The interleukin-1 type 2 receptor gene displays immediate early gene responsiveness in glucocorticoid-stimulated human epidermal keratinocytes.
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Human epidermal keratinocytes (HEKs) in primary culture (P2-P4) were used to study glucocorticoid (GC)-mediated transcription of the genes encoding the constitutively expressed interleukin-1 type 1 receptor (IL-1R1) and the inducible interleukin-1 type 2 receptor (IL-1R2). Utilizing Northern dot blot analysis and a quantitative reverse transcription-polymerase chain reaction protocol for IL-1R1 and IL-1R2, dexamethasone and, in particular, the budesonide epimer R were shown to effectively and rapidly induce transcription from the IL-IR2 gene when compared with IL-1R1 or beta-actin RNA message levels in the same sample. Southern blot analysis of newly generated IL-1R2 reverse transcription-polymerase chain reaction products using end-labeled IL-1R2 intron probes suggested that GC enhancement of IL-1R2 expression was regulated primarily at the level of de novo transcription. GC-induced IL-1R2 gene transcription displayed features characteristic of a classical immediate early gene response, including a signal transduction function, a relatively low basal abundance, a rapid, transient induction, cycloheximide superinduction, actinomycin D suppression, and a rapid decay of IL-1R2 RNA message. Parallel time course kinetic analysis of IL-1R2 RNA message levels with Western immunoblotting revealed tight coupling of de novo IL-IR2 gene transcription with translation of the IL-1R2 RNA message; a newly synthesized ( approximately 46-kDa) IL-1R2 protein was detected in the HEK growth medium as early as 1 h after budesonide epimer R treatment. These data indicate that different GC compounds can variably up-regulate the IL-1R2 response in HEKs through transcription-mediated mechanisms and, for the first time, suggest that a gene encoding a soluble cytokine receptor can respond like an immediate early gene. (+info)
Randomised controlled trial of budesonide for the prevention of post-bronchiolitis wheezing.
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BACKGROUND: Previous studies suggest that recurrent episodes of coughing and wheezing occur in up to 75% of infants after acute viral bronchiolitis. AIM: To assess the efficacy of budesonide given by means of a metered dose inhaler, spacer, and face mask in reducing the incidence of coughing and wheezing episodes up to 12 months after acute viral bronchiolitis. METHODS: Children under the age of 12 months admitted to hospital with acute viral bronchiolitis were randomised to receive either budesonide or placebo (200 microg or one puff twice daily) for the next eight weeks. Parents kept a diary card record of all episodes of coughing and wheezing over the next 12 months. RESULTS: Full follow up data were collected for 49 infants. There were no significant differences between the two study groups for the number of infants with symptom episodes up to six months after hospital discharge. At 12 months, 21 infants in the budesonide group had symptom episodes compared with 12 of 24 in the placebo group. The median number of symptom episodes was 2 (range, 0-13) in those who received budesonide and 1 (range, 0-11) in those who received placebo. Because there is no pharmacological explanation for these results, they are likely to be caused by a type 1 error, possibly exacerbated by there being more boys in the treatment group. CONCLUSION: Routine administration of budesonide by means of a metered dose inhaler, spacer, and face mask system immediately after acute viral bronchiolitis cannot be recommended. (+info)
A cortisol suppression dose-response comparison of budesonide in controlled ileal release capsules with prednisolone.
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AIM: To assess the systemic effect of oral budesonide, given as Entocort controlled ileal release capsules, over a dose range of 3-15 mg/day, compared with that of a moderate dose (20 mg/day) of prednisolone. METHODS: Twenty four healthy subjects were given 3, 9 or 15 mg budesonide or 20 mg prednisolone once daily, or 4.5 mg budesonide b.d., or placebo for 5 days in a randomized, double-blind crossover study. The area under the curve (AUC) of plasma cortisol concentration and the amount of cortisol excreted in the urine were monitored. RESULTS: Both plasma and urine cortisol suppression showed a dose-response for the daily doses of budesonide. Prednisolone, 20 mg, suppressed plasma cortisol (AUC) statistically significantly more than 15 mg budesonide (P = 0.014), and 3 mg budesonide statistically significantly more than placebo (P = 0.010). No difference in AUC was detected between 9 mg and 4.5 mg budesonide b.d. Similar results for budesonide vs. placebo were obtained from urine cortisol excretion data. However, prednisolone affected urine cortisol less than it affected plasma cortisol. CONCLUSION: After 5 days of administration, budesonide controlled ileal release capsules, in both clinical (9 mg/day) and high doses (15 mg/day), affected plasma cortisol less than a moderate (20 mg/day) dose of prednisolone. (+info)
Systemic availability and pharmacokinetics of nebulised budesonide in preschool children.
