Flonase
Effects of topical corticosteroids on inflammatory mediator-induced eicosanoid release by human airway epithelial cells.

Aksoy MO, Li X, Borenstein M, Yi Y, Kelsen SG.

Pulmonary Division, Department of Medicine, Temple University School of Medicine, Philadelphia, USA.

BACKGROUND: Airway epithelial cells are among the first cells to come in contact with aerosolized corticosteroids. However, the relative potencies and time course of action of the several commonly used aerosolized corticosteroids on eicosanoid production by airway epithelial cells are unknown. OBJECTIVES: This study compared the effects of fluticasone, budesonide, and triamcinolone on eicosanoid output by human airway epithelial cells in vitro. We also determined the spectrum of eicosanoids affected and the mechanism for corticosteroid action. METHODS: Cultured BEAS-2B airway epithelial cells (a transformed cell line) were exposed to corticosteroids (1 nmol/L to 1 micromol/L) for 2 to 48 hours and then assayed for basal- and bradykinin (BK)-stimulated eicosanoid output. The eicosanoid profile was identified by HPLC in tritiated arachidonic acid prelabelled cells, and PGE2, the major eicosanoid product, was quantitated by RIA. The effect of corticosteroids on the immunoreactivity of key proteins involved in eicosanoid metabolism (ie, cyclooxygenase [COX], phospholipase A2 [PLA2], and Clara cell protein, a PLA2 inhibitor) was determined by Western blotting. RESULTS: Eicosanoid output was largely confined to prostaglandins with values of 5 +/- 2 and 82 +/- 35 ng PGE2/10(6) cells for basal- and BK stimulation, respectively (n = 8). All 3 corticosteroids inhibited basal- and BK-induced PGE2 output in a dose- and time-dependent manner. Fluticasone and budesonide completely eliminated PGE2 output in nanomolar concentrations in contrast to triamcinolone, which required micromolar concentration. The rank order of potency was: fluticasone = budesonide > triamcinolone. The time course of action for PGE2 inhibition also differed, with budesonide acting more slowly than the other 2 corticosteroids (P = .04). All 3 corticosteroids markedly reduced COX2 with little effect on COX1, cPLA2 (Type IV), or iPLA2 (Type VI) immunoreactivity or their relative distribution in cytosol versus membrane fractions. Clara cell protein immunoreactivity was undetectable in control and corticosteroid-treated cell lysates. CONCLUSION: These results show that in a human airway epithelial cell line, the 3 inhaled corticosteroids commonly used to treat asthma differ in onsets of action as inhibitors of prostaglandin synthesis and vary considerably in potency. All 3 corticosteroids act mechanistically in similar fashion by inhibiting COX2 synthesis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10359890&dopt=Abstract fluticasone Flonase



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Ligand-induced differentiation of glucocorticoid receptor (GR) trans-repression and transactivation: preferential targetting of NF-kappaB and lack of I-kappaB involvement.

Adcock IM, Nasuhara Y, Stevens DA, Barnes PJ.

Thoracic Medicine, Imperial College School of Medicine at NHLI, London.

1. Glucocorticoids are highly effective in controlling chronic inflammatory diseases, such as asthma and rheumatoid arthritis, but the exact molecular mechanism of their anti-inflammatory action remains uncertain. They act by binding to a cytosolic receptor (GR) resulting in activation or repression of gene expression. This may occur via direct binding of the GR to DNA (transactivation) or by inhibition of the activity of transcription factors such as AP-1 and NF-kappaB (transrepression). 2. The topically active steroids fluticasone propionate (EC50= 1.8 x 10(-11) M) and budesonide (EC50=5.0 x 10(-11) M) were more potent in inhibiting GM-CSF release from A549 cells than tipredane (EC50 = 8.3 x 10(-10)) M), butixicort (EC50 = 3.7 x 10(-8) M) and dexamethasone (EC50 = 2.2 x 10(-9) M). The anti-glucocorticoid RU486 also inhibited GM-CSF release in these cells (IC50= 1.8 x 10(-10) M). 3. The concentration-dependent ability of fluticasone propionate (EC50 = 9.8 x 10(-10) M), budesonide (EC50= 1.1 x 10(-9) M) and dexamethasone (EC50 = 3.6 x 10(-8) M) to induce transcription of the beta2-receptor was found to correlate with GR DNA binding and occurred at 10-100 fold higher concentrations than the inhibition of GM-CSF release. No induction of the endogenous inhibitors of NF-kappaB, IkappaBalpha or I-kappaBbeta, was seen at 24 h and the ability of IL-1beta to degrade and subsequently induce IkappaBalpha was not altered by glucocorticoids. 4. The ability of fluticasone propionate (IC50=0.5 x 10(-11) M), budesonide (IC50=2.7 x 10(-11) M), dexamethasone (IC50=0.5 x 10(-9) M) and RU486 (IC50=2.7 x 10(-11) M) to inhibit a 3 x kappaB was associated with inhibition of GM-CSF release. 5. These data suggest that the anti-inflammatory properties of a range of glucocorticoids relate to their ability to transrepress rather than transactivate genes.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10433509&dopt=Abstract fluticasone Flonase



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Dose response with fluticasone propionate on adrenocortical activity and recovery of basal and stimulated responses after stopping treatment.

Wilson AM, Sims EJ, Lipworth BJ.

