Effect of inhaled budesonide on oropharyngeal, Gram-negative bacilli colonization in asthma patients

BACKGROUND AND OBJECTIVE: The effect of inhaled budesonide on oropharyngeal Gram-negative bacilli colonization (OGNBC) in asthmatic patients was investigated. METHODS: Oropharyngeal cultures were obtained from asthmatic patients attending the hospital respiratory outpatient clinic, at baseline and 1 month after treatment with 800 microg/day of inhaled budesonide. Cultures were evaluated for OGNBC and compared with those of healthy controls. RESULTS: A total of 148 cultures (74 from asthma patients, 74 from healthy controls) were evaluated. Six cultures (8.1%) from healthy controls, eight cultures (10.8%) from asthma patients obtained before treatment and 20 cultures (27.0%) obtained after treatment were positive for OGNBC (P < 0.05). Gender, age, presence of atopy and the degree of illness were not found to be related to the presence of OGNBC in and healthy control cultures. In the cultures obtained from the patients after treatment, OGNBC was higher in patients >50 years and in those with FEV1 < 70% (P < 0.05). Nine (18.8%) of 48 patients <50 years compare with 11 (42.3%) of the 26 patients >50 revealed OGNBC (P < 0.05). OGNBC were observed in 18.9% of the patients with FEV1 = 70% and in 47.6% of those with FEV1 < 70% (P < 0.05). CONCLUSIONS: The increased rate of OGNBC in asthma patients treated with inhaled budesonide was found to be related to increased age and lower level of FEV1. Further studies with larger numbers of patients are required for the interpretation of this colonization in the course of lower respiratory infections in these patients.     

The dose-response relationship of inhaled corticosteroids in asthma

Inhaled corticosteroids are the only class of asthma medication that can reduce symptoms, improve lung function, reduce the frequency of severe exacerbations, including hospital and ICU admissions, and decrease the risk of mortality. The therapeutic dose range for all clinical outcome measures in adults is 100 to 1000 ώg/d of beclomethasone dipropionate or budesonide, or 50 to 500 ώg/d of fluticasone propionate. Doses in excess of this range are not recommended for routine use because they are likely to increase the risk of systemic side-effects without further major improvement in efficacy. The recommendations are qualified by the recognition that there is considerable individual variability in the response to inhaled corticosteroids in asthma, which would suggest that some patients might obtain greater benefit at higher doses, just as some might obtain maximum benefit at lower doses.     

Effect of inhaled budesonide on bronchial hyperresponsiveness in adolescents with clinical remission of asthma

STUDY OBJECTIVE: Many children with asthma go into long-term clinical remission at adolescence, but bronchial hyperresponsiveness (BHR) persists in some of these subjects. The regular use of inhaled corticosteroids improves BHR in patients with symptomatic asthma. The aim of this study was to determine whether BHR in adolescents with asthma remission could be reduced by prolonged treatment with inhaled corticosteroids. DESIGN: A randomized, double-blind, placebo-controlled, parallel study. PATIENTS: Thirty-seven adolescents with BHR and long-term remission of their asthma (neither symptoms nor any medication use during the previous 2 years). INTERVENTION: Subjects received inhaled budesonide (two 200-microg puffs bid; budesonide group, n = 19) or identical placebo (placebo group, n = 18) for 9 months. A separate group of patients with symptomatic asthma (symptomatic group, n = 19), using the same regimen of budesonide, was also studied. MEASUREMENTS AND RESULTS: The provocative concentration of methacholine producing a 20% fall in FEV(1) (PC(20)) was measured before and every 3 months during treatment. There was no significant difference among the three groups for the baseline PC(20). In neither the placebo nor the budesonide group did the geometric mean of PC(20) change significantly over the 9-month period. In contrast, a significant increase in PC(20) was noted in the symptomatic group as a result of the budesonide treatment. CONCLUSION: Our data have shown that budesonide inhaled regularly for 9 months did not cause a significant improvement in the BHR of adolescents with long-term asthma remission. This suggests that the mechanism underlying BHR in this clinical setting may be different from that in symptomatic asthma.     

