Effect of differing doses of inhaled budesonide on markers of airway inflammation in patients with mild asthma. Systemic activity of inhaled topical steroid in toddlers studied by knemometry. Nebulized budesonide for the treatment of moderate to severe asthma in infants and toddlers. High or standard initial dose of budesonide to control mild-to-moderate asthma? Initial loading (400 micrograms twice daily) versus static (400 micrograms nocte) dose budesonide for asthma management. PLAN Research Group. Dose-responses over time to inhaled fluticasone propionate treatment of exercise- and methacholine-induced bronchoconstriction in children with asthma. Comparison of high and low dose of the inhaled steroid, budesonide, as an initial treatment in newly detected asthma. Budesonide treatment of moderate and severe asthma in children: a dose-response study. Eosinophil and neutrophil activity in asthma in a one-year trial with inhaled budesonide. The impact of smoking. Fluticasone propionate aerosol: efficacy in patients with mild to moderate asthma. Fluticasone Propionate Asthma Study Group. Effectiveness of low doses (50 and 100 microg b.i.d) of beclomethasone dipropionate delivered as a CFC-free extrafine aerosol in adults with mild to moderate asthma. Study Group. Use of inhaled corticosteroids in patients with mild asthma. One-year treatment with different dosing schedules of fluticasone propionate in childhood asthma. Effects on hyperresponsiveness, lung function, and height. The effect of inhaled fluticasone propionate in the treatment of young asthmatic children: a dose comparison study. Clinical efficacy of low-dose inhaled budesonide once or twice daily in children with mild asthma not previously treated with steroids. Efficacy and safety of beclomethasone dipropionate extrafine aerosol in childhood asthma: a 12-week, randomized, double-blind, placebo-controlled study. [Effects of high doses of beclomethasone dipropionate in bronchial asthma]. Low- and high-dose fluticasone propionate in asthma; effects during and after treatment. Rapid induction of clinical response with a short-term high-dose starting schedule of budesonide nebulizing suspension in young children with recurrent wheezing episodes. Starting with a higher dose of inhaled corticosteroids in primary care asthma treatment. Significant variability in response to inhaled corticosteroids for persistent asthma. Dose-related response to inhaled fluticasone propionate in patients with methacholine-induced bronchial hyperresponsiveness: a double-blind, placebo-controlled study. A 12-week dose-ranging study of fluticasone propionate powder in the treatment of asthma.
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.
                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.
                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.
                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. The short-term linear growth rate of the lower leg in toddlers was measured and evaluated in order to study the possible effect of inhaled budesonide on this factor in toddlers with mild recurrent wheezing. The short-term linear growth rate of the lower leg was measured weekly using a hand-held knemometer. Eighteen toddlers aged 13-36 months (mean 27 months) with a history of recurrent wheezing requiring inhaled topical steroids, but without need of regular medication during the months prior to the study, were studied. The children were randomized blindly through three consecutive treatment periods of four weeks with placebo or budesonide in daily doses of 200 micrograms and 800 micrograms administered as a pressurized aerosol inhaled via a spacer with a face mask. Twenty-nine percent (median) of the nominal dose was delivered at the mouth of the children. Three children were withdrawn because of exacerbations and one because of non-compliance. The precision of the measurement procedure was 51 microns/day. The mean growth rate during placebo, low-dose and high-dose steroid treatment was 92 microns/day, 114 microns/day and 46 microns/day respectively. The growth rate during the high-dose treatment was suppressed significantly compared to placebo treatment (95% CI -76 microns/day to -17 microns/day), whereas the growth rate during low-dose steroid treatment was indistinguishable from placebo treatment (95% CI -7 to +52 microns/day). In conclusion, measurement of short-term linear growth rate by knemometry in toddlers is a fast and gentle method with a high level of precision.(ABSTRACT TRUNCATED AT 250 WORDS) Maintenance treatment with nebulized budesonide was studied in young children with asthma not controlled without steroids. In a blind parallel-group study for 18 weeks, 102 children, mean age 22 (5- 47) months, were randomized for treatment starting with 0.25 or 1 mg b.i.d. The patients were reviewed every 3 weeks, and if symptom control had been achieved the dose was reduced, otherwise it was kept. The clinical effect was very good with both dose regimens. The median time to 7 consecutive days without any asthma symptoms was about 1 month with both, highlighting the importance of the duration of therapy rather than the benefits of a high starting dose. In 18 of 24 children who attained the placebo stage, symptoms had reappeared at the last visit. Although an overall minimal effective maintenance dose could not be