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Decreased cortisol response to insulin induced hypoglycaemia in asthmatics treated with inhaled fluticasone propionate.

Mahachoklertwattana P, Sudkronrayudh K, Direkwattanachai C, Choubtum L, Okascharoen C.

Department of Pediatrics, Ramathibodi Hospital, Faculty of Medicine, Mahidol University, Bangkok, Thailand 10400. rapmw mahidol.ac.th

AIMS: To assess adrenal function in asthmatic children treated with inhaled fluticasone propionate for up to 16 weeks. METHODS: Children with asthma and bronchial hyperresponsiveness to inhaled methacholine were treated with inhaled fluticasone 250-750 microg/day via Volumatic spacer. The insulin tolerance test (ITT) was performed to assess adrenal function. RESULTS: Eighteen asthmatic patients (10 boys, 8 girls), aged 7-17 years received inhaled fluticasone therapy at a median dose of 477 microg/m2 per day for 5-16 weeks. Adrenal suppression, defined as 60 minute serum cortisol less than 500 nmol/l, was found in 9 of 18 children. Following the ITT, the median basal and 60 minute serum cortisol concentrations of the suppressed group were 135.0 and 350.0 nmol/l, respectively; the corresponding values for the unsuppressed group were 242.2 and 564.7 nmol/l. Repeat ITT in the suppressed group 2-3 months after discontinuation of fluticasone revealed that all patients had a 60 minute serum cortisol greater than 500 nmol/l. CONCLUSION: After therapy for asthma with inhaled fluticasone at approximately 500 microg daily for up to 16 weeks, half the children had evidence of adrenal suppression.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15499064&dopt=Abstract fluticasone Flonase



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Observational study of the effects of using montelukast vs fluticasone in patients matched at baseline.

Allen-Ramey FC, Duong PT, Riedel AA, Markson LE, Weiss KB.

Merck & Co Inc, West Point, Pennsylvania 19486-0004, USA. felicia_ramey merck.com

BACKGROUND: The relative effectiveness of inhaled corticosteroids and leukotriene receptor antagonists in asthma therapy continues to be the subject of clinical studies. Recent studies have examined the impact of these therapies using a retrospective design. Retrospective studies require special attention to nonrandom assignment of participants to treatment groups and, consequently, to the need to appropriately account for baseline differences. OBJECTIVE: To examine the relative effectiveness of montelukast sodium vs fluticasone propionate as controller monotherapy in patients with asthma. METHODS: A retrospective cohort analysis of claims data from 6,160 individuals continuously enrolled in 1 of 20 US managed care plans. Patients using fluticasone were matched to those treated with montelukast using propensity scores and age (2-55 years). Health care use was determined for the 12-month periods before and after the initial controller prescription. Outcomes included asthma-related hospitalizations and emergency department visits, along with use of oral corticosteroids and short-acting beta-agonists. Logistic regression analyses were also performed. RESULTS: Overall, controller therapy significantly reduced the odds of postindex asthma-related hospitalizations (odds ratio, 0.56; 95% confidence interval, 0.38-0.79); no significant difference was observed with asthma-related emergency department visits (odds ratio, 0.89; 95% confidence interval, 0.76-1.04). Differences in the relative effect in the montelukast and fluticasone groups were not observed. Similarly, increases in the postindex rate of short-acting beta-agonist use and increases in oral corticosteroid use for both montelukast and fluticasone patients were noted. CONCLUSIONS: Similar outcomes were observed in montelukast and fluticasone users in this matched cohort analysis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15521374&dopt=Abstract fluticasone Flonase



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Efficacy of fluticasone propionate on lung function and symptoms in wheezy infants.

Hofhuis W, van der Wiel EC, Nieuwhof EM, Hop WC, Affourtit MJ, Smit FJ, Vaessen-Verberne AA, Versteegh FG, de Jongste JC, Merkus PJ; Anti-Inflammatory Treatment in Infants with Recurrent Wheeze (AIR) Study Group[.

Division of Respiratory Medicine, Department of Pediatrics, Erasmus University MC/Sophia Children's Hospital, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands.

