Maximal response plateau to methacholine as a reliable index for reducing inhaled budesonide in moderate asthma.
(17/669)
Although some studies suggest that asthma deteriorates after reducing inhaled steroids, results of long-term studies indicate that this might not be true for all patients. The aim of this study was to determine the utility of the detection of a plateau on the concentration-response curves to inhaled methacholine as a marker for safely reducing the dose of inhaled budesonide in asthmatic patients who are well-controlled with a moderately high dose of this inhaled steroid. A total of 46 patients with moderate asthma, well-controlled for at least 6 months by treatment with 800 microg budesonide daily, were included in the study. Subjects were treated for a 2-week run-in period with their usual dose of budesonide. At the end of the run-in, all subjects were challenged with methacholine (0.095-200 mg x mL(-1)). Plateau responses, median effective concentration values, slopes and provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second (FEV1) values were measured. For the subsequent 12 weeks, patients were treated in an open design with budesonide at a reduced dose (200 microg once daily), and were asked to record their peak expiratory flow (PEF) in the morning and in the evening. In addition, asthma symptoms and use of rescue terbutaline were recorded in diaries. Plateaus were present in 24 patients, whereas 22 subjects showed concentration-response curves without evidence of a plateau. Ten patients in the nonplateau group deteriorated after reducing inhaled budesonide, compared to one patient in the plateau group (p = 0.002). In the nonplateau group, FEV1 decreased from a baseline value of 3.28+/-0.19 L to 2.94+/-0.20 L at week 12 (p<0.0001). Likewise, morning PEF decreased from 419+/-19 L x min(-1) at baseline to 394+/-19 L x min(-1) at week 12 (p = 0.02). By contrast, these variables remained unchanged in the plateau group. In conclusion, in asthmatic patients, well-controlled with a moderately high dose of budesonide, the detection of a plateau on the concentration-response curve to inhaled methacholine may be used as a marker for safely reducing the corticosteroid dose. (+info)
Mucosal inflammation in severe glucocorticoid-dependent asthma.
(18/669)
To improve our understanding of the inflammatory mechanisms underlying severe disease, a biopsy study was performed comparing 15 clinically unstable glucocorticoid-dependent asthmatics, 10 mild asthmatics, and 10 control subjects. Compared with mild asthma, severe asthma was characterized by reduced mucosal eosinophilia. Whilst no significant differences were found in the numbers of mast cells, neutrophils, CD3+ and CD4+ T-cells between the three groups, up to a 4-fold increase In the numbers of activated T-lymphocytes bearing the interleukin (IL)-2 receptor (IL-2R) was found in the mucosa in severe asthma compared to mild asthma (p = 0.03) and control subjects (p = 0.003). Compared to control subjects, the mucosa of severe asthmatics contained significantly (p = 0.02) higher numbers of IL-5+ cells, with no differences between mild and severe disease. In contrast, staining for the anti-IL-4 monoclonal antibody 3H4 revealed that biopsies from mild asthmatics contained more IL4+ cells than biopsies from severe asthmatics and control subjects (p = 0.0008). In the severe asthmatics, a close correlation (r(s) = 0.76, p = 0.005) was found between the numbers of IL-2R-bearing cells and the variability in peak expiratory flow. In conclusion, persistent T-cell activation is a prominent feature of severe asthma. These results also indicate that interleukin-5, and not interleukin-4, is upregulated in severe disease. (+info)
Adrenalectomy permits a late, local TNF-alpha release in LPS-challenged rat airways.
(19/669)
The normal rise of circulating endogenous glucocorticosteroids (GCS), in response to immunological stimuli, can be impaired in patients with inflammatory diseases. The aim of this study was to investigate whether abolition of the endogenous GCS response promotes local production of the pro-inflammatory cytokine, tumour necrosis factor (TNF)-alpha, in challenged airways and affects the cellular response in rats. In adrenalectomized or sham operated rats, the trachea and main bronchi were lavaged at various times after intratracheal instillation of low dose lipopolysaccharide (LPS). TNF-alpha in lavage fluid and plasma corticosterone were measured, and cells were differentiated. In adrenalectomized rats, LPS-induced in the airways a biphasic TNF-alpha release peaking at 2 and 6 h, whereas in sham operated rats the second peak was absent; probably inhibited by the strong rise of plasma corticosterone. The second peak was abolished in adrenalectomized rats by pretreatment with exogenous GCS. The LPS-induced neutrophil influx and a decrease in mononuclear cells were prolonged in adrenalectomized rats. In conclusion, abolition of the endogenous glucocorticosteroid response promotes the late release of tumour necrosis factor-alpha in the airways and prolongs the cellular response. This suggests that a normal rise of endogenous glucocorticosteroid after an immunological trigger contributes to a dampening of the late inflammatory activity. (+info)
NO in exhaled air is correlated with markers of eosinophilic airway inflammation in corticosteroid-dependent childhood asthma.