demonstrated, 47% achieved symptom control on 0.25 mg b.i.d., i.e. fulfilled criteria for further dose reduction. No significant side effects were seen. On average, 25% of the nominal dose reached the patients. Guidelines on the use of inhaled steroids in asthma advocate that the daily dose should be chosen according to the severity of the disease. However, the question of the optimal starting dose remains to be properly addressed, as does the issue of the adjustment in dose required for a given patient. Whether a high initial dose of budesonide (800 microg b.i.d) was more efficacious than a standard dose (200 microg b.i.d) in controlling mild-to-moderate asthma was investigated, and whether the dose could be decreased, based on peak expiratory flow (PEF), symptom-score, beta2-agonist use in a double-blind, randomized, parallel-group 18-week study. One-hundred and sixty-nine patients (mean age 38 yrs, mean forced expiratory volume in one second 74% predicted) were enrolled. No difference was detected between the two groups in improvement in morning PEF (+61 L x min(-1) in the high-dose group, +60 L x min(-1) in the standard-dose group by 16 weeks). Morning and evening PEF values stabilized before the end of the first 4 weeks. No difference between groups was observed in symptom score, beta2-agonist use, number of exacerbation per interval and the best forced expiratory volume in one second achieved. The proportion of subjects being able to decrease the doses of budesonide was similar in both treatment strategies. It is concluded that both high and standard initial doses are equally effective in controlling symptoms and improving lung function in mild-to-moderate asthma. This double-blind study aimed to determine whether superior asthma control is achieved with budesonide (Pulmicort Turbohaler) at a loading dose (LD) (400 micrograms b.d.) for 6 weeks, followed by step down to 400 micrograms nocte for 12 weeks, compared with a static dose (SD) (400 micrograms nocte) for 18 weeks. A total of 682 patients (mean peak expiratory flow rate (PEFR) 413 l/min), who demonstrated > or = 15% reversibility in PEFR, were randomised into the study. After 18 weeks, patients experienced improvements in morning PEFR (+45 l/min, both groups), symptom score (LD -0.57, SD -0.49, on a scale of 0-3), sleep disturbance (LD -1.21 nights/week, SD -1.06 nights/week) and beta 2-agonist use (LD -1.36 puffs/day, SD -1.06 puffs/day), within both groups (each p = 0.0001). At 18 weeks, 82% (LD) and 84% (SD) of patients benefited from no nocturnal wakening in the previous 7 days. Overall, at 18 weeks, asthma control was not significantly different between the groups. After 6 weeks, improvements in morning PEFR (LD +36 l/min, SD +26 l/min) and beta 2-agonist use (LD -1.10 puffs/day, SD -0.94 puffs/day) were greater in the loading dose than in the static dose group (each p < 0.05). The greater improvement in morning PEFR in the loading dose group was significant by day 7 (p < 0.05). While both regimens are equally effective in achieving asthma control at 18 weeks, early clinical advantage is gained with initial loading dose budesonide (400 micrograms b.d.). When treating bronchial hyperresponsiveness to so-called direct and indirect stimuli, distinct pathophysiological mechanisms might require differences in dose and duration of inhaled corticosteroid therapy. To test this hypothesis in children with asthma, we investigated the time- and dose-dependent effects of 2 doses of fluticasone propionate (FP, 100 or 250 microg bid.) in improving exercise- (EIB) and methacholine-induced bronchoconstriction during 6 months of treatment, using a placebo-controlled parallel group study design. Thirty-seven children with asthma (aged 6 to 14 years; forced expired volume in 1 sec (FEV(1)) >/=70% predicted; EIB >/=20% fall in FEV(1) from baseline; no inhaled steroids during the past 4 months) participated in a double-blind, placebo-controlled, 3-arm parallel study. Children receiving placebo were re-randomized to active treatment after 6 weeks. Standardized dry air treadmill exercise testing (EIB expressed as %fall in FEV(1) from baseline) and methacholine challenge using a dosimetric technique (expressed as PD(20)) were performed repeatedly during the study. During FP-treatment, the severity of EIB decreased significantly as compared to placebo within 3 weeks, the geometric mean % fall in FEV(1) being reduced from 34.1% to 9.9% for 100 microg FP bid, and from 35.9% to 7.6% for 250 microg FP bid (P < 0.05). These reductions in EIB did not differ between the 2 doses and were sustained throughout the treatment period. PD(20) methacholine improved significantly during the first 6 weeks as compared to placebo (P < 0.04) and steadily increased with time in both treatment limbs (P = 0.04), the difference in improvement between doses (100 microg FP bid, 1.6 dose steps; 250 microg FP bid, 3.3 dose steps) approaching significance after 24 weeks (P = 0.06). We conclude that in childhood asthma, the protection afforded by inhaled fluticasone propionate against methacholine-induced bronchoconstriction is time- and dose-dependent, whereas protection against EIB is not. This suggests different modes of action of inhaled steroids in protecting against these pharmacological and physiological stimuli. This has to be taken into account when monitoring asthma treatment.
