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Distribution of inhaled fluticasone propionate between human lung tissue and serum in vivo.

Esmailpour N, Hogger P, Rabe KF, Heitmann U, Nakashima M, Rohdewald P.

Institut fur Pharmazeutische Chemie, Westfalische Wilhelms-Universitat Munster, Germany.

High retention of inhaled glucocorticoids in the airways means prolonged anti-inflammatory action and low delivery into the serum. The objective of this study was to investigate the retention in and distribution of inhaled fluticasone propionate (FP) between central and peripheral human lung tissue and serum in vivo. In 17 patients undergoing lung resection surgery, a single 1.0 mg dose of FP was inhaled at varying time-points (range 2.8-21.7 h) preoperatively. Peripheral and central lung tissue was obtained, and blood was drawn simultaneously. FP concentrations in central lung tissue were approximately three to four times higher than peripheral lung tissue concentrations, which in turn, exceeded those found in serum by 10 times. FP was detectable up to 21 and 16 h, respectively, after inhalation, with drug levels falling almost in parallel in peripheral lung tissue and in serum. The results of this study demonstrate that fluticasone propionate is retained in lung tissue for a long time. Serum concentrations after a single inhaled dose are low. Retention of high concentrations of fluticasone propionate in the airways may promote high topical anti-inflammatory activity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9230236&dopt=Abstract fluticasone Flonase



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The inhibitory effects of topically active glucocorticoids on IL-4, IL-5, and interferon-gamma production by cultured primary CD4+ T cells.

Umland SP, Nahrebne DK, Razac S, Beavis A, Pennline KJ, Egan RW, Billah MM.

Schering-Plough Research Institute, Kenilworth, N.J. 07033, USA.

This study was conducted to directly compare the in vitro efficacy and potency of several glucocorticoids in inhibiting T-cell cytokine production. The glucocorticoids tested were fluticasone propionate, budesonide, triamcinolone acetonide, and beclomethasone dipropionate, which are currently inhaled therapies for the treatment of allergic airway disease. Also used were betamethasone phosphate and the newly developed mometasone furorate. With a novel cell culture system, purified peripheral blood CD4+ T cells from normal donors were stimulated with immobilized anti-CD3 and soluble anti-CD28 monoclonal antibodies to induce high levels of IL-4, IL-5, and interferon-gamma. By cell sorting, it was found that the IL-5 produced originated from memory cells, whereas both memory and naive cells produced interferon-gamma. Mometasone and fluticasone inhibited IL-5 and IL-4 similarly (mometasone IL-5 inhibitory concentration of 50% = 0.27 +/- 0.1 nmol/L and IL-4 = 0.19 +/- 0.08 nmol/L). For both cytokines, the results indicate that mometasone and fluticasone were more potent than beclomethasone, triamcinolone, budesonide, and betamethasone. Of clinical importance is the finding that all steroids demonstrated less efficacy versus interferon-gamma than IL-4 and IL-5. Glucocorticoid reduction of Th2 cytokines with lesser effects on interferon-gamma would serve to reverse the exaggerated Th2 response that contributes to pathophysiology observed in allergic disease. Therefore the use of topically active glucocorticoids with low systemic bioactivity for the treatment of allergic inflammation may be particularly effective in modulating the cytokine activity that is an important component of the allergic response.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9338546&dopt=Abstract fluticasone Flonase



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RPR 106541, a novel, airways-selective glucocorticoid: effects against antigen-induced CD4+ T lymphocyte accumulation and cytokine gene expression in the Brown Norway rat lung.

Underwood SL, Raeburn D, Lawrence C, Foster M, Webber S, Karlsson JA.

Rhone-Poulenc Rorer Ltd., Dagenham Research Centre, Essex.

1. The effects of a novel 17-thiosteroid, RPR 106541, were investigated in a rat model of allergic airway inflammation. 2. In sensitized Brown Norway rats, challenge with inhaled antigen (ovalbumin) caused an influx of eosinophils and neutrophils into the lung tissue and airway lumen. In the lung tissue there was also an accumulation of CD4+ T lymphocytes and increased expression of mRNA for interleukin-4 (IL-4) and IL-5, but not interferon-gamma (IFN-gamma). These findings are consistent with an eosinophilia orchestrated by activated Th2-type cells. 3. RPR 106541 (10-300 microg kg[-1]), administered by intratracheal instillation into the airways 24 h and 1 h before antigen challenge, dose-dependently inhibited cell influx into the airway lumen. RPR 106541 (100 microg kg[-1]) caused a significant (P<0.01) (98%) inhibition of eosinophil influx and a significant (P<0.01) (100%) inhibition of neutrophil influx. RPR 106541 was approximately 7 times and 4 times more potent than budesonide and fluticasone propionate, respectively. 4. When tested at a single dose (300 microg kg[-1]), RPR 106541 and fluticasone each caused a significant (P<0.01) (100%) inhibition of CD4+ T cell accumulation in lung tissue. Budesonide (300 microg kg[-1]) had no significant effect. RPR 106541 and fluticasone (300 microg kg[-1]), but not budesonide (300 microg kg[-1]), significantly (P<0.05) inhibited the expression within lung tissue of mRNA for IL-4. RPR 106541 (300 microg kg[-1]) also significantly (P<0.05) inhibited expression of mRNA for IL-5. 5. The high topical potency of RPR 106541 in this model, which mimics important aspects of airway inflammation in human allergic asthmatics, suggests that this glucocorticoid may be useful in the treatment of bronchial asthma.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9351499&dopt=Abstract fluticasone Flonase