A comparison of inhaled budesonide and beclomethasone dipropionate in childhood asthma

The objective of this study was to compare the clinical effects of beclomethasone dipropionate (BDP) and budesonide in asthmatic children using two common ways of administration. Twenty-one children, aged 4-14 years, who regularly used inhaled corticosteroids for their control of asthma were included in the study. The drugs were studied by using a double-blind randomized cross-over design trial with a single-blind placebo period at the end. Each period lasted 3 weeks. The dosage was 100 micrograms b.i.d. for both drugs. Budesonide was administered via a spacer inhaler (Inhalet), and beclomethasone dipropionate via a standard actuator. Compared with placebo, both drugs significantly improved PEFR values for morning (20% for budesonide and 14% for BDP) and evening (14% for budesonide and 9% for BDP). Both morning and/or evening peak flows were significantly higher during the budesonide treatment as compared with the BDP treatment. In comparison with the placebo period, FEV1.0 was significantly improved with budesonide but not with BDP. Plasma cortisol, WBC counts, differential and eosinophilia counts in blood were determined at the beginning and the end of each period. All of the values except for the eosinophil counts were within normal ranges. Candida was looked for but not found in any case. No other adverse effects were registered. For most of the children, a deterioration of the state of their asthma and increased need for concomitant therapy during the placebo period confirmed their steroid dependence. The number of administrations with concomitant anti-asthmatic therapy increased during placebo by 61% as compared with the budesonide therapy, and by 40% compared with the BDP therapy.     

Serum leptin in children with asthma treated with inhaled budesonide.

Leptin, a 167-amino-acid peptide, is a recently discovered hormone which is believed to play a major role in the regulation of body weight. Systemic administration of exogenous glucocorticoids has been found to increase circulating leptin levels. In this study, we aimed to assess serum leptin in children with asthma treated with inhaled budesonide 800 micrograms day-1. Ten boys and three girls with asthma, all adolescents aged from 12.9 to 16.6 years, were studied in a randomized double-blind two-period cross-over trial with 4-week treatment periods and a 1-week wash out. Placebo was given during one period and 800 micrograms budesonide during the other via a 750 ml volume spacer (Nebuhaler, Astra Draco, Lund, Sweden). On the last day of the placebo and budesonide periods blood samples were taken and serum leptin was measured by a specific radioimmunoassay. The difference in mean (SEM) leptin concentration between the budesonide and placebo period was 0.2 (0.4) microgram l-1 (P = 0.71; t = -0.4; df = 12, 95% confidence interval -0.9-0.7 microgram l-1). Inhaled budesonide 800 micrograms per day from a Nebuhaler does not influence circulating leptin levels, suggesting that regulation of body weight is unaffected.     

Dose-response relationship of inhaled budesonide in adult asthma: a meta-analysis.

The aim of this study was to examine the dose-response relationship of inhaled budesonide in adolescents and adults with asthma. A meta-analysis was carried out on placebo-controlled, randomised clinical trials, presenting data on at least one outcome measure of asthma and using at least two doses of budesonide, delivered by turbuhaler or metered-dose inhaler + spacer twice daily. A total of six studies of 1,435 adolescents and adults, with mild to moderately severe asthma, met the inclusion criteria for the meta-analysis. A negative exponential model indicated that 80% of the benefit at 1,600 micrograms.day-1 was achieved at doses of approximately 200-400 micrograms.day-1 and 90% by 300-600 micrograms.day-1. Meta-regression with a quadratic term in dose showed that the maximum effect was obtained with doses of approximately 1,000 micrograms.day-1. In conclusion, the available published data indicate that, in adolescents and adults with mild to moderate asthma, most of the therapeutic benefit of budesonide delivered by turbuhaler or metered-dose inhaler + spacer is achieved with a dose of approximately 400 micrograms.day-1 and the maximum effect is achieved at approximately 1,000 micrograms.day-1. This conclusion is qualified by the recognition that there is considerable individual variability in the response to inhaled corticosteroids and that the subjects included in this meta-analysis had predominantly mild to moderate asthma.     