                Copyright 2000 Wiley-Liss, Inc. The importance of early initiation of inhaled steroids even in mild asthma has been documented in several studies. It is not, however, clear whether the treatment should be started with a high or a low dose of the inhaled steroid. We have compared the effects of high and low dose inhaled steroid, budesonide, in patients with newly detected asthma. We studied 101 adult patients with newly detected bronchial asthma who were without inhaled steroid or any regular pharmacological treatment for their asthma. The patients were randomly allocated to two treatment groups: one to receive 800 microg inhaled budesonide per day and the other to receive 200 microg inhaled budesonide per day. The drugs were given with a Turbuhaler dry powder inhaler. During the 3-month treatment period, no significant differences between the treatment groups were noted in morning or evening PEF values, in spirometric parameters, in asthmatic symptoms or in the use of rescue beta2-agonists. The decrease in bronchial hyperresponsiveness was, however, more marked in the high dose budesonide group, reaching a borderline significance (P=0.10 high vs. low dose budesonide). In addition, in serum markers of asthmatic inflammation significant differences were shown between the treatment groups. The decrease in the number of blood eosinophils during the treatment was more marked in the high dose budesonide group (P=0.02; high vs. low dose budesonide). In serum ECP no change was observed in the low dose budesonide group, but a marked decrease in the high-dose budesonide group (P=0.008; high vs. low dose budesonide). The change was even more marked with regard to serum EPX (P=0.005; high vs. low dose budesonide). Our results support the view that the treatment of newly detected asthma should be started with a high dose of inhaled steroid. The low dose may not be enough to suppress asthmatic inflammation despite good clinical primary response. The purpose of the study was to evaluate the dose-response relationships of the inhaled corticosteroid budesonide in a double blind crossover study in 19 children with moderate and severe asthma.
                A 2-week placebo treatment period (run-in) was followed by three 4-week treatment periods during which 100, 200, and 400 micrograms of budesonide were given per day in randomized order. Urinary cortisol excretion, lung functions, and protection against exercise-induced asthma were assessed at the end of run-in and each treatment period. Furthermore, morning and evening peak expiratory flow rates, day and night symptoms, and use of rescue beta 2-agonists were recorded throughout the study.
                One hundred micrograms of budesonide per day markedly improved symptoms, morning and evening peak expiratory flow rates, and use of rescue beta 2-agonists (p < 0.01). No further improvement was seen in these parameters with increasing doses of budesonide. In contrast, a significant dose-response effect was found on lung functions measured at the hospital and fall in lung functions after exercise (p < 0.001); 200 micrograms was significantly better than 100 micrograms, and 400 micrograms was significantly better than 200 micrograms. About 53% of the maximum effect against exercise-induced asthma was achieved by the lowest budesonide dose (p < 0.001), and about 83% by the highest dose. No significant differences were seen in urinary cortisol excretion between run-in and the various budesonide doses.