(20/669)
The relationship between nitric oxide in exhaled air, levels of sputum eosinophils, sputum eosinophil cationic protein (ECP) and urinary eosinophil protein X (EPX) excretion has not yet been investigated in corticosteroid-dependent childhood asthma. Therefore, taking 25 children with stable asthma (mean age 11.2 yrs) treated with inhaled corticosteroids and nine nonatopic healthy control children (mean age 12.8 yrs) the level of exhaled NO was measured by means of a chemiluminescence analyser before and after sputum induction. This was conducted as a slow vital capacity manoeuvre under standardized conditions with a target flow of 70 mL x s(-1) against a resistance of 100 cm H2O x L(-1) x s. Sputum induction was performed by inhalation of hypertonic saline (3, 4, and 5%) in a standardized manner and a single sample of urine was collected. Exhaled NO (p = 0.01), absolute eosinophil cell counts in sputum (p = 0.02), sputum ECP (p = 0.09) and urinary EPX excretion (p = 0.02) were higher in asthmatics compared to control children. Exhaled NO was positively correlated with sputum ECP (r(s) = 0.59, p = 0.002), urinary EPX (r(s) = 0.42, p = 0.03), and sputum eosinophils (r(s) = 0.30, p = 0.15) in the asthmatic children. These correlations appeared to be pronounced after sputum induction, where NO values had decreased (p = 0.01). None of the correlations were observed in the group of nonatopic control subjects. Additionally there were significant correlations between sputum ECP and sputum eosinophils (r(s) = 0.69, p<0.001) as well as between sputum ECP and urinary EPX excretion (r(s) = 0.58, p = 0.003) in the asthmatics. Exhaled NO provides information about the degree of eosinophilic airway inflammation and thus appears to be a useful and easy-to-perform inflammatory marker in corticosteroid-dependent asthma. (+info)
The cost-effectiveness of inhaled fluticasone propionate and budesonide in the treatment of asthma in adults and children.
(21/669)
Inhaled corticosteroids form the mainstay of the treatment and management of asthma and the results of a meta-analysis comparing two of the most frequently prescribed inhaled corticosteroids, fluticasone propionate and budesonide, administered in a clinically equivalent 1:2 dose ratio to 1980 patients with asthma, demonstrated that fluticasone propionate had an improved efficacy:safety ratio. However, limited data are available on the relative economic benefits of fluticasone propionate and budesonide. The database for clinically relevant parameters, for which the efficacy:safety meta-analysis had demonstrated statistical significance between the two corticosteroids, was used for this pharmacoeconomic analysis. Treatment with fluticasone propionate was more cost-effective than budesonide with respect to improvement in morning peak expiratory flow rate, successfully treated weeks, symptom-free days, symptom-free 24 h and episode-free days. The costs of treatment for fluticasone propionate and budesonide were 7.78 Pounds per week and 12.33 Pounds per week, respectively. The main contributing factor to the higher costs of budesonide was the higher cost of health care contacts, which were 4.53 Pounds per week for budesonide and 0.57 Pounds per week for fluticasone propionate. The pharmacoeconomic difference increased in favour of fluticasone propionate as the criteria for success were made more stringent. These results demonstrate that, for asthma patients requiring modification of therapy treatment with fluticasone propionate is more effective and also cheaper, in terms of overall health-care costs, than treatment with budesonide. (+info)
Patient compliance in a clinical trial with inhaled budesonide in children with mild asthma.