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AIM: To evaluate the systemic availability and basic pharmacokinetic parameters of budesonide after nebulisation and intravenous administration in preschool children with chronic asthma. METHODS: Plasma concentrations of budesonide were measured for three hours after an intravenous infusion of 125 micrograms budesonide. The children then inhaled a nominal dose of 1 mg budesonide through the mouthpiece of a Pari LC Jet Plus nebuliser connected to a Pari Master compressor, and the plasma concentrations of budesonide were measured for another six hours. The amount of budesonide inhaled by the patient ("dose to subject") was determined by subtracting from the amount of budesonide put into the nebuliser, the amount remaining in the nebuliser after nebulisation, the amount emitted to the ambient air (filter), and the amount found in the mouth rinsing water. RESULTS: Ten patients aged 3 to 6 years completed both the intravenous and the inhaled treatment. The mean dose to subject was 23% of the nominal dose. The systemic availability of budesonide was estimated to be 6.1% of the nominal dose (95% confidence intervals (CI), 4.6% to 8.1%) or 26.3% of the dose to subject (95% CI, 20.3% to 34.1%). Budesonide clearance was 0.54 l/min (95% CI, 0.46 to 0.62), steady state volume of distribution 55 litres (95% CI, 45 to 68), and the terminal half life was 2.3 hours (95% CI, 2.0 to 2.6). CONCLUSIONS: Approximately 6% of the nominal dose (26% of the dose to subject) reached the systemic circulation of young children after inhalation of nebulised budesonide. This is about half the systemic availability found in healthy adults using the same nebuliser. (+info)
One year prospective open study of the effect of high dose inhaled steroids, fluticasone propionate, and budesonide on bone markers and bone mineral density.
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BACKGROUND: Inhaled corticosteroids are recognised as the most effective agents in the treatment of asthma. However, concerns have been expressed about the effects of high doses of inhaled corticosteroids on safety in relation to bone resorption and formation. This study measures the effects of two inhaled corticosteroids on bone markers and bone mineral density (BMD) over one year. METHODS: A one year randomised, prospective, open parallel study comparing inhaled fluticasone propionate (FP), 500 micrograms twice daily in 30 patients, and budesonide (BUD), 800 micrograms twice daily in 29 patients, delivered by metered dose inhaler and large volume spacers was performed in adults with moderate to severe asthma. Biochemical markers of bone turnover (osteocalcin, procollagen type 1 C-terminal propeptide (PICP), immunoreactive free deoxypyridinoline (iFDpd), N-terminal crosslinked telopeptides of type I collagen (NTx)), BMD at the spine and femoral neck, and serum cortisol concentrations were measured at baseline and 12 months later. RESULTS: There were no significant differences between the inhaled steroids on bone markers of bone resorption and formation or bone mineral density. Bone mineral density of the spine increased slightly in both groups over the 12 month period. Serum osteocalcin levels increased from baseline in both treatment groups (FP 16.9%, p = 0.02; BUD 14.3%, p = 0.04). PICP did not differ significantly from baseline. Both markers of bone resorption (iFDpd, NTx) varied considerably with no significant changes after one year. There was a significant correlation in percentage change from baseline between BMD of the spine and osteocalcin at 12 months (r = 0.4, p = 0.017). Mean serum cortisol levels remained within the normal range in both groups following treatment. CONCLUSION: There was no evidence of a decrease in BMD during 12 months of treatment with high doses of either FP or BUD. The change in spine BMD correlated with the increase in osteocalcin. Studies extending over several years are needed to establish whether these findings persist. (+info)
Peak flow variation in childhood asthma: correlation with symptoms, airways obstruction, and hyperresponsiveness during long-term treatment with inhaled corticosteroids. Dutch CNSLD Study Group.
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BACKGROUND: Guidelines for asthma management focus on treatment with inhaled corticosteroids and on home recording of peak expiratory flow (PEF). The effect of maintenance treatment with inhaled corticosteroids on PEF variation and its relation to other parameters of disease activity were examined in 102 asthmatic children aged 7-14 years. METHODS: During 20 months of treatment with inhaled salbutamol, with or without inhaled budesonide (600 micrograms daily), forced expiratory volume in one second (FEV1), the dose of histamine required to provoke a fall in FEV1 of more than 20% (PD20), the percentage of symptom free days, and PEF variation were assessed bimonthly. PEF variation was computed as the lowest PEF as a percentage of the highest PEF occurring over 14 days, the usual way of expressing PEF variation in asthma self-management plans. For each patient using inhaled corticosteroids within subject correlation coefficients (rho) were computed of PEF variation to the percentage of symptom free days, FEV1, and PD20. RESULTS: PEF variation decreased significantly during the first two months of treatment with inhaled corticosteroids and then remained stable. The same pattern was observed for symptoms and FEV1. In contrast, PD20 histamine continued to improve throughout the whole follow up period. In individual patients predominantly positive associations of PEF variation with symptoms, FEV1, and PD20 were found, but the ranges of these associations were wide. CONCLUSIONS: During treatment with inhaled corticosteroids the changes in PEF variation over time show poor concordance with changes in other parameters of asthma severity. When only PEF is monitored, clinically relevant deteriorations in symptoms, FEV1, or PD20 may be missed. This suggests that home recording of PEF alone may not be sufficient to monitor asthma severity reliably in children. (+info)
Effect of differing doses of inhaled budesonide on markers of airway inflammation in patients with mild asthma.