                Low doses of budesonide, which are not associated with any systemic side effects, have a marked antiasthma effect in children. Protection against exercise-induced asthma requires higher doses than achievement of symptom control. The object of this investigation was to study the long-term effects of antiasthma treatment on blood markers of inflammation and lung function in adult asthmatic subjects. For this purpose 85 allergic and nonallergic asthmatic subjects were randomized into three groups, which were given high-dose (1,600 micrograms/d) inhaled budesonide, low-dose (400 micrograms/d) inhaled budesonide, and oral theophylline (600 mg/d), respectively, and were followed for 11 mo with testing of lung function and blood sampling for the assay in serum of eosinophil cationic protein (ECP), eosinophil protein x/eosinophil derived neurotoxin (EPX/EDN) as eosinophil markers, and myeloperoxidase (MPO) and lactoferrin (LF) as neutrophil markers. Lung functions (FEV1% predicted, and histamine PC20) and the eosinophil markers ECP and EPX/EDN were improved and reduced, respectively, by budesonide in a dose-dependent and temporally parallel fashion. Theophylline did not alter lung functions but reduced ECP and EPX/EDN after prolonged treatment. The treatment efficacy of budesonide was attributed solely to an effect on nonsmoking asthmatic subjects, since neither lung functions nor eosinophil markers changed in smokers even with high-dose budesonide. MPO but not LF was reduced after several months of treatment in all three groups, but only in nonsmokers. We conclude that ECP and EPX/EDN may be used to monitor antiinflammatory treatment in asthmatic patients, and that smoking asthmatic subjects are resistant to inhaled corticosteroids. This double-blind, randomized, parallel-group, placebo-controlled study investigated the efficacy and tolerability of fluticasone propionate aerosol (25, 50, or 100 mg bid for 12 weeks) administered as primary maintenance therapy to patients whose mild to moderate asthma was inadequately controlled by as-needed use of an inhaled beta-agonist.
                At all clinic visits, fluticasone propionate compared with placebo was associated with significant (P<.05) improvement in pulmonary function indexed by forced expiratory volume in 1 second (FEV1) as well as fewer night awakenings and less use of rescue albuterol. Values for patient-measured morning peak expiratory flow rates (PEFR) were significantly (P<.05) higher and the use of rescue albuterol was significantly (P<.05) lower beginning 3 to 5 days after initiation of therapy in the groups treated with fluticasone propionate, compared with the placebo group. Maximal improvement in FEV1 was achieved during the second week of treatment and maintained throughout the course of therapy. Differences among the three fluticasone propionate dosing groups for these efficacy measures were not statistically significant. The incidence of adverse events was similar across groups.
                These data indicate that fluticasone propionate aerosol is an effective and well-tolerated treatment for asthma and significantly improves pulmonary function within days of initiation of treatment in patients whose asthma is inadequately controlled with as-needed beta-agonists. The objective of this study was to evaluate the efficacy and safety of low doses (50 and 100 microg b.i.d.) of hydrofluoroalkane-134a (HFA) beclomethasone dipropionate (BDP) extrafine aerosol in improving asthma control. Reformulation of BDP in a new chlorofluorocarbon (CFC)-free propellant (HFA) has produced an extrafine aerosol with increased delivery of the drug to the airways of the lung. The study population comprised 270 steroid-naive patients with mild to moderate asthma (mean baseline forced expiratory volume in 1 sec [FEV1] as a percentage of predicted normal of 65%-85%). This was a 6-week, blinded, placebo-controlled, multicenter study. Patients were randomized to receive 50 or 100 microg b.i.d. HFA-BDP or HFA-placebo. Treatment with either 50 or 100 microg b.i.d. HFA-BDP resulted in a significantly greater improvement compared with placebo in FEV1 (mean change from baseline as percentage of predicted normal of 6.7%, 8.6%, and 0.4%, respectively; p < or = 0.01 active treatment groups vs. placebo), with a significant trend toward increasing improvement with increasing doses (p < or = 0.0001). Treatment also resulted in significantly greater mean changes from baseline in morning peak expiratory flow compared with placebo (29.5, 33.8, and 5.0 L/min, respectively; p < or = 0.01 active treatment groups vs. placebo). All other pulmonary function and asthma symptom measures supported these data. The study treatments were well tolerated. These results show that low doses of HFA-BDP extrafine aerosol effectively improve asthma control in adult patients with mild to moderate asthma. However, it is important that inhaled corticosteroid therapy is still given at a dose high enough to control airway inflammation as well as asthma symptoms. A double blind, parallel group study was carried out to investigate the effect of inhaled budesonide in a moderate (200 micrograms) and a low (100 micrograms) twice daily dosage compared with the effect of placebo in 103 adults with mild symptomatic asthma. Subjects recorded peak expiratory flow (PEF), asthma symptoms, and beta 2 agonist consumption at home for a period of seven weeks (a one week run in and six weeks' treatment). Morning baseline PEF (around 80% of predicted normal) increased non-significantly to 88% with 200 micrograms budesonide daily and to 90% (p less than 0.05) with 400 micrograms, compared with 81% with placebo. Evening PEF (around 94% of