The role of inhaled corticosteroids in the treatment of recurrent or persistent wheeze in infancy remains unclear. We evaluated the effect of 3 months of treatment with inhaled fluticasone propionate, 200 microg daily (FP200), on lung function and symptom scores in wheezy infants. Moreover, we evaluated whether infants with atopy and/or eczema respond better to FP200 as compared with non-atopic infants. Forced expiratory flow (Vmax(FRC)) was measured at baseline and after treatment. Sixty-five infants were randomized to receive FP200 or placebo, and 62 infants (mean age, 11.3 months) completed the study. Mean Vmax(FRC), expressed as a Z score, was significantly below normal at baseline and after treatment in both groups. The change from baseline of Vmax(FRC) was not different between the two treatment arms. After 6 weeks of treatment, and not after 13 weeks, the FP200 group had a significantly higher percentage of symptom-free days and a significant reduction in mean daily cough score compared with placebo. Separate analysis of treatment effect in infants with atopy or eczema showed no effect modification. We conclude that in wheezy infants, after 3 months of treatment with fluticasone, there was no improvement in lung function and no reduction in respiratory symptoms compared with placebo.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15531753&dopt=Abstract fluticasone Flonase



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Differential regulation of chemokine expression by peroxisome proliferator-activated receptor gamma agonists: interactions with glucocorticoids and beta2-agonists.

Nie M, Corbett L, Knox AJ, Pang L.

Division of Respiratory Medicine, City Hospital, University of Nottingham, Nottingham NG5 1PB, United Kingdom. mszmn1 gwmail.nottingham.ac.uk

Chemokine-mediated inflammatory cell infiltration is a hallmark of asthma. We recently demonstrated that glucocorticoids and beta(2)-agonists additively or synergistically suppress tumor necrosis factor-alpha (TNFalpha)-induced production of chemokines eotaxin and interleukin-8 (IL-8), respectively, in human airway smooth muscle (HASM) cells, which may partly explain their combined benefits in asthma. Peroxisome proliferator-activated receptors (PPARs) also modulate inflammatory gene expression. We reported here that the PPARgamma agonists 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) and troglitazone, but not PPARalpha agonist WY-14643, inhibited TNFalpha-induced production of eotaxin and monocyte chemotactic protein-1 (MCP-1) but not IL-8. Eotaxin inhibition was transcriptional and additively enhanced by the glucocorticoid fluticasone and the beta(2)-agonist salmeterol, whereas MCP-1 inhibition was post-transcriptional and additively and synergistically enhanced by fluticasone and salmeterol, respectively. Coimmunoprecipitation revealed that 15d-PGJ(2) induced a protein-protein interaction between PPARgamma and the glucocorticoid receptor (GR) in TNFalpha-treated HASM cells, which was enhanced by fluticasone and salmeterol. 15d-PGJ(2), fluticasone, and salmeterol all inhibited TNFalpha-induced histone H4 acetylation at the eotaxin promoter and NF-kappaB p65 binding to the eotaxin promoter and induced PPARgamma and GR association with the eotaxin promoter, as analyzed by chromatin immunoprecipitation assay. Our data suggest that chemokine expression in HASM cells is differentially regulated by PPARgamma agonists and that the interaction between PPARgamma and GR may be responsible for the additive and synergistic inhibition of chemokine expression by PPARgamma agonists, glucocorticoids, and beta(2)-agonists, particularly the chromatin-dependent suppression of eotaxin gene transcription. The interaction may have wide applications and may provide a potential target for pharmacological and molecular intervention.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15531761&dopt=Abstract fluticasone Flonase



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Systemic and pulmonary effects of fluticasone administered through a metered-dose inhaler in rats.

Sorkness RL, Remus JL, Rosenthal LA.

Morris Institute for Respiratory Research and the School of Pharmacy, University of Wisconsin, 777 Highland Avenue, Madison, WI 53705, USA. rlsorkne wisc.edu

BACKGROUND: Metered-dose inhalers (MDIs) are convenient, simple, inexpensive, and reproducible devices for administering aerosolized drugs through the pulmonary route, but methods have not been available for use of these devices in small animals. OBJECTIVE: We sought to test the efficacy of delivery of fluticasone through an MDI to rats with a rodent-adapted spacer chamber and to compare this treatment with systemic dexamethasone for the acute pulmonary allergic inflammatory response. METHODS: Changes in body and thymus weights were used as indicators for systemic steroid effects. Rats were sensitized to ragweed pollen extract 2 weeks before the experiment, and pulmonary allergic responses were evaluated 48 hours after a single aerosolized antigen challenge on the basis of bronchoalveolar leukocytes, lung tissue sections, total lung capacity, and forced expiratory volumes. RESULTS: Inhaled fluticasone caused dose-related systemic effects, indicating successful pulmonary drug delivery. Inhaled fluticasone was more effective than placebo but less effective than systemic dexamethasone in attenuating the increase in lung eosinophils and inflammatory infiltrates and the decrease in total lung capacity associated with the allergic inflammatory response. Inhaled fluticasone prevented airway obstruction and proximal inflammation, as did dexamethasone, but it appeared to have less effect in areas of lung served by the most distal airways. CONCLUSION: This is an effective method for use of MDIs to deliver inhaled drugs to small laboratory animals, and it should be valuable for investigations of treatment effects, as well as for in vivo testing of delivery devices.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15536405&dopt=Abstract fluticasone Flonase