Effects of early intervention with inhaled budesonide on lung function in newly diagnosed asthma

STUDY OBJECTIVES: Asthmatic patients lose lung function faster than normal subjects. The effectiveness of early intervention with inhaled corticosteroids on this decline in lung function is not established in recent-onset disease. DESIGN: The Inhaled Steroid Treatment as Regular Therapy in Early Asthma study was a randomized, double-blind study in 7,165 patients (5 to 66 years old), with persistent asthma for < 2 years to determine whether early intervention with low-dose inhaled budesonide prevents severe asthma-related events and the decline in lung function. Patients received budesonide (200 mug qd for children < 11 years old and 400 mug qd for others) or placebo for 3 years in addition to usual asthma medications. RESULTS: Treatment with budesonide significantly improved prebronchodilator and postbronchodilator FEV(1) percentage of predicted and reduced the mean declines from baseline for postbronchodilator FEV(1) at 1 year and 3 years: - 0.62% and - 1.79% for budesonide and - 2.11% and - 2.68% for placebo, respectively (p < 0.001). The decline was more marked for male patients, active smokers, and patients > 18 years old, and the smallest treatment effects were in adolescents. CONCLUSIONS: Long-term, once-daily treatment with low-dose budesonide improved both prebronchodilator and postbronchodilator FEV(1) in patients with recent-onset, persistent asthma, and reduced the loss of lung function over time.     

Effect duration and dose-response relation of molsidomine in patients with coronary heart disease

The dose-effect relation and duration of action of 2 mg, 4 mg and 6 mg molsidomine on ischemic ST-segment depression in the exercise-ECG were determined in a randomized and double-blind acute study of 12 patients with confirmed coronary artery disease. With 2 mg molsidomine a significant reduction in the amount of ischemic ST-depression from 18.0 mm to 8.1 mm, 45% of the baseline-figure, resulted. With 6 mg molsidomine a diminuation of the ST-segment depression from 16.2 mm to 6 mm, approximately 40%, was noted. The significant antianginal effect of 2 mg molsidomine lasted at least 3 hours. After 5 hours an effect was seen only in some patients. 4 mg and 6 mg molsidomine still showed a significant reduction of ST-segment depression after 5 hours. A sufficient antianginal efect over 24 hours is only achieved with a 2-mg dose administered 5-6 times or with a 4-6 mg dose applied 4-5 times daily. The most marked fall in blood pressure was noticed after 6 mg molsidomine. On average, the systolic blood pressure fell 41 mm Hg (22%). Orthostatic reactions were not seen. The maximal dose-dependent plasma levels were 15.8 ng/ml, 30.1 ng/ml and 50.0 ng/ml. A definite, reliable clinical effect was seen in some cases from plasma levels above 2 ng/ml.     

Effect of inhaled budesonide on surfactant protein expression in asthmatic mice

Pulmonary surfactant dysfunction may significantly contribute to small airway obstruction during the asthmatic response. Inhaled corticosteroids have been routinely used in the treatment of asthma, but neither its exact role nor its regulation on pulmonary surfactant is completely understood. The aim of this study was to determine the effect of budesonide on surfactant protein (SP) expression in asthmatic mice. Moreover, we investigated the function of transforming growth factor (TGF) beta signaling in the pulmonary surfactant system to identify a novel target for the treatment of asthma. Mice were sensitized and challenged by ovalbumin (OVA) to establish a murine model of asthma. To assess the effect of budesonide on asthmatic mice, animals were treated with aerosolized budesonide before OVA challenge. The levels of TGF-beta(1) in bronchoalveolar lavage fluid were analyzed by ELISA. The expressions of TGF-beta type I receptor, TGF-beta type II receptor, Smad2/3, Smad4, Smad7, and SPs were measured by immunochemistry technique and computerized image analysis system. SP-A and SP-B were significantly decreased after allergic sensitization and challenge, accompanied by active TGF-beta/Smad signal transduction. A dramatic increase in the expressions of SP-A and SP-B was observed after budesonide treatment. This was also accompanied by up-regulation of Smad7 expression and down-regulation of TGF-beta type I receptor expression. A possible explanation for the result is that an early budesonide inhaled treatment inhibits TGF-beta-induced reduction of SP-A and SP-B expression through inhibition of active TGF-beta/Smad signal transduction pathway in asthmatic mice. TGF-beta signaling may be a potentially important therapeutic target for antiasthma drugs.     