predicted normal) did not change significantly with active or placebo treatment. By comparison with placebo, there was a significant decrease in nocturnal asthma symptoms and beta 2 agonist consumption. The changes during the day were less pronounced and significant only for 400 micrograms budesonide daily. No significant differences between the two active treatments were detected. It is concluded that low doses of inhaled budesonide are effective in patients with mild symptomatic asthma, particularly for night time symptoms and early morning lung function. The early introduction of inhaled corticosteroids for patients with mild asthma and night time symptoms may improve their quality of life during the night and early morning. Dose-dependent effects of inhaled corticosteroids have been described. Although it has been advised to start treatment with inhaled corticosteroids with a high dose tapering off subsequently (stepdown approach), no clinical studies have assessed this strategy. We compared two different dosage schedules of inhaled fluticasone propionate (FP) in chronic persistent childhood asthma with respect to efficacy (airways hyperresponsiveness [PD(20)], lung function, exhaled nitric oxide [eNO]) and safety (height). During this double-blind study, children with asthma (aged 6-10 yr) were randomized to receive either FP 200 microg/d (constant dose approach) or to start with 1000 microg/d with two monthly reductions to 500, 200, and 100 microg/d (stepdown approach). PD(20) improved in both approaches during treatment with FP, with a significantly better PD(20) after 2 mo of 1000 microg/d followed by 500 microg/d in the stepdown approach versus 200 microg/d in the constant dose approach. No significant differences in PD(20) or other efficacy parameters were found after 1 yr. Changes in standing height were similar in both treatment approaches. This study showed no superior clinical effect of a stepdown approach compared with a constant dose strategy of FP for 1 yr in children with chronic persistent asthma. The response in asthmatic young children to inhaled steroids within the usual pediatric dose range is unknown. We therefore evaluated the dose-related response in young children with moderate asthma to inhaled fluticasone propionate (FP) (delivered via the Babyhaler spacer device) within the pediatric dose range. A total of 237 children (mean age 28 mo, range 12 to 47) with moderate asthmatic symptoms were studied in this multicenter, randomized, double-blind, parallel group, placebo-controlled study of 12 wk treatment following a 4-wk run-in period. The median use of rescue medication was 1 dose in 2 d during the run-in period. FP 50 micrograms twice daily (FP100) and 100 micrograms twice daily (FP200) was compared with placebo inhaled from a pressurized metered-dose inhaler (pMDI) and the Babyhaler spacer device. With FP200 there was a statistically significant improvement from baseline, as compared with the placebo group, in 8 of 10 diary card parameters, including the three symptom domains of wheeze, cough, and breathlessness, and use of rescue medication. FP100 produced a significant reduction in 5 of these 10 parameters, whereas no significant differences were found between the FP200 and FP100. The numbers of patients with at least one exacerbation during treatment with placebo, FP100, and FP200 were 37%, 26%, and 20%, respectively. This difference between placebo and FP200, as well as the dose-related order was significant (p < 0.05). Both FP doses were as well tolerated as placebo over the 12 wk treatment with a similar incidence of adverse effects. Asthmatic symptoms in 1- to 3-yr-old children responded in a significant and dose-related manner to treatment with FP within a pediatric dose range. The aim of the present study was to examine the efficacy of low-dose inhaled budesonide (BUD) administered via Turbuhaler once or twice daily on symptoms, lung function and bronchial hyperreactivity in children with mild asthma. One hundred and sixty-three children (mean age 9.9 yrs, 56 females/107 males) with mild asthma (forced expiratory volume in one second (FEV1) 103% of predicted, morning peak expiratory flow (PEF) 87% pred, reversibility in FEV1 3%, fall in FEV1 after exercise 10.4% from pre-exercise value) and not previously treated with inhaled steroids, were included in a double-blind, randomized, parallel-group study. After a two-week run-in period, the children received inhaled BUD 100 microg or 200 microg once daily in the morning, 100 microg twice daily or placebo for 12 weeks. Exercise and methacholine challenges were performed before and at the end of treatment. After 12 weeks of therapy, the fall in FEV1 after an exercise test was significantly less in all three BUD groups (43-5.1%) than in the placebo group (8.6%). Bronchial hyperreactivity to methacholine with the provocative dose causing a 20% fall in FEV1 decreased significantly in the BUD 100 microg twice-daily group compared with placebo (ratio at the end of treatment 156%). Changes in baseline lung function (FEV1 and PEF) were less marked than changes in bronchial responsiveness. In conclusion, low doses of inhaled budesonide, given once or twice daily, provided protection against exercise-induced bronchoconstriction in children with mild asthma and near normal lung function. Beclomethasone dipropionate (BDP) has been formulated as an extrafine aerosol (hydrofluoroalkane-134a [HFA]-BDP) [QVAR; 3M Pharmaceuticals; St Paul, MN], which gives improved lung deposition compared with chlorofluorocarbon (CFC)-BDP. The clinical efficacy of HFA-BDP has been established in adult asthma at a required dose below that of CFC-BDP, but has not been evaluated in children.