(22/669)
Children's use of inhalation devices can give valuable information about their adherence to asthma therapy. The aim of this study was to examine treatment adherence of low dose inhaled budesonide or placebo administered via Turbuhaler twice daily in children with mild asthma participating in an asthma trial, by comparing diary registration with the number of doses remaining in the inhaler. A total of 163 children (age 7-16 yrs, 56 females, 107 males) with mild asthma (mean baseline forced expiratory volume in one second (FEV1) was 103% of predicted), were included into a double blind, randomized study. After a two-week run-in period, the children received inhaled budesonide, either 100 microg or 200 microg daily, and/or placebo for 12 weeks. All patients used daily diary cards throughout the study. Results from 161 patients were analysed. Mean compliance according to the diary was 93%, whereas estimated mean compliance when counting remaining doses in the Turbuhaler was 77%. Overuse of medication was found in 7% of the children. There was no significant difference in compliance between sex in the study group, whereas children aged < or =9 yrs had significantly better drug adherence than older children. No significant relationship was found between symptom score and compliance. In conclusion, even with optimal patient follow-up in a clinical trial, adherence to prophylactic asthma treatment is considerably lower than the patients own reports from the use of daily diary cards. (+info)
Dose-proportional pharmacokinetics of budesonide inhaled via Turbuhaler.
(23/669)
AIMS: The present pharmacokinetic study was undertaken to determine the dose proportionality of three different doses of budesonide-400 microg, 800 microg or 1600 microg administered twice daily by a dry-powder inhaler (Turbuhaler ) in adult patients with mild asthma. METHODS: A total of 38 patients received budesonide by inhalation, 13 received 400 microg twice daily, 12 received 800 microg twice daily and 13 received 1600 microg twice daily. Mean FEV1 at inclusion was 3.4, 4.0 and 3.9 l min-1 in the three groups, respectively. Blood samples were taken after a single dose, and after 3 weeks of daily treatment, for pharmacokinetic evaluation. Plasma concentrations of budesonide were determined by liquid chromatography plus mass spectrometry. RESULTS: Eleven evaluable patients remained in each dose group. Mean time to peak budesonide plasma concentration (tmax ) was short (0.28-0.40 h) and did not differ between treatment groups. Budesonide concentrations declined rapidly thereafter, indicating efficient pulmonary absorption and rapid elimination with a half-life of approximately 3 h. Cmax was 1. 4(2.0) nmol l-1 (single (repeated) doses), 2.6(3.6) nmol l-1 and 5. 4(6.4) nmol l-1 after 400, 800 and 1600 microg twice daily, respectively. The corresponding results for the area under the plasma concentration vs time curve (AUC) were 271(325), 490(628) and 915(1096) nmol l-1 min. Ninety percent confidence intervals for pairwise dose-normalized Cmax and AUC comparisons between groups were large but contained unity in all cases, thus indicating dose-proportional pharmacokinetics. Regression on analysis supported these findings. Mean AUC after repeated doses (AUC(0,12 h,RD)) was on average 23% higher than the mean AUC after single doses (AUC(0, infinity,SD)(P=0.04) with no significant differences between doses, indicating slight accumulation following bid dosing. CONCLUSIONS: In this relatively small study, budesonide inhaled via Turbuhaler appeared to have dose-proportional pharmacokinetics, both within and above the clinically recommended dose range for asthmatic patients. (+info)
Damage to the enteric nervous system in experimental colitis.
(24/669)
Inflammation of the intestine causes pain and altered motility, at least in part through effects on the enteric nervous system. While these changes may be reversed with healing, permanent damage may contribute to inflammatory bowel disease (IBD) and post-enteritis irritable bowel syndrome. Since little information exists, we induced colitis in male Sprague-Dawley rats with dinitrobenzene sulfonic acid and used immunocytochemistry to examine the number and distribution of enteric neurons at times up to 35 days later. Inflammation caused significant neuronal loss in the inflamed region by 24 hours, with only 49% of neurons remaining by days 4 to 6 and thereafter, when inflammation had subsided. Eosinophils were found within the myenteric plexus at only at the earliest time points, despite a general infiltration of neutrophils into the muscle wall. While the number of myenteric ganglia remained constant, there was significant decrease in the number of ganglia in the submucosal plexus. Despite reduced neuronal number and hyperplasia of smooth muscle, the density of axons among the smooth muscle cells remained unchanged during and after inflammation. Intracolonic application of the topical steroid budesonide caused a dose-dependent prevention of neuronal loss, suggesting that evaluation of anti-inflammatory therapy in inflammatory bowel disease should include quantitative assessment of neural components. (+info)