小量吸入布地乃德对支气管哮喘的疗效

目的研究小剂量吸入激素合用茶碱对中度哮喘患者症状、肺功能的影响。方法通过4周较大剂量(布地乃德BUD400ug bid)治疗,66例中度哮喘患者随机分为3组,包括A组吸入BUD300μg bid;B组BUD100μg bid;C组BUD100μg bid并加用茶碱缓释片200mg口服每天2次,以上治疗共6月。结果4周大剂量基础治疗后,患者症状明显缓解、肺功能明显改善,并且在以后4个月的治疗研究阶段患者多较稳定,只有少数急性发作,急性发作次数或天数,C组少于B组(P<0.05),各组患者肺功能进一步好转,但B组肺功能变化与基础治疗后比较差异不显著。结论大剂量BUD吸入对中度哮喘具有良好的治疗效果,在稳定阶段给予小剂量BUD加用茶硷似有更好疗效。     

Addition of montelukast versus double dose of inhaled budesonide in moderate persistent asthma

BACKGROUND: Although current guidelines suggest the use of inhaled corticosteroids as the first line therapy in persistent asthma, the concerns about high-dose corticosteroids may limit their usage. We aimed to investigate the efficacy of inhaled budesonide plus oral montelukast versus a double dose of inhaled budesonide. METHODOLOGY: Thirty patients with moderate asthma took part in the study. Following a 2-week run in period, the patients were randomized into two groups to receive 400 microg/day of inhaled budesonide plus 10 mg/day of montelukast (BUD + M group) or 800 microg/day of inhaled budesonide (high BUD group). The patients were evaluated at 2-week intervals (during a total treatment period of 6 weeks) for symptom scores, asthma exacerbations, lung function, use of short-acting beta2 agonist, blood eosinophil counts and adverse events. RESULTS: At the end of the study, morning and daytime symptom scores were significantly reduced within the groups. Although there was a significant decrease in the frequency of short-acting beta2 agonist use in the BUD + M group, the decrease in the high BUD group was not significant. During the study period, no patient in either group experienced an asthma exacerbation. Blood eosinophil levels significantly declined in both the BUD + M (0.87 +/- 0.31%) and high BUD groups (0.67 +/- 0.29%) as compared with baseline levels (BUD + M = 2.60 +/- 0.65%, high BUD group = 2.60 +/- 0.47%; P < 0.05). CONCLUSION: Our results suggest that the addition of montelukast to low-dose inhaled budesonide is as effective as a double dose of inhaled budesonide in asthma control.     

Effect of long-term treatment with inhaled budesonide or theophylline on lung function,airway reactivity and asthma symptoms