Department of Clinical Pharmacology and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, UK.

OBJECTIVE: To evaluate the dose-response relationship for adrenocortical activity with fluticasone propionate (FP) and to assess basal and dynamic markers after stopping treatment for 3 days. PATIENTS AND DESIGN: Fourteen asthmatic patients were recruited: mean age 33.3 years, forced expiratory volume in 1 s (FEV1): 91.3% predicted, forced mid expiratory flow rate (FEF25-75): 58.1% predicted. A single blind study design was used comparing a placebo run-in with sequentially low, medium and high doses of FP and a placebo washout. All active treatments, placebo and washout were each for 3 days. FP was given at steady-state with twice daily divided dosing at 0800 h and 2200 h at doses of 375 micrograms, 875 micrograms, and 1750 micrograms per day. MEASUREMENTS: A 100 micrograms i.v. bolus hCRF test was performed at 0800 h after the run-in and washout periods. Blood samples were taken for 0800 h serum cortisol and osteocalcin as well as an overnight 10 h urine collection for cortisol/creatinine excretion after the run-in period, each dose of active treatment and washout. RESULTS: For serum cortisol (pre and post hCRF stimulation) there was no significant difference between placebo and washout values. Mean (SE) cortisol (nmol/1) values pre hCRF were run-in: 644.5 (59.7), washout: 550.3 (42.8) and post hCRF were run-in: 690.9 (42.9), washout: 719.1 (43.8). There was a significant (P < 0.05) difference between run-in vs medium and high doses for 0800 h serum cortisol, overnight urinary cortisol and overnight urinary cortisol/creatinine excretion; and vs high dose for serum osteocalcin. The fold difference (95% CI for difference) between run-in and high dose was: 2.2 (1.5-3.2) for overnight urinary cortisol, 2.5 (1.5-4.1) for overnight urinary cortisol/creatinine, 2.0 (1.1-3.6) for serum cortisol, and 1.2 (1.1-1.3) for serum osteocalcin. CONCLUSION: Fluticasone propionate exhibited dose related adrenal suppression with treatment. The suppressive effects of fluticasone propionate on adrenocortical activity were greater than those observed on osteocalcin.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10435058&dopt=Abstract fluticasone Flonase



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Morphometric studies in duodenal biopsies from patients with coeliac disease: the effect of the steroid fluticasone propionate.

Zaitoun A, Record CO.

Gastroenterology Unit, Royal Victoria Infirmary, Newcastle upon Tyne, UK.

Morphometric measurements have been performed on small intestinal biopsy specimens from patients with untreated coeliac disease before and after six weeks oral treatment with a steroid of low systemic bioavailability (fluticasone propionate). Measurements were obtained by point counting and also by a computer-aided measuring system with reference to a constant area of the muscularis mucosa. Fluticasone propionate led to a parallel reduction in the intraepithelial lymphocyte count within the surface (P less than 0.001) and crypt epithelium (P less than 0.01). The intra-epithelial lymphocyte count assessed by reference to constant areas of the muscularis mucosa and surface epithelium were decreased two-fold (P less than 0.01) and seven-fold (P less than 0.001) respectively. Fluticasone propionate treatment also led to significant increases in the absorptive surface epithelium as shown by an increase in the villus:crypt ratio (P less than 0.01), the epithelial cell height (P less than 0.01) and two- to three-fold increases in the area and length of the surface epithelium (P less than 0.001). Short-term fluticasone propionate treatment appears to exert a powerful beneficial effect upon duodenal morphology in patients with coeliac disease. Whether the alterations seen are comparable to a similar period of gluten withdrawal is not yet known.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1716168&dopt=Abstract fluticasone Flonase



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A pilot study of fluticasone propionate in untreated coeliac disease.

Mitchison HC, al Mardini H, Gillespie S, Laker M, Zaitoun A, Record CO.

Gastroenterology Unit, Royal Victoria Infirmary and University, Newcastle upon Tyne.

Although gluten withdrawal is likely to remain the mainstay of treatment for adult coeliac disease, many patients find the diet inconvenient and unpalatable and compliance among asymptomatic patients is often poor. Oral corticosteroids have been used for patients who seem to be resistant to gluten withdrawal but preparations with low systemic bioavailability might be preferable. We have given a new glucocorticoid (fluticasone propionate) to 12 adults with untreated coeliac disease for six weeks while they were on a normal diet. One patient defaulted and one suffered a relapse in a pre-existing neoplasm. Excluding these, there was an improvement of symptoms, a mean weight gain of 2 kg, and a rise in albumin of 5.4 g/l. There was a significant improvement in the lactulose/mannitol excretion ratio (p less than 0.05) and in all histological variables examined in paired biopsy specimens (surface and crypt intraepithelial lymphocyte/enterocyte and goblet cell/enterocyte ratios and enterocyte height, p less than 0.01 or better). In six paired specimens sucrase and alkaline phosphatase activity increased in all (p less than 0.05) and lactase in five of six. No appreciable side effects were observed, but two patients had suppressed cortisol values and synacthen responses at six weeks. A further three, with normal pretrial results, had a blunted tetracosactrin response at six weeks. Fluticasone propionate seems worthy of further assessment in the treatment of coeliac disease as an adjunct to gluten withdrawal.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1901562&dopt=Abstract fluticasone Flonase