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BACKGROUND: It is desirable to prescribe the minimal effective dose of inhaled steroids to control asthma. To ensure that inflammation is suppressed whilst using the lowest possible dose, a sensitive and specific method for assessing airway inflammation is needed. METHODS: The usefulness of exhaled nitric oxide (NO), sputum eosinophils, and methacholine airway responsiveness (PC20) for monitoring airway inflammatory changes following four weeks of treatment with an inhaled corticosteroid (budesonide via Turbohaler) were compared. Mild stable steroid naive asthmatic subjects were randomised into two double blind, placebo controlled studies. The first was a parallel group study involving three groups receiving either 100 micrograms/day budesonide (n = 8), 400 micrograms/day budesonide (n = 7), or a matched placebo (n = 6). The second was a crossover study involving 10 subjects randomised to receive 1600 micrograms budesonide or placebo. The groups were matched with respect to age, PC20, baseline FEV1 (% predicted), exhaled NO, and sputum eosinophilia. RESULTS: There were significant improvements in FEV1 following 400 micrograms and 1600 micrograms budesonide (11.3% and 6.5%, respectively, p < 0.05). This was accompanied by significant reductions in eosinophil numbers in induced sputum (0.7 and 0.9 fold, p < 0.05). However, levels of exhaled NO were reduced following each budesonide dose while PC20 was improved only with 1600 micrograms budesonide. These results suggest that exhaled NO and PC20 may not reflect the control of airway inflammation as accurately as the number of eosinophils in sputum. There were dose dependent changes in exhaled NO, sputum eosinophils, and PC20 to inhaled budesonide but a plateau response of exhaled NO was found at a dose of 400 micrograms daily. CONCLUSION: Monitoring the number of eosinophils in induced sputum may be the most accurate guide to establish the minimum dose of inhaled steroids needed to control inflammation. This, however, requires further studies involving a larger number of patients. (+info)
Randomised trial of an inhaled beta2 agonist, inhaled corticosteroid and their combination in the treatment of asthma.
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BACKGROUND: Although many asthmatic patients are treated with a combination of beta2 agonist and corticosteroid inhalers, the clinical effects of combining the drugs are unknown. Studies on the early asthmatic response to allergen suggest that beta2 agonists may reduce the benefit of inhaled corticosteroids. A study of the effects of combining the drugs on asthma control was undertaken. METHODS: Sixty one subjects with mild to moderate asthma were randomised to a double blind crossover comparison of inhaled budesonide (200-400 microg twice daily), terbutaline (500-1000 microg four times daily), combined treatment, and placebo. Each treatment was given for six weeks following a four week washout period. Ipratropium was used for symptom relief. Treatments were ranked from worst (1) to best (4) based on need for oral steroid, mean morning peak flow, nocturnal awakening, ipratropium use, and asthma symptoms. Lung function and bronchial hyperresponsiveness were measured before and after each treatment. RESULTS: Evaluable data for all four treatments were obtained from 47 subjects. The mean rank of each treatment was: placebo = 2.05; terbutaline = 2.13; budesonide = 2.48; combined treatment = 3.34. Combined treatment was ranked significantly better than any other treatment (p<0.01). Mean (95% CI) morning and evening peak flows were 14 (5 to 23) and 24 (15 to 34) l/min higher, respectively, during combined treatment than during budesonide, and 27 (17 to 37) and 15 (7 to 23) l/min higher than during terbutaline. Asthma symptoms tended to be least frequent during combined treatment but were not significantly different from budesonide alone. There was no significant difference between combined treatment and budesonide alone for lung function and bronchial hyperresponsiveness. CONCLUSIONS: In this group of mild to moderate asthmatic subjects the combination of beta2 agonist and corticosteroid gave better asthma control than either treatment alone. There was no evidence that regular beta2 agonist treatment impaired the beneficial effect of inhaled corticosteroid. (+info)