Asthma is characterized by inflammation of the airways and long-term treatment with inhaled glucocorticosteroids improve clinical control in patients previously treated with inhaled rescue beta-2 agonist. We investigated whether the dose of inhaled glucocorticosteroid was related to outcome compared with oral theophylline. Budesonide 800 microg bd, budesonide 200 microg bd, or theophylline (Theo-Dur 300 mg bd was given double-blind, double-dummy and randomized, in a parallel group design for 9 months; when therapy was stopped patients were followed for an additional 3 months. Forced expiratory volume in 1 sec (FEV1), bronchial reactivity and asthma symptom scores were assessed before entering the study and after 1, 2, 3, 5, 7, and 9 months of treatment and monthly after treatment was stopped. Eighty-five patients (38 females and 47 males) were enrolled in the study during 1 1/2 year. Withdrawal from the study due to exacerbations during the treatment period was significantly increased (P <0.01) in the theophylline group. After treatment was stopped more patients withdrew in the budesonide group. In the budesonide 800 microg bd group, FEV1 improved significantly after 1 months treatment (P <0.01) and persisted throughout the study period. In the budesonide 200 microg bd group, FEV1 improved slightly and reached significance (P=0.05) after 5 months of treatment. In the theophylline group, FEV1 was unchanged during the 9 months of treatment. In both budesonide groups, FEV1 deteriorated significantly (P<0.01 and P<0.02, respectively) after termination of study medication and reached pretreatment values during the first month. In the budesonide 800 microg bd group, the concentration of histamine causing a 20% fall in FEV1 (PC20) increased significantly (P<0.01) after 1 months treatment and increased further after 9 months (P<0.0001), equivalent to two doubling dilutions. In the budesonide 200 microg bd, group PC20 histamine significantly increased (P <0.005) after 2 months of treatment and remained constant; theophylline was unchanged. After treatment with budesonide 800 microg bd and 200 microg bd were stopped, PC20 decreased significantly (P<0.002 and P=0.05, respectively) within the first month. PC20 remained unchanged after theophylline was stopped. After budesonide 800 microg bd and 200 microg bd treatment, symptom severity decreased in a dose-related and highly significant manner (P < 0.00001 and P < 0.0001, respectively). With theophylline, asthma symptoms decreased slightly after 1 and 2 months treatment (P < 0.01 and P < 0.02, respectively) and when treatment was stopped no increase in asthma symptoms was evident. Oral theophylline slightly reduced airways symptoms and had no influence on FEV1 and PC20 histamine. Maintenance treatment with inhaled budesonide gave a dose-related reduction in airways obstruction, bronchial reactivity and asthma symptom severity. The efficacy of inhaled corticosteroid was superior to oral theophylline.     

Acute anti-inflammatory effects of inhaled budesonide in asthma: a randomized controlled trial

Corticosteroids can have acute effects on airway function and methacholine airway responsiveness in asthma as early as 6 h after dosing, suggesting there may be an acute anti-inflammatory effect of inhaled corticosteroid in asthma. This study aimed to determine the effects of a single dose of inhaled budesonide on sputum eosinophils and mast cells in adults with asthma, and to examine whether the mechanism of clearance of eosinophils was by apoptosis. A randomized, double-blind, placebo-controlled, crossover study was conducted. At the screening visit, adults with stable asthma (n = 41) ceased inhaled corticosteroid therapy for 4 d and those with significant sputum eosinophilia (> or = 7%) were randomized (n = 26) to a single dose of budesonide 2,400 microg or placebo via Turbuhaler, on two separate study days. Symptoms and lung function were followed for 6 h, then sputum was induced and airway responsiveness to hypertonic saline determined. Sputum eosinophils (mean, SE) were significantly lower 6 h after budesonide (25%, 4.5), compared with placebo (37%, 6.2, p < 0.05). There was a 2.2-fold (95% CI 1.45 to 3.33) improvement in airway responsiveness with budesonide. No significant difference was seen on mast cells, apoptotic eosinophils, symptoms, or lung function. In conclusion, a single dose of inhaled corticosteroids has beneficial effects on airway inflammation and airway hyperresponsiveness as early as 6 h after dosing. This may be clinically useful as therapy during mild exacerbations of asthma.     

Long-term effects of budesonide on airway responsiveness and clinical asthma severity in inhaled steroid-dependent asthmatics

Budesonide 400 micrograms daily, in nonsteroid-dependent asthma, can produce improvements in airway responsiveness and clinical asthma severity, with some patients returning to normal responsiveness and becoming asymptomatic. This study examined whether similar improvements occur when asthmatics, who are dependent upon inhaled steroids, take either a regular maintenance dose of inhaled steroid or twice that amount for a year. Thirty two asthmatics were each stabilized on the minimum amount of inhaled steroid that would keep symptoms non-troublesome. In a double-blind, randomized manner, half were assigned to remain on a maintenance dose (MD) and the rest received twice that dose (MDx2) for one year. Before and monthly throughout the study, airway responsiveness to methacholine was measured and clinical asthma severity assessed by questionnaire, inhaled bronchodilator use and number of asthma exacerbations. There was a significant improvement in airway responsiveness and clinical asthma severity in both treatment groups. Those on MDx2 showed the greatest improvement but the difference between the two groups did not reach significance. This study provides strong evidence that prolonged use of inhaled steroids is associated with improvement in airway responsiveness and clinical asthma severity in inhaled steroid-dependent asthma with a suggestion that the improvements are dose related.     

