Glucocorticoids fluticasone

Callejas, S.L. Biddlecombe, R.A. Jones, A.E. Joyce, K.B. Pereira, A.I. Pleasance, S. Determination of the glucocorticoid fluticasone propionate in plasma by automated solid-phase extraction and liquid chromatography-tandem mass spectrometry, J.Chromatogr.B, 1998, 718, 243-250. 

Asthma is a chronic inflammatory disease. Therefore steroids represent the most important and most frequently used medication. Already after the fust treatment, steroids reduce cellular infiltration, inflammation, and the LAR, whereas changes in the EAR require prolonged treatment to lower the existent IgE levels. The mechanisms of steroid actions are complex and only incompletely understood. Besides their general antiinflammatory properties (see chapter glucocorticoids), the reduction of IL-4 and IL-5 production from T-lymphocytes is particularly important for asthma therapy. The introduction of inhaled steroids, which have dramatically limited side effects of steroids, is considered one of the most important advancements in asthma therapy. Inhaled steroids (beclomethasone, budesonide, fluticasone, triamcinolone, momethasone) are used in mild, moderate, and partially also in severe asthma oral steroids are used only in severe asthma and the treatment of status asthmaticus. Minor side effects of most inhaled steroids are hoarseness and candidasis, which are avoided by the prodrug steroid ciclesonide. 

Corticosteriods Beclomethasone Fluticasone Glucocorticoid receptor NR3C1... 

The first inhaled glucocorticoid, beclomethasone dipropionate, revolutionized asthma therapy, when it was found that topical delivery to the lung resulted in reduced systemic side-effects (adrenal suppression, oseteoporosis and growth inhibition) typically seen with oral steroid treatments. Interestingly, a further reduction in systemic exposure was achieved with the introduction of fluticasone propionate (1). The evolution of this drug stemmed from observations with the steroid 17-carboxylates that showed that these esters were active topically when esterified, while the parent acids were inactive. Thus it was realized that enzymatic hydrolysis of the ester would lead to systemic deactivation. SAR studies led to a series of carbothioates, which were very active in vivo when topically applied to rodents, but were inactive after oral administration. It was shown that fluticasone propionate (1) underwent first pass metabolism in the liver to the corresponding inactive 173-carboxylic acid (la) (Scheme 1). This observation was... 

Systemic availability of inhaled glucocorticoids can be reduced in two ways. First, by using esters that reduced local absorption in the case of beclomethasone the dipropionate is used. Secondly, by using glucocorticoids that are extensively metabolized in the liver after absorption from the gut, such as fluticasone and budesonide. These strategies can be combined fluticasone is given as the ester fluticasone propionate. 

In healthy volunteers, high doses of both budesonide and fluticasone were readily absorbed after inhalation from a mete red-dose aerosol (2). Fluticasone is extensively metabolized by the liver, so measurable concentrations of parent drug in the systemic circulation reflect efficient absorption across the lung. Lower doses of these inhaled glucocorticoids also result in some systemic absorption, reflected in effects on the hypothalamic-pituitary-adrenal axis (3). 

A 32-month-old girl developed hypoglycemic seizures (61). She had been given fluticasone propionate 440-880 micrograms/day and up to 5 months before the incident oral glucocorticoids. 

There were no differences in relative fracture risks with different drugs, for example fluticasone, budesonide, beclomethasone (109). In an earlier retrospective study, there was a dose-dependent increase in bone fracture risk with oral glucocorticoids (110). 

In a small cross-sectional study, bone mineral density was studied in 20 prepubertal asthmatic patients treated with moderate to high doses of inhaled glucocorticoids (under 400 micrograms/day beclomethasone or budesonide or over 200 micrograms/day fluticasone) (114). Volumetric trabecular bone mineral density of the lumbar spine and distal radius were measured using dual energy X-ray absorptiometry and were within the reference ranges. 

The efficacy and safety of fluticasone 750 micrograms/ day and beclomethasone 1500 micrograms/day delivered by a spacer device have been compared in 30 asthmatic children in a 12-week, randomized, double-blind, crossover study (118). All of the children had persistent asthma requiring 1000-2000 micrograms/day of inhaled glucocorticoids before the trial. There was no significant... 

Oral glucocorticoids such as dexamethasone and prednisolone are still used in patients with severe asthma, though these agents are associated with adverse systemic effects. Inhaled glucocorticoid therapy was introduced in 1972 with beclomethasone dipropionate, which dramatically reduced systemic effects. Fluticasone propionate (launched in 1993) is very efficiently inactivated in the liver, and exhibits low oral bioavailability, which in turn leads to a further reduction in systemic exposure. 

Fluticasone (Flovent /GlaxoSmithKline) is a synthetic corticosteroid derivative that is a selective agonist at the human glucocorticoid... 

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