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Induction of the E-selectin promoter by interleukin 1 and tumour necrosis factor alpha, and inhibition by glucocorticoids.

Ray KP, Farrow S, Daly M, Talabot F, Searle N.

Department of Cell Biology, Glaxo Wellcome Research and Development, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.

Cytokine-induced expression of the endothelial cell surface adhesion molecule E-selectin is inhibited by glucocorticoids (GCs). To investigate possible mechanisms for steroid inhibition, a reporter gene (ESAP) was constructed, comprising the cytokine responsive region of the E-selectin gene (nt -383 to +81) coupled to alkaline phosphatase (AP). In A549 cells stably transfected with the ESAP gene, AP production was highly responsive to the cytokines interleukin 1beta (IL-1beta) and tumour necrosis factor alpha, with ED50 values of 3 pM and 1000 pM respectively. Furthermore the cytokine-induced AP responses were inhibited by GCs, indicating that both transcriptional activation and GC suppression of the E-selectin gene were mediated via regulatory elements within the same region of the promoter. The relative potencies of GC drugs as inhibitors of IL-1beta (10 pM)-stimulated ESAP-gene activation were fluticasone> beclomethasone>dexamethasone, with IC50 values of 0.13, 1.1 and 2.7 nM respectively. Inhibition by fluticasone was blocked by the GC receptor (GR) antagonist drug mifepristone (Ru486), which is consistent with the suppressive effects of GCs being mediated via the GR. However, because the E-selectin promoter lacks a consensus glucocorticoid responsive element, mechanisms for inhibition independent of GR-DNA binding were investigated. Evidence that GCs also inhibited cytokine activation of a synthetic nuclear factor kappaB (NFkappaB)-driven reporter gene transiently transfected into A549 cells suggested that interference with the activation and/or function of this transcription factor was important for GC inhibition of ESAP. However, in A549-ESAP cells, fluticasone (100 nM) did not affect IL-1beta (10 pM)-induced IkBalpha degradation, NFkappaB-p65 nuclear translocation or the DNA-binding capacity of nuclear NFkappaB complexes, over a period during which cytokine-induced ESAP-gene activation was inhibited. Finally, there was no evidence to suggest that GC enhancement of IkBalpha gene expression contributed to the suppression of the cytokine response. We conclude that interference by GR with the transcriptional activation potential of DNA-bound NFkappaB complexes might contribute to mechanisms underlying the anti-inflammatory effects of GCs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9371735&dopt=Abstract fluticasone Flonase



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Dependency of cortisol suppression on the administration time of inhaled corticosteroids.

Meibohm B, Hochhaus G, Rohatagi S, Mollmann H, Barth J, Wagner M, Krieg M, Stockmann R, Derendorf H.

Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville 32610, USA.

Endogenous cortisol suppression is one of the major systemic side effects of inhaled corticosteroids in the treatment of asthma. A previously developed pharmacokinetic/ pharmacodynamic approach was used to evaluate the influence of administration time on the cumulative cortisol suppression (CCS) after single doses of the inhaled corticosteroids flunisolide and fluticasone propionate. Administration time-dependent simulations of CCS were performed with drug-specific pharmacokinetic and pharmacodynamic parameters obtained from previous clinical trials. Both drugs showed similar diurnal variation in CCS, dependent on the administration time, with maximum suppression when administered in the early morning at approximately 3 AM. The optimum administration time for minimized CCS was in the afternoon but was shifted from 3 PM for fluticasone propionate to later time points around 7 PM for flunisolide, probably because of the shorter terminal elimination half-life of flunisolide. Regarding peak to trough fluctuation, however, CCS after fluticasone propionate showed only half the administration time dependency as after flunisolide. Therefore, the ratio between CCS after flunisolide and after fluticasone propionate also followed administration time-dependent variations. This led to the conclusion that administration time has to be considered as a pivotal influential factor in clinical studies comparing CCS among different inhaled corticosteroids.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9378842&dopt=Abstract fluticasone Flonase