Greater effect of inhaled budesonide on adenosine 5'-monophosphate-induced than on sodium-metabisulfite-induced bronchoconstriction in asthma.

Inhaled glucocorticosteroids (GCS) decrease airway responsiveness (AR) in asthma by mechanisms that may involve suppressing airway inflammation and a reduction in the number of inflammatory cells in the airways. To investigate the functional response to a reduction in airway inflammatory cells in asthma, we studied the effects of inhaled budesonide on AR to three different bronchial challenges, adenosine 5'-monophosphate (AMP), which primarily activates mast cells; methacholine (MCh), a direct stimulus, and sodium metabisulfite (MBS), a neural stimulus. In a double-blind randomized crossover manner, with a washout period of 28 days, 12 subjects with mild asthma underwent inhalation challenge with doubling increments of MCh, MBS, and AMP before and after 14 days of treatment with budesonide 0.8 mg twice daily from a multidose dry-powder delivery system (Turbohaler) or matched placebo. Treatment with budesonide reduced AR to MCh and MBS to a similar degree, displacing the dose-response curve of each agonist to the right by 1.17 (95% confidence intervals, 0.34 to 2.00) and 1.06 (0.34 to 1.78) doubling dilutions, respectively, when compared with placebo (p less than 0.01). Budesonide caused an additional and significantly greater reduction in AR to AMP, displacing the dose-response curve to the right by 2.92 (2.12 to 3.72) doubling dilutions when compared with placebo (p less than 0.001) and to the other challenges (p less than 0.01). We conclude that budesonide reduces AR to MCh and MBS by an action common to the effects of both direct and neural stimuli on airway smooth muscle contraction. The greater reduction in AR to AMP suggests that budesonide may have an additional action by reducing airway mast cell numbers and/or function.     

Optimal asthma control, starting with high doses of inhaled budesonide.

The aim of this study was to determine whether outcomes in poorly controlled asthma can be further improved with a starting dose of inhaled budesonide higher than that recommended in international guidelines. The study had a parallel-group design and included 61 subjects with poorly controlled asthma, randomized to receive 3,200 microg or 1,600 microg budesonide daily by Turbuhaler for 8 weeks (double-blind), then 1,600 microg x day(-1) for 8 weeks (single-blind), followed by 14 months of open-label budesonide dose down-titration using a novel algorithm, with a written asthma crisis plan based on electronic peak expiratory flow monitoring. The primary outcome variable for weeks 1-16 was change in airway hyperresponsiveness (AHR), and, for the open-label phase, mean daily budesonide dose. By week 16, there were large changes from baseline in all outcomes, with no significant differences between the 3,200- and 1,600-microg x day(-1) starting dose groups (AHR increased by 3.2 versus 3.0 doubling doses, p=0.7; morning peak flow increased by 134 versus 127 L x min(-1), p=0.8). Subjects starting with 3,200 microg x day(-1) were 3.8 times more likely to achieve AHR within the normal range, as defined by a provocative dose of histamine causing a 20% fall in forced expiratory volume in one second (PD20) of > or = 3.92 micromol by week 16 (p=0.03) [corrected]. During dose titration, there was no significant difference in mean budesonide dose (1,327 versus 1,325 microg x day(-1), p>0.3). Optimal asthma control was achieved in the majority of subjects (at completion/withdrawal: median symptoms 0.0 days x week(-1), beta2-agonist use 0.2 occasions x day(-1), and PD20 2.4 micromol). In subjects with poorly controlled asthma, a starting dose of 1,600 microg x day(-1) budesonide was sufficient to lead to optimal control in most subjects. The high degree of control achieved, compared with previous studies, warrants further investigation.