                To examine the efficacy and safety of HFA-BDP in childhood asthma.
                A 12-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study involving 353 children aged 5 to 12 years with moderate, symptomatic asthma. After a 2-week run-in period, patients were randomized to HFA-BDP, 80 micro g/d (n = 120); HFA-BDP, 160 micro g/d (n = 117); or HFA-placebo (n = 116) administered twice daily.
                Hospital outpatient.
                HFA-BDP, 80 micro g/d and 160 micro g/d, produced a significant, dose-related increase from baseline in FEV(1) percent predicted compared with placebo. At week 12, mean changes from baseline in FEV(1) percent predicted were 9.2% (p < or = 0.01 vs placebo), 10% (p < or = 0.01 vs placebo), and 3.9% for the HFA-BDP 80 micro g/d, HFA-BDP 160 micro g/d, and placebo groups, respectively. There was also a significant decrease in daily beta-agonist use, improvement in peak expiratory flow, and increase [correction] in the percentage of days free from asthma symptoms (p < or = 0.05 for HFA-BDP, 160 micro g/d, vs placebo at weeks 11 to 12). HFA-BDP was well tolerated, with no significant differences in the incidence or nature of adverse events between HFA-BDP and placebo groups. Neither were there significant differences between groups in mean percentage change from baseline in the morning plasma cortisol level at week 12 or in the percentage of patients with morning plasma cortisol levels below the reference range at baseline and week 12. In a subgroup tested, the percentage of patients with an abnormal response to low-dose adrenocorticotropic hormone stimulation at week 12 was low and similar among all groups.
                HFA-BDP, 80 to 160 micro g/d, is effective and safe in childhood asthma. To evaluate the clinical efficacy of high dose inhaled steroids, we examined the effects of standard doses (400 micrograms/day) and high doses (800 micrograms/day) of inhaled beclomethasone dipropionate (BDP, Becotide Inhaler), and the dose for regular use (800 micrograms/day) of salbutamol (Salb. Asmidon Air) on pulmonary function, bronchial hyperresponsiveness and asthma attack score. The subjects were 17 out-patients with mild or moderate bronchial asthma who were not receiving any anti-allergics or steroids. The patients were randomly allocated into three groups i.e., Group I: BDP 400 micrograms/day, Group II: BDP 800 micrograms/day and Group III: Salb. 800 micrograms/day. The administration period was 8 weeks. Pulmonary function test were performed and bronchial hyperresponsiveness was examined before and after the 8 weeks of treatment and attack scores were recorded during this period. It was found that inhalations of 400 micrograms/day and 800 micrograms/day BDP improved FEV1.0% value, peak flow, F-V curve, Dmin. and SGrs/Grs cont. Particularly, inhalation of 800 micrograms/day of BDP significantly improved these values and reduced attack scores in the early stages of the 8 week treatment. In contrast, there was a trend for inhalation of Salbutamol to enhance bronchial hyperresponsiveness and not to improve pulmonary function and asthma attack score. In conclusion, 800 micrograms/day of inhaled BDP is considered to be useful in the treatment of mild or moderate bronchial asthma. The dose dependency of the effects of inhaled corticosteroids on markers of asthmatic airway inflammation have not been well studied. There is a need to study the dose/response effects on this inflammation. In order to determine the dose/response effects of fluticasone propionate (FP), 24 asthmatic subjects were randomized to low- (100 microg x day(-1)) or high-dose (1,000 microg x day(-1)) FP for six weeks followed by placebo for 3 weeks. During treatment, the median increase in forced expiratory volume in one second (FEV1)was 12% in the high-dose group (p<0.05) and 10% in the low-dose group (p<0.05) (p>0.05 between groups); the median decrease in the percentage of sputum eosinophils was 93% in the high-dose group (p<0.05) and 46% in the low-dose group (p<0.05) (p>0.05 between groups). Symptoms, salbutamol use, morning peak flow, provocative concentration of methacholine causing a 20% fall in FEV1 (PC20), sputum eosinophil cationic protein concentration and tryptase activity improved significantly in both groups (p<0.05), but only the improvement in salbutamol use was greater in the high-dose group (p<0.05). During the run-out, the improvements in FEV1 and PC20 were rapidly reversed in both groups, but the improvements in peak flow and tryptase activity persisted; the improvement in sputum eosinophil concentration persisted only in the high-dose group (p<0.05). It was concluded that dose/response effects for FP are not easily demonstrable because low-dose FP is quite effective. For most outcomes, the effects of high- and low-dose FP are relatively short-lived after treatment is stopped. This finding raises questions about the extent to which inhaled corticosteroids are disease-modifying in asthma. There are no data currently available on the correct schedule for the initiation of treatment with nebulized suspension of budesonide in children with recurrent wheezing episodes. We compared the efficacy and safety of starting with a high dose followed by a stepwise decrease to a continuous low dose.
