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Inhibition of chemokine production from human airway smooth muscle cells by fluticasone, budesonide and beclomethasone.

John M, Oltmanns U, Binder C, Meiners S, Gellert K, Chung KF, Witt C.

Department of Pneumology, University Hospital Charite, Schumannstr. 20/21, Berlin 10098, Germany. matthias.john charite.de

Human airway smooth muscle cells (HASMC) contribute to the process of airway wall remodelling in asthma by virtue of their secretory functions. This study was performed to investigate the effectiveness of the commonly used steroids beclomethasone, budesonide and fluticasone in downregulating HASMC production of RANTES and IL-8. HASMC (n=5) were cultured from dissected bronchi using collagenase digestion. Confluent HASMC were exposed to TNFalpha and IL-1beta (10 ng/ml) for 24 h. All stimulations were set with and without pre-treatment with beclomethasone, budesonide or fluticasone for 2 h at concentrations of 10(-9)-10(-6)M. IL-8 and RANTES mRNA expression was assessed by RT-PCR and protein secretion was determined by ELISA. Pre-treatment with beclomethasone, budesonide or fluticasone reduced TNFalpha- and IL-1beta-stimulated IL-8 and RANTES release from HASMC in a dose dependent manner. However, beclomethasone was 22-28% less effective than fluticasone and budesonide in inhibiting chemokine production. TNFalpha- and IL-1beta-induced RANTES and IL-8 expression was reduced on the transcriptional level by pre-treatment with fluticasone and budesonide. The results suggest that the topical steroids fluticasone, budesonide and to a lesser extent beclomethasone may have beneficial effects on airway inflammation in asthma by reducing RANTES and IL-8-induced leukocyte infiltration into the airway wall.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14643170&dopt=Abstract fluticasone Flonase



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Drug disposition analysis: a comparison between budesonide and fluticasone.

Kallen A, Thorsson L.

AstraZeneca R&D Lund, S-221 87 Lund, Sweden. anders.kallen astrazeneca.com

The characterisation of distribution and elimination properties of a drug is usually done using parameters like clearance and distributional volumes. To refine this characterisation, in this paper, we use drug disposition analysis to compare the distribution and elimination of the two glucocorticosteroids budesonide and fluticasone propionate, known to differ in this respect. This gives a more detailed description of the well known differences in distributional volumes using concepts like mean residence time and fraction of dose outside the central compartment. It clearly shows that fluticasone, although having lower plasma concentrations, still resides in the body in appreciable quantities.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14650373&dopt=Abstract fluticasone Flonase



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Simultaneously evaluating the effects of one-week fluticasone propionate inhalation therapy on lung ventilation and permeability in children with asthma.

Chen AC, Tsai FJ, Tsai CH, Lin CC, Lee CC, Kao CH.

Department of Pediatrics, China Medical University Hospital, Taichung, Taiwan.

This study evaluated the effects of fluticasone propionate inhalation therapy on lung ventilation and alveolar permeability by quantitative Tc-99m DTPA radioaerosol inhalation lung scintigraphy in 15 children with asthma. Lung ventilation was evaluated as the distribution percentage (D%) of Tc-99m DTPA radioaerosols in the central, intermediate and peripheral regions of the right lung. Alveolar permeability was measured by the rate of Tc-99m DTPA radioaerosol clearance curve from the peripheral alveoli of the right lung and represented as slope. The D% and slopes were calculated before and after one-week inhalation therapy (100 microg fluticasone propionate two times daily for one-week) to evaluate the effects of inhalation therapy on lung ventilation and alveolar permeability. The preliminary results revealed statistically significantly improved lung ventilation but no significant change of alveolar permeability in the right lung after one-week fluticasone propionate inhalation therapy in children with asthma. We suggest that the widely available and noninvasive Tc-99m DTPA radioaerosol inhalation lung scintigraphy can simultaneously evaluate lung ventilation and alveolar permeability in one study and should contribute to any disorder involving both alveoli and airways.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14705772&dopt=Abstract fluticasone Flonase



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Pro- and anti-inflammatory factors cooperate to control hyaluronan synthesis in lung fibroblasts.

