (n = 144) administered in a unique, side-actuated device. Efficacy measures included total nasal symptom score (TNSS) and total ocular symptom score (TOSS). Patients also reported their overall response to therapy and rated their quality of life using the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ). Fluticasone furoate significantly improved the mean change from baseline in daily reflective TNSS compared with placebo (treatment difference of -1.757; P < 0.001). Fluticasone furoate was also significantly more effective in improving the morning predose instantaneous TNSS (treatment difference of -1.898; P < 0.001) and daily reflective TOSS (treatment difference of -0.741; P = 0.001). A significant treatment effect was observed as early as day 1. Compared with placebo-treated patients, fluticasone furoate-treated patients showed significantly greater improvements in overall evaluation of response to therapy (P < 0.001), as well as in overall RQLQ score (P < 0.001). Fluticasone furoate was well tolerated. Fluticasone furoate nasal spray 110 mug od was effective in improving the nasal symptoms of SAR. It also produced significant improvements in ocular symptoms.Allergy 09/2007; 62(9):1078-84. DOI:10.1111/j.1398-9995.2007.01522.x · 6.00 Impact Factor