                In a double-blind design, 42 children aged 6 months to 3 years were randomly allocated to receive either a high starting dose of 1 mg budesonide twice daily followed by a stepwise decrease of 25% every second day for 1 week (group A) or a low dose of 0.25 mg twice daily for 1 week (group B). Efficacy was assessed with daily symptom scores and the systemic effect of the corticosteroids with the adrenocorticotropic hormone test.
                The two groups were comparable for all parameters evaluated. During the first week of treatment, there was a significant decrease in asthmatic symptomatology only in group A: a 59% decrease for wheezing (p = 0.0001), 39% for diurnal cough (p = 0.036), and 39% for nocturnal cough (p = 0.04). Mean time to clinical response was 3.0 days in group A and 5.7 days in group B (p = 0.02). This early improvement was sustained for the rest of the follow-up period. The high dose starting schedule was not associated with any change in serum cortisol level.
                The administration of nebulized suspension of budesonide at a high starting dose schedule followed by a rapid (1 week) stepwise decrease yields a significant early improvement in asthma symptoms and causes no change in serum cortisol levels. New British guidelines on the treatment of asthma (9) advocate starting with a higher dose of inhaled corticosteroids in newly detected asthma patients. We investigated whether initiating inhaled steroid treatment with a higher dose is clinically more effective than a lower dose in steroid naive patients with asthma. The study had a 13-wk randomized, double-blind, parallel design: 1-mo treatment with 400 microg budesonide twice a day, or 100 microg budesonide twice a day by dry powder inhaler, and follow-up treatment period of 2 mo with 200 microg budesonide once daily for all patients. Forty patients started with 400 microg budesonide twice daily, 44 with 100 microg budesonide twice daily. Mean age was 32 yr, baseline FEV1 value 84% predicted, reversibility 9% from baseline, and mean bronchodilator use 1.6 inhalations/d in the run-in period. After 4 wk of treatment with 400 microg and 100 microg budesonide twice daily mean morning peak expiratory flow (PEF) increased 27 L/min (SD 50), and 38 L/ min (SD 53), respectively (p = 0.30); mean symptom score improved from 1.1 to 0.6 and from 1.1 to 0.5. These effects were maintained in the 2 mo follow-up. This study suggests that starting inhaled corticosteroids at a higher dose is not superior to a lower dose in the treatment of newly detected asthma. A clinical model is needed to compare inhaled corticosteroids (ICSs) with respect to efficacy.
                The purpose of this investigation was to compare the relative beneficial and systemic effects in a dose-response relationship for 2 ICSs.
                A 24-week, parallel, open-label, multicenter trial examined the benefit-risk ratio of 2 ICSs in persistent asthma. Benefit was assessed by improvements in FEV(1) and PC(20); risk was assessed by overnight plasma cortisol suppression. Thirty subjects were randomized to either beclomethasone dipropionate (BDP) 168, 672, and 1344 microg/day (n = 15) or fluticasone propionate (FP) 88, 352, and 704 microg/day (n = 15), both administered by means of a metered dose inhaler (MDI) with chlorofluorocarbon propellant via a spacer, in 3 consecutive 6-week intervals; this was followed by 3 weeks of FP dry powder inhaler (DPI) 2000 microg/day.