Wilkinson TS, Potter-Perigo S, Tsoi C, Altman LC, Wight TN.

Department of Vascular Biology, The Hope Heart Institute, Seattle, WA 98104-2046, USA.

Hyaluronan (HA) is an important constituent of the extracellular matrix and accumulates during inflammatory lung diseases like asthma. Little is known about the factors that regulate HA synthesis by lung cells. Accordingly, we investigated the effect of T-helper 1 (TH1) and 2 (TH2) cytokines and the anti-inflammatory agents fluticasone and salmeterol on HA synthesis in human lung fibroblasts. Interleukin-1beta (IL-1beta) and tumor necrosis factor (TNF)-alpha were the most potent stimulators of HA synthesis and when combined, caused synergistic increases in HA accumulation. Time-course analysis of HA accumulation and [3H]-glucosamine incorporation into HA demonstrated continued synthesis over the 24 h of stimulation. Peak synthesis at 6-12 h coincided with an increased proportion of high molecular weight HA. Reverse transcriptase polymerase chain reaction (RT-PCR) revealed that IL-1beta and TNF-alpha induced HA synthase-2 messenger RNA (mRNA) 3 h following stimulation and remained elevated throughout the 24-h stimulation period. Fluticasone inhibited IL-1beta and TNF-alpha induced HA synthesis (44.5%) whereas salmeterol had no effect. When combined, fluticasone and salmeterol inhibited HA synthesis to a greater extent (85.2%). Further, fluticasone attenuated IL-1beta and TNF-alpha stimulated hyaluronan synthase-2 messenger RNA (mRNA), and the addition of salmeterol cooperatively enhanced this inhibition. These results indicate that enhanced synthesis of HA by the proinflammatory cytokines IL-1beta and TNF-alpha can be abrogated by specific corticosteroid and beta2 blocker combinations shown to be effective in the treatment of asthma.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14764429&dopt=Abstract fluticasone Flonase



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Determining factors of aerosol deposition for four pMDI-spacer combinations in an infant upper airway model.

Janssens HM, Krijgsman A, Verbraak TF, Hop WC, de Jongste JC, Tiddens HA.

Department of Pediatrics, Division of Respiratory Medicine, Erasmus MC-Sophia Children's Hospital, 3000 CB Rotterdam, The Netherlands.

The aim of this study was to measure and compare the influence of tidal volume (Vt) respiratory rate (RR) and pMDI/spacer combination on aerosol deposition of 4 pMDI/spacer combinations, which are used for infants. An anatomically correct upper airway model of a 9-month-old infant was connected to a breathing simulator. Sinusoidal breathing patterns were simulated with; duty cycle T(i)/T(tot) = 0.42, Vt: 25, 50, 75, 100, 150, 200 ml (RR: 30 breaths/min); and RR: 20, 30, 42, 60, 78 breaths/min (Vt: 100 mL). pMDI/Spacers tested were: budesonide 200 microg/Nebuchamber, fluticasone 125 microg/Babyhaler and both budesonide and fluticasone with Aerochamber. Plastic spacers were detergent coated to reduce electrostatic charge. Spacer-output and lung dose were measured by a filter positioned between spacer and facemask or between model and breathing simulator. Particle size distribution of lung dose was assessed with an impactor during simulated breathing. Spacer-output was significantly positively correlated with Vt for all pMDI/spacers (all R > 0.77, p < 0.001), but not correlated with RR. Lung doses initially increased from Vt = 25 to 50 mL (Nebuchamber, Aerochamber) or to 100 mL (Babyhaler) and then decreased, with increasing Vt and RR (R: -0.98 to -0.82, p < 0.001). Lung doses of fluticasone were 1.5-6-fold higher compared with budesonide, irrespective of spacer type (p < 0.001). MMAD decreased with increasing Vt and RR. Dose to the lungs of particles <2.1 microm was independent of Vt and RR. Lung dose decreases with increasing inspiratory flow (increasing Vt or RR) by increasing impaction of coarse particles in the upper airways. Deposition of particles <2.1 microm is relatively flow independent. When electrostatic charge of spacers is reduced, lung dose is pMDI dependent and spacer independent.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15120013&dopt=Abstract fluticasone Flonase