Fluticasone propionate — an update on preclinical and clinical experience

Abstract

Fluticasone propionate (FP) is a novel androstane glucocorticoid with potent anti-inflammatory activity which has been effectively used, intranasally, as therapy for seasonal and allergic perennial rhinitis. When taken by the inhaled route, FP has shown significant therapeutic efficacy in the management of asthma. Fluticasone propionate is a highly lipophilic molecule with good uptake, binding and retention characteristics in human lung tissue. Fluticasone propionate has high glucocorticoid receptor selectivity and affinity, demonstrating rapid receptor association and slow receptor dissociation. In vitro, FP has been shown to potently inhibit T lymphocyte proliferation, cytokine generation, tumour necrosis factor alpha (TNF-alpha)-induced adhesion molecule expression, interleukin-5-induced eosinophilia, mucosal oedema and toluene 2,4-diisocyanate-induced mast cell proliferation, while promoting secretory leucocyte protease inhibitor production and eosinophil apoptosis. In human studies, FP has demonstrated marked vasoconstrictor potency in normal subjects and inhibited antigen-induced mucosal platelet activating factor/eicosanoid production, T lymphocytes and CD25+ cells in patients with rhinitis. Biopsy data from mild asthmatics demonstrate FP-associated reduction in CD3, CD4, CD8 and CD25 cells, with an accompanying reduction in eosinophil and mast cell markers. Clinical studies have evaluated lung function, bronchial reactivity, exacerbation rates and oral corticosteroid-sparing effect. Results show that FP has at least twice the clinical potency of beclomethasone dipropionate and budesonide. This appears to be achieved without an accompanying increase in systemic effects, suggesting a therapeutic index which may be higher than other currently available inhaled corticosteroids.

Pharmacokinetics and systemic activity of fluticasone via Diskus® and pMDI, and of budesonide via Turbuhaler®

“…An extensive distribution into tissues, as indicated by a high volume of distribution, appears to be the cause of the slow elimination of¯uticasone, and the elimination half-life of 12 h in the present study is in agreement with the 10±14 h found in earlier studies [3,5,17]. The slow elimination results in a signi®cant (1.7-fold) accumulation of¯uticasone following repeated dosing.…”

zVAD-fmk, unlike BocD-fmk, does not inhibit caspase-6 acting on 14-3-3/Bad pathway in apoptosis of p815 mastocytoma cells

“…As a matter of fact, the antiinflammatory or antiallergic effect of a certain drug was demonstrated to depend on its apoptosis-inducing effect (Fuller et al, 1995;Park et al, 2001;2002;Kim et al, 2003).…”

Acute adrenal crisis in asthmatics treated with high-dose fluticasone propionate

“…Fluticasone has been preferred for many patients requiring higher dosages of ICS because of a claimed better therapeutic efficacy/safety ratio [11], although this claim has been challenged [12].…”