                Maximum FEV(1) response occurred with the low dose for FP-MDI and the medium dose for BDP-MDI and was not further increased by treatment with FP-DPI. Near-maximum methacholine PC(20) improvement occurred with the low dose for FP-MDI and the medium dose for BDP-MDI. Both BDP-MDI and FP-MDI caused dose-dependent cortisol suppression. Responsiveness to ICS treatment was found to vary markedly among subjects. Good (>15%) FEV(1) response, in contrast to poor (<5%) response, was found to be associated with high exhaled nitric oxide (median, 17.6 vs 11.1 ppb), high bronchodilator reversibility (25.2% vs 8.8%), and a low FEV(1)/forced vital capacity ratio (0.63 vs 0.73) before treatment. Excellent (>3 doubling dilutions) improvement in PC(20), in contrast to poor (<1 doubling dilution) improvement, was found to be associated with high sputum eosinophil levels (3.4% vs 0.1%) and older age at onset of asthma (age, 20-29 years vs <10 years).
                Near-maximal FEV(1) and PC(20) effects occurred with low-medium dose for both ICSs in the subjects studied. High-dose ICS therapy did not significantly increase the efficacy measures that were evaluated, but it did increase the systemic effect measure, overnight cortisol secretion. Significant intersubject variability in response occurred with both ICSs. It is possible that higher doses of ICSs are necessary to manage more severe patients or to achieve goals of therapy not evaluated in this study, such as prevention of asthma exacerbations. Dose-response relationships with inhaled corticosteroids in the treatment of asthma have been difficult to establish. A multicenter, double-blind, parallel-group study was conducted to evaluate the clinical efficacy and safety of low doses of inhaled fluticasone propionate (FP) in patients with mild to moderate asthma. Methacholine challenge testing was conducted in addition to measurement of traditional efficacy variables. After a single-blind screening period, 138 patients > or = 12 years of age were randomly assigned to receive placebo, FP 50 microg, or FP 100 microg, twice daily for 8 weeks. The results of methacholine challenge testing averaged over all visits favored FP 200 microg/day over placebo and FP 100 microg/day (p < 0.05); there were no significant differences between placebo and FP 100 microg/day. Mean changes from baseline to endpoint favored each dose of FP over placebo based on forced expiratory volume in 1 sec (FEV1), patient-measured peak expiratory flow (PEF), total symptom scores, and rescue bronchodilator use (p < 0.05); there were no differences in these parameters between the two doses of FP. The addition of methacholine challenge testing allowed definition of a dose-response relationship that was not apparent with traditional efficacy variables. Fluticasone propionate (FP) administered via metered-dose inhaler is a potent corticosteroid effective in the treatment of asthma. To evaluate the efficacy and safety of FP powder administered via a breath-activated inhaler (Diskhaler), a multicenter, double-blind, randomized, placebo-controlled, parallel-group study was conducted in adolescent and adult patients (n = 331) with mild-to-moderate asthma previously treated with beta 2-agonist therapy alone. Patients received FP powder 50, 100, or 250 micrograms or placebo twice daily for 12 weeks. FP-treated patients compared with placebo-treated patients had significantly (p < 0.001) greater improvements in morning predose forced expiratory volume in 1 sec (21-22% increase vs. 9%). Improvement in morning peak flow rate were also significantly (p < 0.001) greater with FP than with placebo (8-10% increase vs. 2% increase). There was also a significant overall treatment difference in the frequency of inhaled albuterol use (p < 0.001) and number of nighttime awakenings due to asthma (p = 0.005). There were no statistically significant difference among the FP treatment groups in any outcome measure. Physicians' global assessments also indicated significant (p < 0.001) differences in efficacy, with 67-74% of FP-treated patients rated as having "effective" or "very effective" treatment compared with 41% of placebo-treated patients. Significant beneficial effects of FP were observed in lung function and diary card parameters after just 1 week of treatment. Adverse events were similar across treatment groups and primarily related to local irritation. Effect on hypothalamic-pituitary-adrenal axis function was minimal. In summary, all three dosages of inhaled FP powder were well tolerated and improved various asthma-related variables. Improvements in pulmonary function, beyond those achieved with beta 2-agonist therapy alone, were maintained for the duration of the 12-week study.
For patients with asthma who require ICS, commencing with a moderate dose ICS is equivalent to commencing with a high dose ICS and down-titrating. The small significant benefits of commencing with a high ICS dose are not of sufficient clinical benefit to warrant its use when compared to moderate or low dose ICS. Initial moderate ICS dose appears to be more effective than initial low ICS dose. High dose ICS may be more effective than moderate or low dose ICS for airway hyperresponsiveness. There is no benefit in doubling or quadrupling ICS in subjects with stable asthma.