fluticasone-furoate and Hypersensitivity

Single-dose inhaled corticosteroids (ICS) induce direct anti-inflammatory effects in asthma thereby improving airway hyperresponsiveness (AHR). A novel enhanced-affinity ICS, fluticasone furoate (FF), demonstrated a prolonged duration of action in vitro. The aim of this study was to evaluate the efficacy and duration of action of a single dose of FF by studying protection against AHR to adenosine 5'-monophosphate (AMP) and effects on exhaled nitric oxide (eNO).. A randomized, double-blind, placebo-controlled, 6-way crossover study (FFA10026) was performed in 24 patients with allergic asthma (mean age 32.8 years, FEV(1) ≥ 70% predicted and PC(20) AMP ≤ 50 mg/ml). Each subject received a single dose of FF 1000 μg, fluticasone proprionate (FP) 1000 μg, or placebo at 2 (FF only), 14 or 26 h prior to AMP challenge and eNO measurement.. FF significantly improved PC(20) AMP compared to placebo, the difference in doubling concentrations being 2.18 (95% confidence interval: 1.13-3.23), 1.54 (0.48-2.59), and 1.30 (0.26-2.34) at 2, 14 and 26 h. FP improved PC(20) AMP significantly at 14 h compared to placebo, but not at the 26-hour time point, the difference in doubling concentrations being 1.72 (0.70-2.75) and 0.33 (-0.69-1.34). There was no significant effect on eNO after either FF or FP at all time points. FF was well tolerated and there were no serious adverse events.. The new inhaled corticosteroid FF, but not FP, demonstrates prolonged protection up to 26 h against AHR to AMP in asthma patients.

Topics: Adenosine Monophosphate; Administration, Inhalation; Adrenal Cortex Hormones; Adult; Androstadienes; Anti-Allergic Agents; Anti-Asthmatic Agents; Asthma; Bronchial Hyperreactivity; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Exhalation; Female; Fluticasone; Humans; Hypersensitivity; Male; Nitric Oxide; Respiratory Function Tests

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.

Topics: Androstadienes; Animals; Cell Line, Tumor; Cell Membrane Permeability; Chlorocebus aethiops; Disease Models, Animal; Epithelial Cells; Fluticasone; Glucocorticoids; Humans; Hypersensitivity; Inflammation; Lipopolysaccharides; NF-kappa B; Pancreatic Elastase; Rats; Rats, Inbred BN; Receptors, Steroid; Respiration Disorders; Tumor Necrosis Factor-alpha